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1. Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture

Author: Jennifer R. S. Meadows, Jeffrey M. Kidd, Guo-Dong Wang, Heidi G. Parker, Peter Z. Schall, Matteo Bianchi, Matthew J. Christmas, Katia Bougiouri, Reuben M. Buckley, Christophe Hitte, Anthony K. Nguyen, Chao Wang, Vidhya Jagannathan, Julia E. Niskanen, Laurent A. F. Frantz, Meharji Arumilli, Sruthi Hundi, Kerstin Lindblad-Toh, Catarina Ginja, Kadek Karang Agustina, Catherine André, Adam R. Boyko, Brian W. Davis, Michaela Drögemüller, Xin-Yao Feng, Konstantinos Gkagkavouzis, Giorgos Iliopoulos, Alexander C. Harris, Marjo K. Hytönen, Daniela C. Kalthoff, Yan-Hu Liu, Petros Lymberakis, Nikolaos Poulakakis, Ana Elisabete Pires, Fernando Racimo, Fabian Ramos-Almodovar, Peter Savolainen, Semina Venetsani, Imke Tammen, Alexandros Triantafyllidis, Bridgett vonHoldt, Robert K. Wayne, Greger Larson, Frank W. Nicholas, Hannes Lohi, Tosso Leeb, Ya-Ping Zhang, and Elaine A. Ostrander
Subjects: Canine, Dog, Genomics, Variation, Demographic history, Mitochondrial DNA, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract: Abstract Background The international Dog10K project aims to sequence and analyze several thousand canine genomes. Incorporating 20 × data from 1987 individuals, including 1611 dogs (321 breeds), 309 village dogs, 63 wolves, and four coyotes, we identify genomic variation across the canid family, setting the stage for detailed studies of domestication, behavior, morphology, disease susceptibility, and genome architecture and function. Results We report the analysis of > 48 M single-nucleotide, indel, and structural variants spanning the autosomes, X chromosome, and mitochondria. We discover more than 75% of variation for 239 sampled breeds. Allele sharing analysis indicates that 94.9% of breeds form monophyletic clusters and 25 major clades. German Shepherd Dogs and related breeds show the highest allele sharing with independent breeds from multiple clades. On average, each breed dog differs from the UU_Cfam_GSD_1.0 reference at 26,960 deletions and 14,034 insertions greater than 50 bp, with wolves having 14% more variants. Discovered variants include retrogene insertions from 926 parent genes. To aid functional prioritization, single-nucleotide variants were annotated with SnpEff and Zoonomia phyloP constraint scores. Constrained positions were negatively correlated with allele frequency. Finally, the utility of the Dog10K data as an imputation reference panel is assessed, generating high-confidence calls across varied genotyping platform densities including for breeds not included in the Dog10K collection. Conclusions We have developed a dense dataset of 1987 sequenced canids that reveals patterns of allele sharing, identifies likely functional variants, informs breed structure, and enables accurate imputation. Dog10K data are publicly available.
Published: 2023
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2. Author Correction: Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture

Author: Jennifer R. S. Meadows, Jefrey M. Kidd, Guo-Dong Wang, Heidi G. Parker, Peter Z. Schall, Matteo Bianchi, Matthew J. Christmas, Katia Bougiouri, Reuben M. Buckley, Christophe Hitte, Anthony K. Nguyen, Chao Wang, Vidhya Jagannathan, Julia E. Niskanen, Laurent A. F. Frantz, Meharji Arumilli, Sruthi Hundi, Kerstin Lindblad-Toh, Catarina Ginja, Kadek Karang Agustina, Catherine André, Adam R. Boyko, Brian W. Davis, Michaela Drögemüller, Xin-Yao Feng, Konstantinos Gkagkavouzis, Giorgos Iliopoulos, Alexander C. Harris, Marjo K. Hytönen, Daniela C. Kalthof, Yan-Hu Liu, Petros Lymberakis, Nikolaos Poulakakis, Ana Elisabete Pires, Fernando Racimo, Fabian Ramos-Almodovar, Peter Savolainen, Semina Venetsani, Imke Tammen, Alexandros Triantafyllidis, Bridgett vonHoldt, Robert K. Wayne, Greger Larson, Frank W. Nicholas, Hannes Lohi, Tosso Leeb, Ya-Ping Zhang, and Elaine A. Ostrander
Subjects: Biology (General), QH301-705.5, Genetics, QH426-470
Published: 2023
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3. The genome and diet of a 35,000‐year‐old Canis lupus specimen from the Paleolithic painted cave, Chauvet‐Pont d'Arc, France

Author: Jean‐Marc Elalouf, Pauline Palacio, Céline Bon, Véronique Berthonaud, Frédéric Maksud, Thomas W. Stafford Jr, and Christophe Hitte
Subjects: ancient DNA, canid, cave bear, Paleogenomics, Ecology, QH540-549.5
Abstract: Abstract The Chauvet‐Pont‐d'Arc Cave (Ardèche, France) contains some of the oldest Paleolithic paintings recorded to date, as well as thousands of bones of the extinct cave bear, and some remains and footprints of other animals. As part of the interdisciplinary research project devoted to this reference cave site, we analyzed a coprolite collected within the deep cave. AMS radiocarbon dating of bone fragments from the coprolite yielded an age of 30,450 ± 550 RC yr. BP (AAR‐19656; 36,150–34,000 cal BP), similar to ages assigned to Paleolithic artwork and cave bear remains from the same cave sector. Using high‐throughput shotgun DNA sequencing, we demonstrated a high abundance of canid DNA and lesser amounts of DNA from the extinct cave bear. We interpret the sample as feces from a canid that had consumed cave bear tissue. The high amount of canid DNA allowed us to reconstruct a complete canid mitochondrial genome sequence (average coverage: 83×) belonging to a deeply divergent clade of extinct mitochondrial wolf lineages that are most closely related to coeval (~35 ka) Belgian wolves. Analysis of the nuclear genome yielded a similar coverage for the X chromosome (2.4×) and the autosomes (range: 2.3–3.2×), indicating that the Chauvet canid was a female. Comparing the relationship of the nuclear genome of this specimen with that of a variety of canids, we found it more closely related to gray wolves' genomes than to other wild canid or dog genomes, especially wolf genomes from Europe and the Middle East. We conclude that the coprolite is feces from an animal within an extinct wolf lineage. The consumption of cave bear by this wolf likely explains its intrusion into the dark cave sectors and sheds new light on the paleoecology of a major cave site.
Published: 2022
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4. A Point Mutation in a lincRNA Upstream of GDNF Is Associated to a Canine Insensitivity to Pain: A Spontaneous Model for Human Sensory Neuropathies.

Author: Jocelyn Plassais, Laetitia Lagoutte, Solenne Correard, Manon Paradis, Eric Guaguère, Benoit Hédan, Alix Pommier, Nadine Botherel, Marie-Christine Cadiergues, Philippe Pilorge, David Silversides, Maud Bizot, Mark Samuels, Carme Arnan, Rory Johnson, Christophe Hitte, Gilles Salbert, Agnès Méreau, Pascale Quignon, Thomas Derrien, and Catherine André
Subjects: Genetics, QH426-470
Abstract: Human Hereditary Sensory Autonomic Neuropathies (HSANs) are characterized by insensitivity to pain, sometimes combined with self-mutilation. Strikingly, several sporting dog breeds are particularly affected by such neuropathies. Clinical signs appear in young puppies and consist of acral analgesia, with or without sudden intense licking, biting and severe self-mutilation of the feet, whereas proprioception, motor abilities and spinal reflexes remain intact. Through a Genome Wide Association Study (GWAS) with 24 affected and 30 unaffected sporting dogs using the Canine HD 170K SNP array (Illumina), we identified a 1.8 Mb homozygous locus on canine chromosome 4 (adj. p-val = 2.5x10-6). Targeted high-throughput sequencing of this locus in 4 affected and 4 unaffected dogs identified 478 variants. Only one variant perfectly segregated with the expected recessive inheritance in 300 sporting dogs of known clinical status, while it was never present in 900 unaffected dogs from 130 other breeds. This variant, located 90 kb upstream of the GDNF gene, a highly relevant neurotrophic factor candidate gene, lies in a long intergenic non-coding RNAs (lincRNA), GDNF-AS. Using human comparative genomic analysis, we observed that the canine variant maps onto an enhancer element. Quantitative RT-PCR of dorsal root ganglia RNAs of affected dogs showed a significant decrease of both GDNF mRNA and GDNF-AS expression levels (respectively 60% and 80%), as compared to unaffected dogs. We thus performed gel shift assays (EMSA) that reveal that the canine variant significantly alters the binding of regulatory elements. Altogether, these results allowed the identification in dogs of GDNF as a relevant candidate for human HSAN and insensitivity to pain, but also shed light on the regulation of GDNF transcription. Finally, such results allow proposing these sporting dog breeds as natural models for clinical trials with a double benefit for human and veterinary medicine.
Published: 2016
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5. Amy2B copy number variation reveals starch diet adaptations in ancient European dogs

Author: Morgane Ollivier, Anne Tresset, Fabiola Bastian, Laetitia Lagoutte, Erik Axelsson, Maja-Louise Arendt, Adrian Bălăşescu, Marjan Marshour, Mikhail V. Sablin, Laure Salanova, Jean-Denis Vigne, Christophe Hitte, and Catherine Hänni
Subjects: domestication, palaeogenomics, amylase, dog, neolithic, Science
Abstract: Extant dog and wolf DNA indicates that dog domestication was accompanied by the selection of a series of duplications on the Amy2B gene coding for pancreatic amylase. In this study, we used a palaeogenetic approach to investigate the timing and expansion of the Amy2B gene in the ancient dog populations of Western and Eastern Europe and Southwest Asia. Quantitative polymerase chain reaction was used to estimate the copy numbers of this gene for 13 ancient dog samples, dated to between 15 000 and 4000 years before present (cal. BP). This evidenced an increase of Amy2B copies in ancient dogs from as early as the 7th millennium cal. BP in Southeastern Europe. We found that the gene expansion was not fixed across all dogs within this early farming context, with ancient dogs bearing between 2 and 20 diploid copies of the gene. The results also suggested that selection for the increased Amy2B copy number started 7000 years cal. BP, at the latest. This expansion reflects a local adaptation that allowed dogs to thrive on a starch rich diet, especially within early farming societies, and suggests a biocultural coevolution of dog genes and human culture.
Published: 2016
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6. A COLQ Missense Mutation in Sphynx and Devon Rex Cats with Congenital Myasthenic Syndrome.

Author: Marie Abitbol, Christophe Hitte, Philippe Bossé, Nicolas Blanchard-Gutton, Anne Thomas, Lionel Martignat, Stéphane Blot, and Laurent Tiret
Subjects: Medicine, Science
Abstract: An autosomal recessive neuromuscular disorder characterized by skeletal muscle weakness, fatigability and variable electromyographic or muscular histopathological features has been described in the two related Sphynx and Devon Rex cat breeds (Felis catus). Collection of data from two affected Sphynx cats and their relatives pointed out a single disease candidate region on feline chromosome C2, identified following a genome-wide SNP-based homozygosity mapping strategy. In that region, we further identified COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase) as a good candidate gene, since COLQ mutations were identified in affected humans and dogs with endplate acetylcholinesterase deficiency leading to a synaptic form of congenital myasthenic syndrome (CMS). A homozygous c.1190G>A missense variant located in exon 15 of COLQ, leading to a C397Y substitution, was identified in the two affected cats. C397 is a highly-conserved residue from the C-terminal domain of the protein; its mutation was previously shown to produce CMS in humans, and here we confirmed in an affected Sphynx cat that it induces a loss of acetylcholinesterase clustering at the neuromuscular junction. Segregation of the c.1190G>A variant was 100% consistent with the autosomal recessive mode of inheritance of the disorder in our cat pedigree; in addition, an affected, unrelated Devon Rex cat recruited thereafter was also homozygous for the variant. Genotyping of a panel of 333 cats from 14 breeds failed to identify a single carrier in non-Sphynx and non-Devon Rex cats. Finally, the percentage of healthy carriers in a European subpanel of 81 genotyped Sphynx cats was estimated to be low (3.7%) and 14 control Devon Rex cats were genotyped as wild-type individuals. Altogether, these results strongly support that the neuromuscular disorder reported in Sphynx and Devon Rex breeds is a CMS caused by a unique c.1190G>A missense mutation, presumably transmitted through a founder effect, which strictly and slightly disseminated in these two breeds. The presently available DNA test will help owners avoid matings at risk.
Published: 2015
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7. Evidence of coat color variation sheds new light on ancient canids.

Author: Morgane Ollivier, Anne Tresset, Christophe Hitte, Coraline Petit, Sandrine Hughes, Benjamin Gillet, Marilyne Duffraisse, Maud Pionnier-Capitan, Laetitia Lagoutte, Rose-Marie Arbogast, Adrian Balasescu, Adina Boroneant, Marjan Mashkour, Jean-Denis Vigne, and Catherine Hänni
Subjects: Medicine, Science
Abstract: We have used a paleogenetics approach to investigate the genetic landscape of coat color variation in ancient Eurasian dog and wolf populations. We amplified DNA fragments of two genes controlling coat color, Mc1r (Melanocortin 1 Receptor) and CBD103 (canine-β-defensin), in respectively 15 and 19 ancient canids (dogs and wolf morphotypes) from 14 different archeological sites, throughout Asia and Europe spanning from ca. 12 000 B.P. (end of Upper Palaeolithic) to ca. 4000 B.P. (Bronze Age). We provide evidence of a new variant (R301C) of the Melanocortin 1 receptor (Mc1r) and highlight the presence of the beta-defensin melanistic mutation (CDB103-K locus) on ancient DNA from dog-and wolf-morphotype specimens. We show that the dominant K(B) allele (CBD103), which causes melanism, and R301C (Mc1r), the variant that may cause light hair color, are present as early as the beginning of the Holocene, over 10,000 years ago. These results underline the genetic diversity of prehistoric dogs. This diversity may have partly stemmed not only from the wolf gene pool captured by domestication but also from mutations very likely linked to the relaxation of natural selection pressure occurring in-line with this process.
Published: 2013
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8. Centronuclear myopathy in Labrador retrievers: a recent founder mutation in the PTPLA gene has rapidly disseminated worldwide.

Author: Marie Maurer, Jérôme Mary, Laurent Guillaud, Marilyn Fender, Manuel Pelé, Thomas Bilzer, Natasha Olby, Jacques Penderis, G Diane Shelton, Jean-Jacques Panthier, Jean-Laurent Thibaud, Inès Barthélémy, Geneviève Aubin-Houzelstein, Stéphane Blot, Christophe Hitte, and Laurent Tiret
Subjects: Medicine, Science
Abstract: Centronuclear myopathies (CNM) are inherited congenital disorders characterized by an excessive number of internalized nuclei. In humans, CNM results from ~70 mutations in three major genes from the myotubularin, dynamin and amphiphysin families. Analysis of animal models with altered expression of these genes revealed common defects in all forms of CNM, paving the way for unified pathogenic and therapeutic mechanisms. Despite these efforts, some CNM cases remain genetically unresolved. We previously identified an autosomal recessive form of CNM in French Labrador retrievers from an experimental pedigree, and showed that a loss-of-function mutation in the protein tyrosine phosphatase-like A (PTPLA) gene segregated with CNM. Around the world, client-owned Labrador retrievers with a similar clinical presentation and histopathological changes in muscle biopsies have been described. We hypothesized that these Labradors share the same PTPLA(cnm) mutation. Genotyping of an international panel of 7,426 Labradors led to the identification of PTPLA(cnm) carriers in 13 countries. Haplotype analysis demonstrated that the PTPLA(cnm) allele resulted from a single and recent mutational event that may have rapidly disseminated through the extensive use of popular sires. PTPLA-deficient Labradors will help define the integrated role of PTPLA in the existing CNM gene network. They will be valuable complementary large animal models to test innovative therapies in CNM.
Published: 2012
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9. Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping.

Author: Amaury Vaysse, Abhirami Ratnakumar, Thomas Derrien, Erik Axelsson, Gerli Rosengren Pielberg, Snaevar Sigurdsson, Tove Fall, Eija H Seppälä, Mark S T Hansen, Cindy T Lawley, Elinor K Karlsson, LUPA Consortium, Danika Bannasch, Carles Vilà, Hannes Lohi, Francis Galibert, Merete Fredholm, Jens Häggström, Ake Hedhammar, Catherine André, Kerstin Lindblad-Toh, Christophe Hitte, and Matthew T Webster
Subjects: Genetics, QH426-470
Abstract: The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.
Published: 2011
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10. Canine population structure: assessment and impact of intra-breed stratification on SNP-based association studies.

Author: Pascale Quignon, Laetitia Herbin, Edouard Cadieu, Ewen F Kirkness, Benoit Hédan, Dana S Mosher, Francis Galibert, Catherine André, Elaine A Ostrander, and Christophe Hitte
Subjects: Medicine, Science
Abstract: In canine genetics, the impact of population structure on whole genome association studies is typically addressed by sampling approximately equal numbers of cases and controls from dogs of a single breed, usually from the same country or geographic area. However one way to increase the power of genetic studies is to sample individuals of the same breed but from different geographic areas, with the expectation that independent meiotic events will have shortened the presumed ancestral haplotype around the mutation differently. Little is known, however, about genetic variation among dogs of the same breed collected from different geographic regions.In this report, we address the magnitude and impact of genetic diversity among common breeds sampled in the U.S. and Europe. The breeds selected, including the Rottweiler, Bernese mountain dog, flat-coated retriever, and golden retriever, share susceptibility to a class of soft tissue cancers typified by malignant histiocytosis in the Bernese mountain dog. We genotyped 722 SNPs at four unlinked loci (between 95 and 271 per locus) on canine chromosome 1 (CFA1). We showed that each population is characterized by distinct genetic diversity that can be correlated with breed history. When the breed studied has a reduced intra-breed diversity, the combination of dogs from international locations does not increase the rate of false positives and potentially increases the power of association studies. However, over-sampling cases from one geographic location is more likely to lead to false positive results in breeds with significant genetic diversity.These data provide new guidelines for association studies using purebred dogs that take into account population structure.
Published: 2007
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11. Table S2 from Discovery of Human-Similar Gene Fusions in Canine Cancers

Author: Catherine André, Benoît Hédan, Thomas Derrien, Arnaud Le Goff, Thierry Guillaudeux, Benoit Hennuy, David Gilot, Laura Bachelot, Florian Cabillic, Laurence Cornevin, Christophe Hitte, Catherine Thieblemont, Edouard Cadieu, Valentin Wucher, Audrey Rousseau, Nadine Botherel, Jean-Michel Coindre, Clotilde De Brito, Jérôme Abadie, Laetitia Lagoutte, Mathieu Bahin, Mélanie Rault, and Ronan Ulvé
Abstract: Primers used for validation of the canine gene fusions.
Published: 2023
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12. Figure S1 from Discovery of Human-Similar Gene Fusions in Canine Cancers

Author: Catherine André, Benoît Hédan, Thomas Derrien, Arnaud Le Goff, Thierry Guillaudeux, Benoit Hennuy, David Gilot, Laura Bachelot, Florian Cabillic, Laurence Cornevin, Christophe Hitte, Catherine Thieblemont, Edouard Cadieu, Valentin Wucher, Audrey Rousseau, Nadine Botherel, Jean-Michel Coindre, Clotilde De Brito, Jérôme Abadie, Laetitia Lagoutte, Mathieu Bahin, Mélanie Rault, and Ronan Ulvé
Abstract: Characterization of the canine dermatofibrosarcoma protuberans-like.
Published: 2023
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13. Data from Discovery of Human-Similar Gene Fusions in Canine Cancers

Author: Catherine André, Benoît Hédan, Thomas Derrien, Arnaud Le Goff, Thierry Guillaudeux, Benoit Hennuy, David Gilot, Laura Bachelot, Florian Cabillic, Laurence Cornevin, Christophe Hitte, Catherine Thieblemont, Edouard Cadieu, Valentin Wucher, Audrey Rousseau, Nadine Botherel, Jean-Michel Coindre, Clotilde De Brito, Jérôme Abadie, Laetitia Lagoutte, Mathieu Bahin, Mélanie Rault, and Ronan Ulvé
Abstract: Canine cancers represent a tremendous natural resource due to their incidence and striking similarities to human cancers, sharing similar clinical and pathologic features as well as oncogenic events, including identical somatic mutations. Considering the importance of gene fusions as driver alterations, we explored their relevance in canine cancers. We focused on three distinct human-comparable canine cancers representing different tissues and embryonic origins. Through RNA-Seq, we discovered similar gene fusions as those found in their human counterparts: IGK-CCND3 in B-cell lymphoma, MPB-BRAF in glioma, and COL3A1-PDGFB in dermatofibrosarcoma protuberans-like. We showed not only similar partner genes but also identical breakpoints leading to oncogene overexpression. This study demonstrates similar gene fusion partners and mechanisms in human–dog corresponding tumors and allows for selection of targeted therapies in preclinical and clinical trials with pet dogs prior to human trials, within the framework of personalized medicine. Cancer Res; 77(21); 5721–7. ©2017 AACR.
Published: 2023
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14. Canine Oral Melanoma Genomic and Transcriptomic Study Defines Two Molecular Subgroups with Different Therapeutical Targets

Author: Stéphanie Mottier, Anaïs Prouteau, Aline Primot, Jérôme Abadie, Laura Bachelot, David Gilot, Camille Kergal, Benoit Hedan, Thomas Derrien, Florian Cabilic, Christophe Hitte, Nadine Botherel, Laurence Cornevin, Armel Houel, Edouard Cadieu, Kerstin Lindblad-Toh, Sébastien Corre, Catherine André, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Uppsala University, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], This research was funded by CNRS and in the frame of the French Plan Cancer 2009–2013, by Aviesan/INSERM MTS 2012-08. A. Prouteau (salary and direct costs) was funded through the FHU CAMIn (CHU-Univ Rennes-Brittany region & Ligue Nationale contre le cancer). The sample collection performed through the French Cani-DNA BRC was funded by the CRB-Anim infrastructure ANR-11-INBS-0003 in the frame of the Investing for the Future Program (PIA1)., and ANR-11-INBS-0003,CRB-Anim,Réseau de Centres de Ressources Biologiques pour les animaux domestiques(2011)
Subjects: Cancer Research, CDK4, oncogenes, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Biology, Article, Transcriptome, immune checkpoint inhibitors, MDM2, TRPM7, mucosal melanoma, dog model, chromosomal rearrangements, medicine, Genetics, Genetik, Gene, RC254-282, Cancer och onkologi, Mucosal melanoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Chromosome, Cancer, Immunotherapy, medicine.disease, Oncology, Cancer and Oncology, Cancer research, biology.protein, Mdm2
Abstract: Mucosal melanoma (MM) is a rare and aggressive clinical cancer that occurs mostly in the head, neck, and anogenital regions. Despite recent advances in genetics and the development of revolutionary treatments, such as immunotherapy, the prognosis for MM remains poor. Canine MM shares several clinical, histological, and genetic features with its human counterpart, offering a relevant spontaneous and immunocompetent model to decipher the genetic bases and explore treatment options for human MM. We performed an integrative genomic and transcriptomic analysis of 32 canine MM samples, which allowed us to identify two molecular subgroups differing in microenvironment and structural variant (SV) content. The overexpression of genes related to the microenvironment and T-cell response was associated with tumors harboring a lower content of structural variants, whereas the overexpression of pigmentation-related pathways and oncogenes such as TERT were associated with a high SV burden. To detail the SVs, especially those with focal amplifications, whole-genome sequencing was performed on four canine MM cell lines. We showed that focal amplifications characterized complex chromosomal rearrangements targeting oncogenes such as MDM2 or CDK4 and a recurrently amplified region on canine chromosome 30, comprising the genes TRPM7, GABPB1, USP8, and SPPL2A, were candidate oncogenes for MM. We showed that the copy numbers of these genes were significantly correlated with their expression levels. Finally, we demonstrated that the genes TRPM7, GABPB1, and SPPL2A play a role in cell proliferation; thus, these may be considered new candidate oncogenes for human MM. Our findings suggest the existence of two MM molecular subgroups that may benefit from dedicated therapies, such as immune checkpoint inhibitors or targeted therapies. These results illustrate the relevance of dog models for deciphering genetic mechanisms in spontaneous MM, along with the potential to screen for efficient targeted therapies for rare and aggressive cancers in humans.
Published: 2022
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15. Improving the resolution of canine genome-wide association studies using genotype imputation: A study of two breeds

Author: Sally L. Ricketts, Steven G. Friedenberg, Cord Drögemüller, Claire M. Wade, Leonardo Murgiano, Jeffrey J. Schoenebeck, Christophe Hitte, Sheila M. Schmutz, C. A. Jenkins, Doreen Becker, L. De Risio, Anita M. Oberbauer, Tosso Leeb, Brian W. Davis, Kiterie M. E. Faller, Eva Furrow, Catherine Andre, Frank G. van Steenbeek, Ellen Schofield, Urs Giger, Kari J Ekenstedt, Cathryn S. Mellersh, James R. Mickelson, Gustavo Aguirre, Hannes Lohi, Marjo K. Hytönen, Danika Bannasch, Oliver P. Forman, C. S. Mellersh, Kim M. Summers, Vidhya Jagannathan, Jenkins, Christopher A [0000-0001-9082-4270], and Apollo - University of Cambridge Repository
Subjects: Dairy & Animal Science, Genotype, imputation accuracy, 610 Medicine & health, Single-nucleotide polymorphism, Genome-wide association study, Computational biology, Biology, Breeding, Genome, Polymorphism, Single Nucleotide, Article, Dogs, Border Collie, Genetics, Animals, Veterinary Sciences, Polymorphism, Italian Spinone, Genetic Association Studies, Genetic association, Whole genome sequencing, whole genome sequencing, genome-wide association study, Prevention, General Medicine, Single Nucleotide, Genomics, 570 Life sciences, biology, 590 Animals (Zoology), Animal Science and Zoology, Dog Biomedical Variant Database Consortium, Zoology, Imputation (genetics)
Abstract: Funder: Italian Spinone Club of Great Britain, Funder: Kennel Club Charitable Trust, Genotype imputation using a reference panel that combines high-density array data and publicly available whole genome sequence consortium variant data is potentially a cost-effective method to increase the density of extant lower-density array datasets. In this study, three datasets (two Border Collie; one Italian Spinone) generated using a legacy array (Illumina CanineHD, 173 662 SNPs) were utilised to assess the feasibility and accuracy of this approach and to gather additional evidence for the efficacy of canine genotype imputation. The cosmopolitan reference panels used to impute genotypes comprised dogs of 158 breeds, mixed breed dogs, wolves and Chinese indigenous dogs, as well as breed-specific individuals genotyped using the Axiom Canine HD array. The two Border Collie reference panels comprised 808 individuals including 79 Border Collies and 426 326 or 426 332 SNPs; and the Italian Spinone reference panel comprised 807 individuals including 38 Italian Spinoni and 476 313 SNPs. A high accuracy for imputation was observed, with the lowest accuracy observed for one of the Border Collie datasets (mean R2 = 0.94) and the highest for the Italian Spinone dataset (mean R2 = 0.97). This study's findings demonstrate that imputation of a legacy array study set using a reference panel comprising both breed-specific array data and multi-breed variant data derived from whole genomes is effective and accurate. The process of canine genotype imputation, using the valuable growing resource of publicly available canine genome variant datasets alongside breed-specific data, is described in detail to facilitate and encourage use of this technique in canine genetics.
Published: 2021
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16. Long-read assembly of a Great Dane genome highlights the contribution of GC-rich sequence and mobile elements to canine genomes

Author: Aurélien J. Doucet, Christophe Hitte, Elzbieta Sliwerska, Bridget Myers, Thomas Derrien, Julia V. Halo, Feichen Shen, Laura E. Kirby, Amanda L. Pendleton, John V. Moran, Adam R. Boyko, Jeffrey M. Kidd, S. Emery, Bowling Green State University (BGSU), University of Michigan [Ann Arbor], University of Michigan System, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Cornell University [New York], R15GM122028, National Institute of General Medical Sciences, T32HG00040, National Human Genome Research Institute, HAL UR1, Admin, Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: mobile elements, [SDV]Life Sciences [q-bio], Retrotransposon, Biology, Genome, DNA sequencing, Structural variation, 03 medical and health sciences, Dogs, 0302 clinical medicine, Species Specificity, Genetics, Consensus sequence, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, long-read assembly, Gene, Short Interspersed Nucleotide Elements, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Contig, structural variation, Canis familiaris, Biological Sciences, GC Rich Sequence, Interspersed Repetitive Sequences, [SDV] Life Sciences [q-bio], Long Interspersed Nucleotide Elements, Evolutionary biology, Mobile genetic elements, human activities, GC-content, 030217 neurology & neurosurgery, Reference genome
Abstract: Significance Advancements in long-read DNA sequencing technologies provide more comprehensive views of genomes. We used long-read sequences to assemble a Great Dane dog genome that provides several improvements over the existing reference derived from a Boxer. Assembly comparisons revealed that gaps in the Boxer assembly often occur at the beginning of protein-coding genes and have a high-GC content, which likely reflects limitations of previous technologies in resolving GC-rich sequences. Dimorphic LINE-1 and SINEC retrotransposons represent the predominant differences between the Great Dane and Boxer assemblies. Proof-of-principle experiments demonstrated that expression of a canine LINE-1 could promote the retrotransposition of itself and a SINEC_Cf consensus sequence in cultured human cells. Thus, ongoing retrotransposon activity is a major contributor to canine genetic diversity., Technological advances have allowed improvements in genome reference sequence assemblies. Here, we combined long- and short-read sequence resources to assemble the genome of a female Great Dane dog. This assembly has improved continuity compared to the existing Boxer-derived (CanFam3.1) reference genome. Annotation of the Great Dane assembly identified 22,182 protein-coding gene models and 7,049 long noncoding RNAs, including 49 protein-coding genes not present in the CanFam3.1 reference. The Great Dane assembly spans the majority of sequence gaps in the CanFam3.1 reference and illustrates that 2,151 gaps overlap the transcription start site of a predicted protein-coding gene. Moreover, a subset of the resolved gaps, which have an 80.95% median GC content, localize to transcription start sites and recombination hotspots more often than expected by chance, suggesting the stable canine recombinational landscape has shaped genome architecture. Alignment of the Great Dane and CanFam3.1 assemblies identified 16,834 deletions and 15,621 insertions, as well as 2,665 deletions and 3,493 insertions located on secondary contigs. These structural variants are dominated by retrotransposon insertion/deletion polymorphisms and include 16,221 dimorphic canine short interspersed elements (SINECs) and 1,121 dimorphic long interspersed element-1 sequences (LINE-1_Cfs). Analysis of sequences flanking the 3′ end of LINE-1_Cfs (i.e., LINE-1_Cf 3′-transductions) suggests multiple retrotransposition-competent LINE-1_Cfs segregate among dog populations. Consistent with this conclusion, we demonstrate that a canine LINE-1_Cf element with intact open reading frames can retrotranspose its own RNA and that of a SINEC_Cf consensus sequence in cultured human cells, implicating ongoing retrotransposon activity as a driver of canine genetic variation.
Published: 2021
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17. Dog10K_Boxer_Tasha_1.0: A Long-Read Assembly of the Dog Reference Genome

Author: Xiangquan Zhang, Christophe Hitte, Elaine A. Ostrander, Patrick Masterson, Terence Murphy, Yan-Hu Liu, Jeffrey M. Kidd, S. Emery, Brian W. Davis, Tosso Leeb, Ya-Ping Zhang, Reuben M. Buckley, Guo-Dong Wang, Vidhya Jagannathan, University of Bern, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University of Michigan [Ann Arbor], University of Michigan System, National Center for Biotechnology Information (NCBI), Texas A&M University [College Station], National Human Genome Research Institute (NHGRI), Kunming Institute of Zoology, Chinese Academy of Sciences [Beijing] (CAS), 2019YFA0707101, The National Key R&D Program of China, R01GM140135, National Institutes of Health, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Kunming Institute of Zoology (KIZ)
Subjects: clone (Java method), 0301 basic medicine, Canis lupus familiaris, contiguity, 0206 medical engineering, Sequence assembly, 610 Medicine & health, 02 engineering and technology, Computational biology, QH426-470, Biology, resource, Article, Contig Mapping, 03 medical and health sciences, Annotation, high quality, Dogs, 0302 clinical medicine, Pacific biosciences, Genetics, Animals, Canine genetics, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Genome, 630 Agriculture, Shotgun sequencing, Molecular Sequence Annotation, Gene Annotation, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, annotation, 590 Animals (Zoology), 570 Life sciences, biology, 020602 bioinformatics, 030217 neurology & neurosurgery, Reference genome
Abstract: The domestic dog has evolved to be an important biomedical model for studies regarding the genetic basis of disease, morphology and behavior. Genetic studies in the dog have relied on a draft reference genome of a purebred female boxer dog named “Tasha” initially published in 2005. Derived from a Sanger whole genome shotgun sequencing approach coupled with limited clone-based sequencing, the initial assembly and subsequent updates have served as the predominant resource for canine genetics for 15 years. While the initial assembly produced a good-quality draft, as with all assemblies produced at the time, it contained gaps, assembly errors and missing sequences, particularly in GC-rich regions, which are found at many promoters and in the first exons of protein-coding genes. Here, we present Dog10K_Boxer_Tasha_1.0, an improved chromosome-level highly contiguous genome assembly of Tasha created with long-read technologies that increases sequence contiguity &gt, 100-fold, closes &gt, 23,000 gaps of the CanFam3.1 reference assembly and improves gene annotation by identifying &gt, 1200 new protein-coding transcripts. The assembly and annotation are available at NCBI under the accession GCF_000002285.5.
Published: 2021
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18. PTPN11 mutations in canine and human disseminated histiocytic sarcoma

Author: Jean-Yves Blay, Julia Alten, Jean Donadieu, Matthew Breen, Thomas Derrien, Aurore Coulomb-L'Hermine, Jérôme Abadie, Mélanie Rault, Marie Parrens, Emmanuelle Lechapt Zalcman, Gandhi Damaj, Karima Mokhtari, Gunnar Cario, François Le Loarer, Edouard Cadieu, Nadine Botherel, Christiane Copie-Bergman, Patrick Devauchelle, Benoit Hedan, David Gilot, Christophe Hitte, Catherine André, Ronan Ulvé, Laura Bachelot, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), MICEN-Vet, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, GHU Paris Psychiatrie et Neurosciences, Laboratoire d'Hématologie Biologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC), Agence Nationale de la Recherche. Grant Number: ANR‐11‐INBS‐0003, American Kennel Club Canine Health Foundation. Grant Numbers: 1557, 2446, 2667, INCa PLBio. Grant Number: 2012‐103, ANR-11-INBS-0003,CRB-Anim,Réseau de Centres de Ressources Biologiques pour les animaux domestiques(2011), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Jonchère, Laurent, Infrastructures - Réseau de Centres de Ressources Biologiques pour les animaux domestiques - - CRB-Anim2011 - ANR-11-INBS-0003 - INBS - VALID, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, MAPK/ERK pathway, Cancer Research, Biopsy, DNA Mutational Analysis, Protein Tyrosine Phosphatase, Non-Receptor Type 11, [SDV.GEN] Life Sciences [q-bio]/Genetics, Histiocytic sarcoma, PTPN11, medicine.disease_cause, Mutually exclusive events, 0302 clinical medicine, Dog Diseases, Child, Aged, 80 and over, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Middle Aged, 3. Good health, spontaneous model, Oncology, Child, Preschool, 030220 oncology & carcinogenesis, dog, Female, KRAS, Mitogen-Activated Protein Kinases, Adult, MAP Kinase Signaling System, [SDV.CAN]Life Sciences [q-bio]/Cancer, histiocytic sarcoma, Young Adult, 03 medical and health sciences, Dogs, Ribonucleases, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, Animals, Humans, Protein Kinase Inhibitors, Histiocyte, Aged, Cell Proliferation, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Tumor Suppressor Proteins, Infant, Aggressive cancer, Histiocytes, medicine.disease, Disease Models, Animal, Cell culture, Mutation, Cancer research, Drug Screening Assays, Antitumor, business
Abstract: International audience; In humans, histiocytic sarcoma (HS) is an aggressive cancer involving histiocytes. Its rarity and heterogeneity explain that treatment remains a challenge. Sharing high clinical and histopathological similarities with human HS, the canine HS is conversely frequent in specific breeds and thus constitutes a unique spontaneous model for human HS to decipher the genetic bases and to explore therapeutic options. We identified sequence alterations in the MAPK pathway in at least 63.9% (71/111) of HS cases with mutually exclusive BRAF (0.9%; 1/111), KRAS (7.2%; 8/111) and PTPN11 (56.75%; 63/111) mutations concentrated at hotspots common to human cancers. Recurrent PTPN11 mutations are associated to visceral disseminated HS subtype in dogs, the most aggressive clinical presentation. We then identified PTPN11 mutations in 3/19 (15.7%) human HS patients. Thus, we propose PTPN11 mutations as key events for a specific subset of human and canine HS the visceral disseminated form. Finally, by testing drugs targeting the MAPK pathway in eight canine HS cell lines, we identified a better anti-proliferation activity of MEK inhibitors than PTPN11 inhibitors in canine HS neoplastic cells. In combination, these results illustrate the relevance of naturally affected dogs in deciphering genetic mechanisms and selecting efficient targeted therapies for such rare and aggressive cancers in humans.
Published: 2020
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19. Donskoy cats as a new model of oculocutaneous albinism with the identification of a splice-site variant in Hermansky-Pudlak Syndrome 5 gene

Author: Marie Abitbol, Marina Mériot, Vincent Gache, Caroline Dufaure de Citres, Christophe Hitte, Maud Rimbault, VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Antagene, Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation pour la Recherche sur la Biodiversite, 71VAL0419, Genespoir, VetAgro Sup, Fondation pour la Recherche sur la Biodiversité, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Jonchère, Laurent
Subjects: 0301 basic medicine, Candidate gene, RNA Splicing, [SDV]Life Sciences [q-bio], Hermansky-Pudlak Syndrome 5, HPS5, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, albinism, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, ruby-eye 2, medicine, Animals, Humans, Genetic Predisposition to Disease, Felis catus, Gene, Alleles, Genetics, Base Sequence, Homozygote, Intron, Exons, medicine.disease, Disease gene identification, Chromosomes, Mammalian, Oculocutaneous albinism, [SDV] Life Sciences [q-bio], Disease Models, Animal, Phenotype, 030104 developmental biology, Oncology, Albinism, Oculocutaneous, Genetic Loci, 030220 oncology & carcinogenesis, Cats, Albinism, RNA Splice Sites, Hermansky–Pudlak syndrome, Carrier Proteins, BLOC2S2, Genome-Wide Association Study
Abstract: International audience; In the feline Donskoy breed, a phenotype that breeders call "pink‐eye," with associated light‐brown skin, yellow irises and red‐eye effect, has been described. Genealogical data indicated an autosomal recessive inheritance pattern. A single candidate region was identified by genome‐wide association study and SNP‐based homozygosity mapping. Within that region, we further identified HPS5 (HPS5 Biogenesis Of Lysosomal Organelles Complex 2 Subunit 2 ) as a strong candidate gene, since HPS5 variants have been identified in humans and animals with Hermansky–Pudlak syndrome 5 or oculocutaneous albinism. A homozygous c.2571‐1G>A acceptor splice‐site variant located in intron 16 of HPS5 was identified in pink‐eye cats. Segregation of the variant was 100% consistent with the inheritance pattern. Genotyping of 170 cats from 19 breeds failed to identify a single carrier in non‐Donskoy cats. The c.2571‐1G>A variant leads to HPS5 exon‐16 splicing that is predicted to produce a 52 amino acids in‐frame deletion in the protein. These results support an association of the pink‐eye phenotype with the c.2571‐1G>A variant. The pink‐eye Donskoy cat extends the panel of reported HPS5 variants and offers an opportunity for in‐depth exploration of the phenotypic consequences of a new HPS5 variant.
Published: 2020
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20. The Dog Model in the Spotlight Legacy of a Trustful Cooperation

Author: Inès Barthélémy, Christophe Hitte, Laurent Tiret, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Jonchère, Laurent, and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Review, laurasiatheria, rehoming, euarchontoglires, 0302 clinical medicine, 3 R rule, Longitudinal Studies, SMA, ComputingMilieux_MISCELLANEOUS, medicine.diagnostic_test, AAV, Protein Tyrosine Phosphatases, Non-Receptor, myology, gene therapy, [SDV] Life Sciences [q-bio], myopathies, mdx, CNM, Myopathies, Structural, Congenital, MTM1, Computational biology, Dog model, medical costs, genetic testing, 03 medical and health sciences, domestication, Animal model, Dogs, Rare Diseases, DMD, medicine, Animals, Humans, CRISPR/Cas9, Genetic testing, Comparative genomics, Genetic heterogeneity, business.industry, neurology, animal model, Robustness (evolution), Precision medicine, ethics, Review article, Disease Models, Animal, 030104 developmental biology, Mutation, Neurology (clinical), business, comparative medicine, 030217 neurology & neurosurgery
Abstract: Dogs have long been used as a biomedical model system and in particular as a preclinical proof of concept for innovative therapies before translation to humans. A recent example of the utility of this animal model is the promising myotubularin gene delivery in boys affected by X-linked centronuclear myopathy after successful systemic, long-term efficient gene therapy in Labrador retrievers. Mostly, this is due to unique features that make dogs an optimal system. The continuous emergence of spontaneous inherited disorders enables the identification of reliable complementary molecular models for human neuromuscular disorders (NMDs). Dogs’ characteristics including size, lifespan and unprecedented medical care level allow a comprehensive longitudinal description of diseases. Moreover, the highly similar pathogenic mechanisms with human patients yield to translational robustness. Finally, interindividual phenotypic heterogeneity between dogs helps identifying modifiers and anticipates precision medicine issues. This review article summarizes the present list of molecularly characterized dog models for NMDs and provides an exhaustive list of the clinical and paraclinical assays that have been developed. This toolbox offers scientists a sensitive and reliable system to thoroughly evaluate neuromuscular function, as well as efficiency and safety of innovative therapies targeting these NMDs. This review also contextualizes the model by highlighting its unique genetic value, shaped by the long-term coevolution of humans and domesticated dogs. Because the dog is one of the most protected research animal models, there is considerable opposition to include it in preclinical projects, posing a threat to the use of this model. We thus discuss ethical issues, emphasizing that unlike many other models, the dog also benefits from its contribution to comparative biomedical research with a drastic reduction in the prevalence of morbid alleles in the breeding stock and an improvement in medical care.
Published: 2019
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21. Genome-wide analysis of long non-coding RNA profiles in canine oral melanomas

Author: Valentin Wucher, Kerstin Lindblad-Toh, Christophe Hitte, Thomas Derrien, Anaïs Prouteau, Nadine Botherel, Benoit Hedan, Céline Le Béguec, Edouard Cadieu, Catherine André, Aline Primot, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Barcelona Institute of Science and Technology (BIST), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Uppsala University, ANR-11-INBS-0003, Agence Nationale de la Recherche, ANR-11-INBS-0003,CRB-Anim,Réseau de Centres de Ressources Biologiques pour les animaux domestiques(2011), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: 0301 basic medicine, dogs, lcsh:QH426-470, [SDV]Life Sciences [q-bio], Computational biology, transcriptome sequencing, Breeding, Biology, Article, Long non-coding RNAs (lncRNAs), Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Dogs, Gene expression, Genetics, medicine, Animals, Humans, mucosal melanoma, genetics, Dog Diseases, Transcriptome sequencing, Genetik, Melanoma, Gene, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Exome sequencing, Genome, Gene Expression Profiling, Mucosal melanoma, High-Throughput Nucleotide Sequencing, Cell cycle, medicine.disease, Long non-coding RNA, 3. Good health, Transcriptome Sequencing, long non-coding RNAs (lncRNAs), lcsh:Genetics, 030104 developmental biology, 030220 oncology & carcinogenesis, Mouth Neoplasms, RNA, Long Noncoding
Abstract: Mucosal melanomas (MM) are rare aggressive cancers in humans, and one of the most common forms of oral cancers in dogs. Similar biological and histological features are shared between MM in both species, making dogs a powerful model for comparative oncology studies of melanomas. Although exome sequencing recently identified recurrent coding mutations in canine MM, little is known about changes in non-coding gene expression, and more particularly, in canine long non-coding RNAs (lncRNAs), which are commonly dysregulated in human cancers. Here, we sampled a large cohort (n = 52) of canine normal/tumor oral MM from three predisposed breeds (poodles, Labrador retrievers, and golden retrievers), and used deep transcriptome sequencing to identify more than 400 differentially expressed (DE) lncRNAs. We further prioritized candidate lncRNAs by comparative genomic analysis to pinpoint 26 dog&ndash, human conserved DE lncRNAs, including SOX21-AS, ZEB2-AS, and CASC15 lncRNAs. Using unsupervised co-expression network analysis with coding genes, we inferred the potential functions of the DE lncRNAs, suggesting associations with cancer-related genes, cell cycle, and carbohydrate metabolism Gene Ontology (GO) terms. Finally, we exploited our multi-breed design to identify DE lncRNAs within breeds. This study provides a unique transcriptomic resource for studying oral melanoma in dogs, and highlights lncRNAs that may potentially be diagnostic or therapeutic targets for human and veterinary medicine.
Published: 2019
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22. Characterisation and functional predictions of canine long non-coding RNAs

Author: Catherine André, Laetitia Lagoutte, Nadine Botherel, Clotilde De Brito, Edouard Cadieu, Valentin Wucher, BenoÃ®t. Hédan, Céline Le Béguec, Anne-Sophie Guillory, Christophe Hitte, Thomas Derrien, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), 'Cani-DNA_CRB' [ANR-11-INBS-0003], CNRS (Centre National de la Recherche Scientifique), Universite Rennes1, Brittany Region (France), ANR-11-INBS-0003,CRB-Anim,Réseau de Centres de Ressources Biologiques pour les animaux domestiques(2011), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Transposable element, lcsh:Medicine, Genomics, Computational biology, Biology, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Dogs, Biologie animale, Animals, Humans, lcsh:Science, Gene, 030304 developmental biology, Animal biology, 0303 health sciences, [SDV.BA]Life Sciences [q-bio]/Animal biology, lcsh:R, Gene Expression Regulation, Organ Specificity, Tissue type, lcsh:Q, RNA, Long Noncoding, Genotype to phenotype, Databases, Nucleic Acid, 030217 neurology & neurosurgery
Abstract: Long non-coding RNAs (lncRNAs) are a family of heterogeneous RNAs that play major roles in multiple biological processes. We recently identified an extended repertoire of more than 10,000 lncRNAs of the domestic dog however, predicting their biological functionality remains challenging. In this study, we have characterised the expression profiles of 10,444 canine lncRNAs in 26 distinct tissue types, representing various anatomical systems. We showed that lncRNA expressions are mainly clustered by tissue type and we highlighted that 44% of canine lncRNAs are expressed in a tissue-specific manner. We further demonstrated that tissue-specificity correlates with specific families of canine transposable elements. In addition, we identified more than 900 conserved dog-human lncRNAs for which we show their overall reproducible expression patterns between dog and humans through comparative transcriptomics. Finally, co-expression analyses of lncRNA and neighbouring protein-coding genes identified more than 3,400 canine lncRNAs, suggesting that functional roles of these lncRNAs act as regulatory elements. Altogether, this genomic and transcriptomic integrative study of lncRNAs constitutes a major resource to investigate genotype to phenotype relationships and biomedical research in the dog species.
Published: 2018
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23. Dogs accompanied humans during the Neolithic expansion into Europe

Author: Mikhail V. Sablin, László Bartosiewicz, Adrian Bălăşescu, Rivka Rabinovich, Rose-Marie Arbogast, Morgane Ollivier, Christophe Hitte, Laurent A. F. Frantz, Ophélie Lebrasseur, Stéphanie Bréhard, Marjan Mashkour, Greger Larson, Anne Tresset, Catherine Hänni, Adina Boroneanţ, Karyne Debue, Jean-Denis Vigne, Maud Pionnier-Capitan, Plateforme nationale de Paléogénétique (Palgene), École normale supérieure - Lyon (ENS Lyon), Archéozoologie, archéobotanique : sociétés, pratiques et environnements (AASPE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Queen Mary University of London (QMUL), University of Oxford [Oxford], Romanian Academy of Sciences, Etude des Civilisations de l'Antiquité (UMR 7044), Centre National de la Recherche Scientifique (CNRS)-Université Marc Bloch - Strasbourg II-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA)), The Hebrew University of Jerusalem (HUJ), Laboratoire d'Ecologie Alpine (LECA ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), ERC-2013-StG-337574-UNDEAD, H2020 European Research Council, NE/K005243/1 and NE/K003259/1, Natural Environment Research Council, 12676VE, Nestlé Purina, Egide Econet, PN-IIRU-TE-2014-4-0519, Authority for Scientific Research, CNCS - UEFISCDI, AAAA-A17-117022810195-3, ZIN RAS, École normale supérieure de Lyon (ENS de Lyon), University of Oxford, Étude des Civilisations de l'Antiquité : de la Préhistoire à Byzance (ARCHIMEDE), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université Marc Bloch - Strasbourg II-Centre National de la Recherche Scientifique (CNRS), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: 0301 basic medicine, Population, Zoology, Biology, DNA, Mitochondrial, Haplogroup, 03 medical and health sciences, domestication, Dogs, Bronze Age, Animals, Humans, 0601 history and archaeology, Neolithic, education, Domestication, ancient DNA, Mesolithic, education.field_of_study, Evolutionary Biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 060102 archaeology, Fossils, Agriculture, 06 humanities and the arts, Chalcolithic, Sequence Analysis, DNA, Agricultural and Biological Sciences (miscellaneous), Europe, 030104 developmental biology, Ancient DNA, Archaeology, Haplotypes, dog, General Agricultural and Biological Sciences, Human mitochondrial DNA haplogroup
Abstract: International audience; Near Eastern Neolithic farmers introduced several species of domestic plants and animals as they dispersed into Europe. Dogs were the only domestic species present in both Europe and the Near East prior to the Neolithic. Here, we assessed whether early Near Eastern dogs possessed a unique mitochondrial lineage that differentiated them from Mesolithic European populations. We then analysed mitochondrial DNA sequences from 99 ancient European and Near Eastern dogs spanning the Upper Palaeolithic to the Bronze Age to assess if incoming farmers brought Near Eastern dogs with them, or instead primarily adopted indigenous European dogs after they arrived. Our results show that European pre-Neolithic dogs all possessed the mitochondrial haplogroup C, and that the Neolithic and Post-Neolithic dogs associated with farmers from Southeastern Europe mainly possessed haplogroup D. Thus, the appearance of haplogroup D most probably resulted from the dissemination of dogs from the Near East into Europe. In Western and Northern Europe, the turnover is incomplete and haplogroup C persists well into the Chalcolithic at least. These results suggest that dogs were an integral component of the Neolithic farming package and a mitochondrial lineage associated with the Near East was introduced into Europe alongside pigs, cows, sheep and goats. It got diluted into the native dog population when reaching the Western and Northern margins of Europe.
Published: 2018
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24. Discovery of Human-Similar Gene Fusions in Canine Cancers

Author: Thierry Guillaudeux, Audrey Rousseau, Catherine Thieblemont, Laetitia Lagoutte, Florian Cabillic, Nadine Botherel, Christophe Hitte, Jérôme Abadie, Thomas Derrien, Laurence Cornevin, Mathieu Bahin, Mélanie Rault, Valentin Wucher, David Gilot, Clotilde De Brito, Benoit Hennuy, Ronan Ulvé, Catherine André, Laura Bachelot, Jean-Michel Coindre, B. Hedan, Edouard Cadieu, Arnaud Le Goff, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Animaux modèles pour la recherche en oncologie comparée (AMaROC), Service de Pathologie, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Liège, Microenvironnement et cancer (MiCa), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Plate-forme ImPACcell (ImPACcell), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 2012-103, 2012–2016, Centre National de la Recherche Scientifique, ANR-11-INBS-0003, PIA, ANR-11-INBS-0003,CRB-Anim,Réseau de Centres de Ressources Biologiques pour les animaux domestiques(2011), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Chard-Hutchinson, Xavier, and Infrastructures - Réseau de Centres de Ressources Biologiques pour les animaux domestiques - - CRB-Anim2011 - ANR-11-INBS-0003 - INBS - VALID
Subjects: 0301 basic medicine, Cancer Research, Lymphoma, B-Cell, Oncogene Proteins, Oncogene Proteins, Fusion, Blotting, Western, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Bioinformatics, Translocation, Genetic, Fusion gene, 03 medical and health sciences, Chromosome Breakpoints, 0302 clinical medicine, Dogs, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, Fusions, medicine, Animals, Humans, cancer, Oncogene Fusion, Dog Diseases, Gene, Regulation of gene expression, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, business.industry, Reverse Transcriptase Polymerase Chain Reaction, Cancer, Glioma, medicine.disease, 3. Good health, Lymphoma, Gene Expression Regulation, Neoplastic, spontaneous model, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, dog, Personalized medicine, business
Abstract: Canine cancers represent a tremendous natural resource due to their incidence and striking similarities to human cancers, sharing similar clinical and pathologic features as well as oncogenic events, including identical somatic mutations. Considering the importance of gene fusions as driver alterations, we explored their relevance in canine cancers. We focused on three distinct human-comparable canine cancers representing different tissues and embryonic origins. Through RNA-Seq, we discovered similar gene fusions as those found in their human counterparts: IGK-CCND3 in B-cell lymphoma, MPB-BRAF in glioma, and COL3A1-PDGFB in dermatofibrosarcoma protuberans-like. We showed not only similar partner genes but also identical breakpoints leading to oncogene overexpression. This study demonstrates similar gene fusion partners and mechanisms in human–dog corresponding tumors and allows for selection of targeted therapies in preclinical and clinical trials with pet dogs prior to human trials, within the framework of personalized medicine. Cancer Res; 77(21); 5721–7. ©2017 AACR.
Published: 2017
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25. Re-annotation, improved large-scale assembly and establishment of a catalogue of noncoding loci for the genome of the model brown alga Ectocarpus

Author: Erwan Corre, Yves Van de Peer, Valentin Wucher, Misharl Monsoor, Christophe Hitte, Susana M. Coelho, Lieven Sterck, Alexandre Cormier, Agnieszka P. Lipinska, Thomas Derrien, J. Mark Cock, Marie-Mathilde Perrineau, Komlan Avia, Olivier Godfroy, Gwendoline Andres, Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique, ANR-10-BLAN-1727, Agence Nationale de la Recherche, Université Pierre et Marie Curie, 638240, European Research Council, ANR-12-JSV7-0008, Sexseaweed, Brittany Region, Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University (UGENT), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), ABiMS - Informatique et bioinformatique = Analysis and Bioinformatics for Marine Science (ABIMS), Fédération de recherche de Roscoff (FR2424), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Region Bretagne, ANR-10-BTBR-0001,AMAIZING,Développer de nouvelles variétés de maïs pour une agriculture durable: une approche intégrée de la génomique à la sélection(2010), European Project: 638240,H2020,ERC-2014-STG,SEXSEA(2015), Universiteit Gent = Ghent University [Belgium] (UGENT), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), ABiMS - Informatique et bioinformatique = Analysis and Bioinformatics for Marine Science (FR2424), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Department of Plant Systems Biology, State University of Ghent, Department of Plant Biotechnology and Bioinformatics, Ghent University [Belgium] (UGENT), Bioinformatics institute Ghent, and University of Pretoria [South Africa]
Subjects: 0301 basic medicine, Physiology, [SDV]Life Sciences [q-bio], Brown algae, Library science, Plant Science, Genome, Viral, Biology, Phaeophyta, Genome, Models, Biological, Chromosomes, Plant, Marie curie, 03 medical and health sciences, Annotation, reannotation, Databases, Genetic, long noncoding RNAs, Saccharina japonica, ComputingMilieux_MISCELLANEOUS, Conserved Sequence, Genetics, European research, Algal Proteins, Molecular Sequence Annotation, genome reannotation, Ectocarpus, biology.organism_classification, Stramenopile, 030104 developmental biology, Genetic Loci, Long non-coding RNAs, Genetic markers, DNA, Intergenic, RNA, Long Noncoding, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, Alternative splicing
Abstract: International audience; The genome of the filamentous brown alga Ectocarpus was the first to be completely sequenced from within the brown algal group and has served as a key reference genome both for this lineage and for the stramenopiles. We present a complete structural and functional reannotation of the Ectocarpus genome. The large-scale assembly of the Ectocarpus genome was significantly improved and genome-wide gene re-annotation using extensive RNA-seq data improved the structure of 11 108 existing protein-coding genes and added 2030 new loci. A genome-wide analysis of splicing isoforms identified an average of 1.6 transcripts per locus. A large number of previously undescribed noncoding genes were identified and annotated, including 717 loci that produce long noncoding RNAs. Conservation of lncRNAs between Ectocarpus and another brown alga, the kelp Saccharina japonica, suggests that at least a proportion of these loci serve a function. Finally, a large collection of single nucleotide polymorphism-based markers was developed for genetic analyses. These resources are available through an updated and improved genome database.This study significantly improves the utility of the Ectocarpus genome as a high-quality reference for the study of many important aspects of brown algal biology and as a reference for genomic analyses across the stramenopiles.
Published: 2017
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26. Erratum to: Bioinformatics Pipeline for Transcriptome Sequencing Analysis

Author: Sarah Djebali, Sylvain Foissac, Erwan Corre, Valentin Wucher, Christophe Hitte, and Thomas Derrien
Subjects: Pipeline (computing), Biology, Bioinformatics, Illumina dye sequencing, Transcriptome Sequencing
Published: 2016
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27. Genomic and archaeological evidence suggest a dual origin of domestic dogs

Author: Ophélie Lebrasseur, Maud Pionnier-Capitan, Anna Linderholm, Anne Tresset, Catherine Hänni, Sandrine Hughes, Éva Ágnes Nyerges, Matthew D. Teasdale, Olivier Chassaing, Evangelos A. Dimopoulos, Victoria E. Mullin, Valeria Mattiangeli, Erika Gál, Morgane Ollivier, László Bartosiewicz, Angela R. Perri, Greger Larson, Daniel G. Bradley, Benjamin Gillet, Laurent A. F. Frantz, Mikhail V. Sablin, Marilyne Duffraisse, Jean-Denis Vigne, Marjan Mashkour, Finbar McCormick, Stéphanie Bréhard, Christophe Hitte, Adrian Bălăşescu, Keith Dobney, University of Oxford, Trinity College Dublin, Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Archéozoologie, archéobotanique : sociétés, pratiques et environnements (AASPE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute for Evolutionary Anthropology [Leipzig], Max-Planck-Gesellschaft, Texas A&M University [College Station], Aristotle University of Thessaloniki, Queen's University [Belfast] (QUB), Stockholm University, Hungarian Academy of Sciences (MTA), Zoological Institute of Russian Academy of Sciences, Russian Academy of Sciences [Moscow] (RAS), National Museum of Romanian History, Centre National de Recherches Pluridisciplinaires, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Archaeology, University of Aberdeen, University of Aberdeen, 295729-CodeX, H2020 European Research Council, NE/K003259/1, Natural Environment Research Council, PN-II-ID-PCE-2011-3-1015, Autoritatea Natională pentru Cercetare Stiintifică, Junior Research Fellowship, BDI CNRS, University of Oxford [Oxford], École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Max Planck Institute for Evolutionary Anthropology, and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0106 biological sciences, 0301 basic medicine, Mitochondrial DNA, Human Migration, [SDV]Life Sciences [q-bio], Zoology, Dual (grammatical number), DNA, Mitochondrial, 010603 evolutionary biology, 01 natural sciences, 03 medical and health sciences, Dogs, Phylogenetics, Animals, East Asia, Domestication, Phylogeny, Wolves, Multidisciplinary, Asia, Eastern, Human migration, business.industry, Haplotype, Genomics, Europe, 030104 developmental biology, Geography, Archaeology, Haplotypes, Animals, Domestic, business, Far East
Abstract: A dogged investigation of domestication The history of how wolves became our pampered pooches of today has remained controversial. Frantz et al. describe high-coverage sequencing of the genome of an Irish dog from the Bronze Age as well as ancient dog mitochondrial DNA sequences. Comparing ancient dogs to a modern worldwide panel of dogs shows an old, deep split between East Asian and Western Eurasian dogs. Thus, dogs were domesticated from two separate wolf populations on either side of the Old World. Science , this issue p. 1228
Published: 2016
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28. A radiation hybrid map of the European sea bass (Dicentrarchus labrax) based on 1581 markers: Synteny analysis with model fish genomes

Author: Christophe Hitte, Richard Guyon, Naoual Sadequi, Francis Galibert, Michaelle Rakotomanga, Filip Volckaert, Fabrice Senger, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Interactions cellulaires et moléculaires (ICM), Laboratory of Animal Diversity and Systematics, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), De Villemeur, Hervé, and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0106 biological sciences, Sea bass, MESH: Radiation Hybrid Mapping, MESH: Genetic Markers, 01 natural sciences, Genome, MESH: Animals, Genetics, 0303 health sciences, Gene map, MESH: Genomics, Chromosome Mapping, MESH: Synteny, Genomics, MESH: Models, Animal, Mapping, Radiation Chimera, Models, Animal, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Bass, Female, Genetic Markers, RH-panel, MESH: Radiation Chimera, Quantitative trait locus, Biology, Synteny, Perciformes, Cell Line, 03 medical and health sciences, Gene mapping, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, MESH: Genome, 14. Life underwater, 030304 developmental biology, Comparative genomics, Radiation Hybrid Mapping, Tetraodontiformes, biology.organism_classification, MESH: Male, MESH: Tetraodontiformes, MESH: Cell Line, Bass, sense organs, MESH: Chromosome Mapping, MESH: Female, 010606 plant biology & botany
Abstract: International audience; The selective breeding of fish for aquaculture purposes requires the understanding of the genetic basis of traits such as growth, behaviour, resistance to pathogens and sex determinism. Access to well-developed genomic resources is a prerequisite to improve the knowledge of these traits. Having this aim in mind, a radiation hybrid (RH) panel of European sea bass (Dicentrarchus labrax) was constructed from splenocytes irradiated at 3000 rad, allowing the construction of a 1581 marker RH map. A total of 1440 gene markers providing ~4400 anchors with the genomes of three-spined stickleback, medaka, pufferfish and zebrafish, helped establish synteny relationships with these model species. The identification of Conserved Segments Ordered (CSO) between sea bass and model species allows the anticipation of the position of any sea bass gene from its location in model genomes. Synteny relationships between sea bass and gilthead seabream were addressed by mapping 37 orthologous markers. The sea bass genetic linkage map was integrated in the RH map through the mapping of 141 microsatellites. We are thus able to present the first complete gene map of sea bass. It will facilitate linkage studies and the identification of candidate genes and Quantitative Trait Loci (QTL). The RH map further positions sea bass as a genetic and evolutionary model of Perciformes and supports their ongoing aquaculture expansion.
Published: 2010
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29. Amy2B copy number variation reveals starch diet adaptations in ancient European dogs

Author: Adrian Bălăşescu, Erik Axelsson, Christophe Hitte, Mikhail V. Sablin, Marjan Marshour, Laure Salanova, Laetitia Lagoutte, Jean-Denis Vigne, Anne Tresset, Morgane Ollivier, Fabiola Bastian, Catherine Hänni, Maja Louise Arendt, Laboratoire d'Ecologie Alpine (LECA ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Archéozoologie, archéobotanique : sociétés, pratiques et environnements (AASPE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Science for Life Laboratory, Uppsala University-Department of Medical Biochemistry and Microbiology, Musée National d'Histoire de Bucarest (MNIR), MNIR, Zoological Institute of Russian Academy of Sciences, Russian Academy of Sciences [Moscow] (RAS), Archéologie et Philologie d'Orient et d'Occident (AOROC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Département des Sciences de l'Antiquité - ENS Paris (DSA ENS-PSL), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL), CNRS, crédits récurrents, Mairie de Bury, MCC, ENS Lyon, Nestlé Purina, CNCS-UEFISCDI, ZIN RAS, La sépulture de Bury - Oise, École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Ecologie Alpine (LECA), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Joseph Fourier - Grenoble 1 (UJF)-Université Grenoble Alpes (UGA), École normale supérieure - Paris (ENS Paris)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS)-Paris Sciences et Lettres (PSL), Paris Sciences et Lettres (PSL)-École normale supérieure - Paris (ENS Paris)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon)
Subjects: 0301 basic medicine, amylase, Zoology, Context (language use), Biology, Agrarian history, Zoologi, [SHS]Humanities and Social Sciences, 03 medical and health sciences, domestication, 0302 clinical medicine, Extant taxon, Dog, Genetics, Copy-number variation, Neolithic, Genetik, Domestication, lcsh:Science, Gene, Local adaptation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, Biology (Whole Organism), humanities, 030104 developmental biology, Human culture, neolithic, palaeogenomics, dog, lcsh:Q, Ploidy, 030217 neurology & neurosurgery, Research Article
Abstract: Extant dog and wolf DNA indicates that dog domestication was accompanied by the selection of a series of duplications on the Amy2B gene coding for pancreatic amylase. In this study, we used a palaeogenetic approach to investigate the timing and expansion of the Amy2B gene in the ancient dog populations of Western and Eastern Europe and Southwest Asia. Quantitative polymerase chain reaction was used to estimate the copy numbers of this gene for 13 ancient dog samples, dated to between 15 000 and 4000 years before present (cal. BP). This evidenced an increase of Amy2B copies in ancient dogs from as early as the 7th millennium cal. BP in Southeastern Europe. We found that the gene expansion was not fixed across all dogs within this early farming context, with ancient dogs bearing between 2 and 20 diploid copies of the gene. The results also suggested that selection for the increased Amy2B copy number started 7000 years cal. BP, at the latest. This expansion reflects a local adaptation that allowed dogs to thrive on a starch rich diet, especially within early farming societies, and suggests a biocultural coevolution of dog genes and human culture.
Published: 2016
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30. A Spontaneous KRT16 Mutation in a Dog Breed: A Model for Human Focal Non-Epidermolytic Palmoplantar Keratoderma (FNEPPK)

Author: Emmanuel Bensignor, Alain Fautrel, Pascale Bellaud, Frédérique Degorce-Rubiales, Catherine André, Caroline Dufaure de Citres, Éric Guaguère, Jocelyn Plassais, Amaury Vaysse, Guillaume Queney, Pascale Quignon, Christophe Hitte, Céline Bleuart, Anne-Sophie Guillory, Anne Thomas, Emmanuelle Bourrat, Maxence Delverdier, Laetitia Lagoutte, Cécile Kaerle, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Clinique Vétérinaire Saint Bernard, Laboratoire d'Anatomie Pathologique Vétérinaire du Sud-Ouest, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Cancer Genetics Branch, National Institute of Health (NIH)-National Human Genome Research Institute (NHGRI), Animal Genetics Laboratory, Antagene, Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Plate-forme d'histopathologie, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, Clinique Vétérinaire de la Boulais, Service de dermatologie [Paris], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Keratoderma, Palmoplantar, Diffuse, Male, 040301 veterinary sciences, [SDV]Life Sciences [q-bio], Dermatology, Biology, Keratin 16, Real-Time Polymerase Chain Reaction, Biochemistry, 0403 veterinary science, Immunoenzyme Techniques, 03 medical and health sciences, Exon, Focal Non-Epidermolytic Palmoplantar Keratoderma, Dogs, Species Specificity, medicine, Animals, Humans, RNA, Messenger, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Papilloma, Keratin-16, 04 agricultural and veterinary sciences, Exons, Cell Biology, medicine.disease, Molecular biology, Immunohistochemistry, Breed, Disease Models, Animal, Real-time polymerase chain reaction, Microscopy, Fluorescence, Mutation (genetic algorithm), Mutation, Female
Abstract: International audience
Published: 2015
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31. Construction of a 2-Mb resolution BAC microarray for CGH analysis of canine tumors

Author: Cordelia Langford, Jaime F. Modiano, Elaine A. Ostrander, Susan Fosmire, Ewen F. Kirkness, Matthew Breen, Francis Galibert, Rachael Thomas, A. Scott, Christophe Hitte, Travis D. Lorentzen, Kerstin Lindblad-Toh, Cristan M. Jubala, and Elinor K. Karlsson
Subjects: Genetics, Chromosomes, Artificial, Bacterial, Genomic Library, Osteosarcoma, medicine.medical_specialty, medicine.diagnostic_test, Cytogenetics, Nucleic Acid Hybridization, Chromosome, Genomics, Biology, Genome, DNA sequencing, Dogs, Cell Line, Tumor, medicine, Animals, Genomic library, Dog Special/Resources, Cloning, Molecular, In Situ Hybridization, Fluorescence, Genetics (clinical), Fluorescence in situ hybridization, Comparative genomic hybridization
Abstract: Recognition of the domestic dog as a model for the comparative study of human genetic traits has led to major advances in canine genomics. The pathophysiological similarities shared between many human and dog diseases extend to a range of cancers. Human tumors frequently display recurrent chromosome aberrations, many of which are hallmarks of particular tumor subtypes. Using a range of molecular cytogenetic techniques we have generated evidence indicating that this is also true of canine tumors. Detailed knowledge of these genomic abnormalities has the potential to aid diagnosis, prognosis, and the selection of appropriate therapy in both species. We recently improved the efficiency and resolution of canine cancer cytogenetics studies by developing a small-scale genomic microarray comprising a panel of canine BAC clones representing subgenomic regions of particular interest. We have now extended these studies to generate a comprehensive canine comparative genomic hybridization (CGH) array that comprises 1158 canine BAC clones ordered throughout the genome with an average interval of 2 Mb. Most of the clones (84.3%) have been assigned to a precise cytogenetic location by fluorescence in situ hybridization (FISH), and 98.5% are also directly anchored within the current canine genome assembly, permitting direct translation from cytogenetic aberration to DNA sequence. We are now using this resource routinely for high-throughput array CGH and single-locus probe analysis of a range of canine cancers. Here we provide examples of the varied applications of this resource to tumor cytogenetics, in combination with other molecular cytogenetic techniques.
Published: 2005
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32. Le chien, un modèle pour la génétique des mammifères

Author: Francis Galibert, Christophe Hitte, and Catherine André
Subjects: Geography, Animal model, General Medicine, Humanities, General Biochemistry, Genetics and Molecular Biology
Abstract: Tous les chiens modernes seraient issus de la domestication des loups qui remonterait à environ 15 000 ans et proviendraient d’un nombre limité de loups femelles d’Asie orientale. Par des pratiques intensives de sélections et de croisements consanguins, l’homme a créé plus de 350 races ; si chacune représente un véritable isolat génétique, elles offrent, toutes réunies, un ensemble inégalé de polymorphismes. Cette revue recense les raisons faisant du chien un modèle irremplaçable. À l’inverse des modèles classiques utilisés pour l’analyse de la fonction des gènes, le chien offre en effet, avec ses très nombreuses races, une opportunité unique pour l’étude des allèles. Cet article présente également les données récentes obtenues dans la construction de cartes génomiques et dans le programme de séquençage du génome du chien, financé par le National Institute of Health (NIH), et rapporte que, parallèlement au séquençage, une analyse du polymorphisme génétique est indispensable pour profiter au mieux des avantages de ce modèle., Up to recently, studies on dog genetics were rather scare notwithstanding the enormous potential that the canine model can offer in the study of the genotype/phenotype relationship and the analysis of the causes of many genetic diseases, with simple or complex inheritance, that affect dogs but also the human population. This potentiality is essentially due to the natural history of dogs whose domestication from wolves dated back 15,000 years, at least. All modern dogs originated from a limited number of female wolves from Eastern Asia. By applying a combination of selections and strong inbreeding practices, humans have created over 350 breeds, each of them corresponding to a genetic isolate and altogether offering a unique panel of polymorphism never encountered in any other mammals. In this review we summarized what makes dogs an unavoidable model. Contrary to the classical models like the two yeasts, nematode, fish, fly, mouse, or rat mainly used to understand the function of genes, dog with the creation across the centuries of numerous breeds offers a unique opportunity to study the role of their alleles. We report recent data on the construction of genomic maps and on the sequencing program of the dog genome launched by the National Institute of Health (NIH). To take fully advantage of the canine model, we advocate for the systematic construction of a rich canine single nucleotide polymorphisms (SNP) ressource to perform linkage desiquilibrium studies of normal or pathological traits as well as to get insight into the genetic diversity of the canine species.
Published: 2004
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33. A 1-Mb resolution radiation hybrid map of the canine genome

Author: Lisa Kim, Travis D. Lorentzen, Pascale Quignon, Francis Galibert, Christophe Hitte, Heidi G. Parker, Richard Guyon, Elaine A. Ostrander, Hawkins B. DeFrance, Corinne Renier, Boris Gelfenbeyn, Françoise Vignaux, Jennifer K. Lowe, Edouard Cadieu, Stéphanie Gloux, Gregory G. Mahairas, and Catherine André
Subjects: Expressed Sequence Tags, Genetics, Chromosomes, Artificial, Bacterial, Expressed sequence tag, Candidate gene, education.field_of_study, Bacterial artificial chromosome, Genome, Multidisciplinary, Population, Computational biology, Biological Sciences, Hybrid Cells, Biology, Polymorphism, Single Nucleotide, Dogs, Cricetinae, Animals, Human genome, education, Gene, Microsatellite Repeats, Synteny
Abstract: The purebred dog population consists of >300 partially inbred genetic isolates or breeds. Restriction of gene flow between breeds, together with strong selection for traits, has led to the establishment of a unique resource for dissecting the genetic basis of simple and complex mammalian traits. Toward this end, we present a comprehensive radiation hybrid map of the canine genome composed of 3,270 markers including 1,596 microsatellite-based markers, 900 cloned gene sequences and ESTs, 668 canine-specific bacterial artificial chromosome (BAC) ends, and 106 sequence-tagged sites. The map was constructed by using the RHDF5000-2 whole-genome radiation hybrid panel and computed by using multimap and tsp/concorde . The 3,270 markers map to 3,021 unique positions and define an average intermarker distance corresponding to 1 Mb. We also define a minimal screening set of 325 highly informative well spaced markers, to be used in the initiation of genome-wide scans. The well defined synteny between the dog and human genomes, established in part as a function of this work by the identification of 85 conserved fragments, will allow follow-up of initial findings of linkage by selection of candidate genes from the human genome sequence. This work continues to define the canine system as the method of choice in the pursuit of the genes causing mammalian variation and disease.
Published: 2003
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34. Improved canine exome designs, featuring ncRNAs and increased coverage of protein coding genes

Author: Ingrid Gielen, Frank Coopman, Jimmy Saunders, Dieter Deforce, Bernadette Van Ryssen, Jessica Alföldi, Thomas Derrien, Bart J. G. Broeckx, Christophe Hitte, Filip Van Nieuwerburgh, Tim Bosmans, Geert E. C. Verhoeven, Sarah De Keulenaer, Henri van Bree, Kerstin Lindblad-Toh, Ellen De Meester, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Science for Life Laboratory, Uppsala University-Department of Medical Biochemistry and Microbiology, and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Untranslated region, RNA, Untranslated, [SDV]Life Sciences [q-bio], Genomics, Biology, Genome, SEQUENCE, Article, Deep sequencing, 03 medical and health sciences, Dogs, 0302 clinical medicine, DOG, Animals, Ensembl, Exome, Gene, Exome sequencing, Medicinsk genetik, 030304 developmental biology, Genetics, Base Composition, 0303 health sciences, Multidisciplinary, Genetic Variation, High-Throughput Nucleotide Sequencing, Proteins, Reproducibility of Results, Biology and Life Sciences, PERFORMANCE, GENOME, Medical Genetics, 030217 neurology & neurosurgery
Abstract: By limiting sequencing to those sequences transcribed as mRNA, whole exome sequencing is a cost-efficient technique often used in disease-association studies. We developed two target enrichment designs based on the recently released annotation of the canine genome: the exome-plus design and the exome-CDS design. The exome-plus design combines the exons of the CanFam 3.1 Ensembl annotation, more recently discovered protein-coding exons and a variety of non-coding RNA regions (microRNAs, long non-coding RNAs and antisense transcripts), leading to a total size of ≈152 Mb. The exome-CDS was designed as a subset of the exome-plus by omitting all 3’ and 5’ untranslated regions. This reduced the size of the exome-CDS to ≈71 Mb. To test the capturing performance, four exome-plus captures were sequenced on a NextSeq 500 with each capture containing four pre-capture pooled, barcoded samples. At an average sequencing depth of 68.3x, 80% of the regions and well over 90% of the targeted base pairs were completely covered at least 5 times with high reproducibility. Based on the performance of the exome-plus, we estimated the performance of the exome-CDS. Overall, these designs provide flexible solutions for a variety of research questions and are likely to be reliable tools in disease studies.
Published: 2015
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35. A COLQ Missense Mutation in Sphynx and Devon Rex Cats with Congenital Myasthenic Syndrome

Author: Anne Thomas, Christophe Hitte, Laurent Tiret, Nicolas Blanchard-Gutton, Lionel Martignat, Stéphane Blot, Marie Abitbol, Philippe Bossé, Génétique Moléculaire et Cellulaire (UGMC), École nationale vétérinaire - Alfort (ENVA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris-Est Marne-la-Vallée (UPEM), UPR de neurobiologie, École nationale vétérinaire - Alfort (ENVA), Animal Genetics Laboratory, Antagene, Immuno-Endocrinologie Cellulaire et Moléculaire (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), LOOF (Livre Officiel des Origines Felines), Morris Animal Foundation D14FE-563, École nationale vétérinaire d'Alfort (ENVA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École nationale vétérinaire d'Alfort (ENVA), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Ecole Nationale Vétérinaire de Nantes-Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), and Abitbol, Marie
Subjects: Candidate gene, [SDV]Life Sciences [q-bio], Molecular Sequence Data, biology.animal_breed, Mutation, Missense, Muscle Proteins, lcsh:Medicine, Sciences du Vivant, Species Specificity, COLQ, medicine, Animals, Missense mutation, lcsh:Science, Sphynx cat, Myasthenic Syndromes, Congenital, Genetics, Multidisciplinary, CATS, biology, lcsh:R, Life Sciences, Congenital myasthenic syndrome, medicine.disease, Disease gene identification, Acetylcholinesterase, Cats, lcsh:Q, Research Article, Founder effect
Abstract: International audience; An autosomal recessive neuromuscular disorder characterized by skeletal muscle weakness, fatigability and variable electromyographic or muscular histopathological features has been described in the two related Sphynx and Devon Rex cat breeds (Felis catus). Collection of data from two affected Sphynx cats and their relatives pointed out a single disease candidate region on feline chromosome C2, identified following a genome-wide SNP-based homozygosity mapping strategy. In that region, we further identified COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase) as a good candidate gene, since COLQ mutations were identified in affected humans and dogs with endplate acetylcholinesterase deficiency leading to a synaptic form of congenital myasthenic syndrome (CMS). A homozygous c.1190G\textgreaterA missense variant located in exon 15 of COLQ, leading to a C397Y substitution, was identified in the two affected cats. C397 is a highly-conserved residue from the C-terminal domain of the protein; its mutation was previously shown to produce CMS in humans, and here we confirmed in an affected Sphynx cat that it induces a loss of acetylcholinesterase clustering at the neuromuscular junction. Segregation of the c.1190G\textgreaterA variant was 100% consistent with the autosomal recessive mode of inheritance of the disorder in our cat pedigree; in addition, an affected, unrelated Devon Rex cat recruited thereafter was also homozygous for the variant. Genotyping of a panel of 333 cats from 14 breeds failed to identify a single carrier in non-Sphynx and non-Devon Rex cats. Finally, the percentage of healthy carriers in a European subpanel of 81 genotyped Sphynx cats was estimated to be low (3.7%) and 14 control Devon Rex cats were genotyped as wild-type individuals. Altogether, these results strongly support that the neuromuscular disorder reported in Sphynx and Devon Rex breeds is a CMS caused by a unique c.1190G\textgreaterA missense mutation, presumably transmitted through a founder effect, which strictly and slightly disseminated in these two breeds. The presently available DNA test will help owners avoid matings at risk.
Published: 2015
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36. Toward a dog radiation hybrid map

Author: Christophe Hitte, Zhihua Jiang, Françoise Vignaux, Catherine Priat, Angélique Chéron, Corinne Renier, S Jouquand, Catherine André, and Francis Galibert
Subjects: Male, Biopsy, Hybrid Cells, Biology, Polymerase Chain Reaction, Genome, law.invention, Sequence-tagged site, Dogs, law, Genetic linkage, Cricetinae, Genetics, Animals, Humans, Genomic library, Molecular Biology, Gene, Genetics (clinical), Polymerase chain reaction, Gene Library, Sequence Tagged Sites, Expressed Sequence Tags, Expressed sequence tag, Chromosome Mapping, Sequence Analysis, DNA, Fibroblasts, Coculture Techniques, Microsatellite, Microsatellite Repeats, Biotechnology
Abstract: Dog fibroblasts grown from a biopsy performed in a male mongrel were fused after gamma irradiation with thymidine kinase-deficient hamster cells and cultivated in selection medium. A total of 148 clones were obtained and screened by means of PCR amplification using primers corresponding to a dog-specific short repetitive element and to dog microsatellites and genes. One hundred seven cell lines were selected and grown in roller bottles and the distribution of 39 markers was analyzed in the extracted DNA. The results clearly indicate that this panel of hybrid cell lines should prove invaluable for constructing a map of the canine genome. In parallel, for more than 500 microsatellites present in the databases or screened from two libraries of short inserts, we have determined PCR conditions favoring dog-specific products even in the presence of hamster DNA. These highly polymorphic microsatellites should be useful in further linkage studies. We have also characterized 254 markers: dog genes, human expressed sequenced tags (huESTs), and traced orthologous amplified sequenced tags (TOASTs). Once mapped, these will constitute powerful tools to detect regions of conserved synteny in human and other mammalian genomes.
Published: 1999
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37. Autosomal Recessive Ichthyosis in Golden Retriever Dogs: Distribution and Frequency of thePnpla1Mutant Allele in Different Populations

Author: Guillaume Queney, Catherine André, Christophe Hitte, Jacques Fontaine, Anais Grall, Emmanuel Bensignor, Emmanuelle Bourrat, Éric Guaguère, Didier Pin, F. Degorce‐Rubiales, Laetitia Lagoutte, and Anne Thomas
Subjects: Genetics, 0303 health sciences, Pathology, medicine.medical_specialty, 040301 veterinary sciences, Mutant allele, Autosomal recessive ichthyosis, Golden Retriever, 04 agricultural and veterinary sciences, Biology, 0403 veterinary science, 03 medical and health sciences, medicine, Distribution (pharmacology), Abnormal desquamation, 030304 developmental biology
Published: 2013
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38. CRH_Server: an online comparative and radiation hybrid mapping server for the canine genome

Author: Francis Galibert, Thomas Derrien, Elaine A. Ostrander, Christophe Hitte, and Catherine André
Subjects: Statistics and Probability, Genetics, Internet, Adjuvant chemotherapy, DNA Mutational Analysis, Chromosome Mapping, Sequence Analysis, DNA, Biology, computer.software_genre, Online Systems, Biochemistry, Computer Science Applications, User-Computer Interface, Computational Mathematics, Dogs, Computational Theory and Mathematics, Operating system, Canine genome, Animals, Radiation hybrid mapping, Sequence Alignment, Molecular Biology, computer, Algorithms, Software
Abstract: Summary: CRH_Server is an on line Comparative and Radiation Hybrid mapping Server dedicated to canine genomics. CRH_Server allows users to compute their own RH data using the current canine RH map, and allows comparative dog/human mapping analyses. Finally, it suggests multiple options for storage and queries of the dog RH database. Availability: http://idefix.univ-rennes1.fr:8080/Dogs/rh-server.html Supplementary information: All information is available at http://idefix.univ-rennes1.fr:8080/Dogs/help_rh-server.html
Published: 2004
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39. Evidence of coat color variation sheds new light on ancient canids

Author: Sandrine Hughes, Anne Tresset, Maud Pionnier-Capitan, Adrian Bălăşescu, Coraline Petit, Marjan Mashkour, Morgane Ollivier, Adina Boroneant, Marilyne Duffraisse, Rose-Marie Arbogast, Christophe Hitte, Benjamin Gillet, Catherine Hänni, Jean-Denis Vigne, Laetitia Lagoutte, Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Archéozoologie, archéobotanique : sociétés, pratiques et environnements (AASPE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Maison Interuniversitaire des Sciences de l'Homme - Alsace (MISHA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), National Museum of Romanian History, Centre National de Recherches Pluridisciplinaires, Institute of Archaeology Vasile Parvan, PALGENE, the French National Platform of Paleogenetics, École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: 0106 biological sciences, Coat, Molecular Sequence Data, lcsh:Medicine, Zoology, Locus (genetics), Biology, 010603 evolutionary biology, 01 natural sciences, DNA, Mitochondrial, 03 medical and health sciences, Dogs, Animals, lcsh:Science, Domestication, Hair Color, Alleles, 030304 developmental biology, 0303 health sciences, Genetic diversity, Multidisciplinary, Wolves, Melanism, [SDV.BA]Life Sciences [q-bio]/Animal biology, lcsh:R, Paleogenetics, Ancient DNA, Mutation, lcsh:Q, Gene pool, Research Article
Abstract: International audience; We have used a paleogenetics approach to investigate the genetic landscape of coat color variation in ancient Eurasian dog and wolf populations. We amplified DNA fragments of two genes controlling coat color, Mc1r (Melanocortin 1 Receptor) and CBD103 (canine-β-defensin), in respectively 15 and 19 ancient canids (dogs and wolf morphotypes) from 14 different archeological sites, throughout Asia and Europe spanning from ca. 12 000 B.P. (end of Upper Palaeolithic) to ca. 4000 B.P. (Bronze Age). We provide evidence of a new variant (R301C) of the Melanocortin 1 receptor (Mc1r) and highlight the presence of the beta-defensin melanistic mutation (CDB103-K locus) on ancient DNA from dog-and wolf-morphotype specimens. We show that the dominant K(B) allele (CBD103), which causes melanism, and R301C (Mc1r), the variant that may cause light hair color, are present as early as the beginning of the Holocene, over 10 000 years ago. These results underline the genetic diversity of prehistoric dogs. This diversity may have partly stemmed not only from the wolf gene pool captured by domestication but also from mutations very likely linked to the relaxation of natural selection pressure occurring in-line with this process.
Published: 2013
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40. Novel origins of copy number variation in the dog genome

Author: Christophe Hitte, Michael C. Zody, Michele Perloski, Jonas Berglund, Matthew T. Webster, Hannes Lohi, Ted Sharpe, Elisa M. Nevalainen, Anna-Maja Molin, Catherine André, Kerstin Lindblad-Toh, Science for Life Laboratory, Uppsala University-Department of Medical Biochemistry and Microbiology, Department of Basic Veterinary Biosciences, HMNC Brain Health-Biomedicum Helsinki-Folkhälsan Institute of Genetics, Department of Animal Bredding and Genetics, Swedish University of Agricultural Sciences (SLU), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), The LUPA consortium (lupa) (marilou.ramospamplona@ULG.AC.BE), European Project: 201370,EC:FP7:HEALTH,FP7-HEALTH-2007-A,LUPA(2008), De Villemeur, Hervé, Unravelling the molecular basis of common complex human disorders using the dog as a model system - LUPA - - EC:FP7:HEALTH2008-01-01 - 2012-06-30 - 201370 - VALID, and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Male, 0106 biological sciences, Genome instability, DNA Copy Number Variations, Genotype, Breeding, Biology, 01 natural sciences, Genome, Genomic Instability, Structural variation, 03 medical and health sciences, Dogs, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Naturvetenskap, Animals, Copy-number variation, Gene, PRDM9, 030304 developmental biology, Genetics, Comparative Genomic Hybridization, 0303 health sciences, Research, Reproducibility of Results, Phenotype, Genetic Loci, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Natural Sciences, GC-content, 010606 plant biology & botany, Comparative genomic hybridization
Abstract: BACKGROUND: Copy number variants (CNVs) account for substantial variation between genomes and are a major source of normal and pathogenic phenotypic differences. The dog is an ideal model to investigate mutational mechanisms that generate CNVs as its genome lacks a functional ortholog of the PRDM9 gene implicated in recombination and CNV formation in humans. Here we comprehensively assay CNVs using high-density array comparative genomic hybridization in 50 dogs from 17 dog breeds and 3 gray wolves. RESULTS: We use a stringent new method to identify a total of 430 high-confidence CNV loci, which range in size from 9 kb to 1.6 Mb and span 26.4 Mb, or 1.08%, of the assayed dog genome, overlapping 413 annotated genes. Of CNVs observed in each breed, 98% are also observed in multiple breeds. CNVs predicted to disrupt gene function are significantly less common than expected by chance. We identify a significant overrepresentation of peaks of GC content, previously shown to be enriched in dog recombination hotspots, in the vicinity of CNV breakpoints. CONCLUSIONS: A number of the CNVs identified by this study are candidates for generating breed-specific phenotypes. Purifying selection seems to be a major factor shaping structural variation in the dog genome, suggesting that many CNVs are deleterious. Localized peaks of GC content appear to be novel sites of CNV formation in the dog genome by non-allelic homologous recombination, potentially activated by the loss of PRDM9. These sequence features may have driven genome instability and chromosomal rearrangements throughout canid evolution. Additional author: The LUPA Consortium (www.eurolupa.org)
Published: 2012
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41. A high-resolution map of the Nile tilapia genome: a resource for studying cichlids and other percomorphs

Author: Helena D'Cotta, Nikkie E. M. Van Bers, Jean-François Baroiller, Richard Guyon, Jean Pierre Coutanceau, Thomas D. Kocher, Matthew A. Conte, Lucile Soler, Naoual Azzouzi, Francis Galibert, Marguerite Rodier-Goud, Angélique D'Hont, Christophe Hitte, Céline Bonillo, Michaelle Rakotomanga, Richard P. M. A. Crooijmans, David J. Penman, Elodie Pepey, Catherine Ozouf-Costaz, Galibert, Francis, Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Intensification raisonnée et écologique pour une pisciculture durable (UMR INTREPID), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Department of Biology, University of Maryland [College Park], University of Maryland System-University of Maryland System, Animal Breeding and Genomics Centre, Wageningen University and Research [Wageningen] (WUR), Institute of Aquaculture, University of Stirling, Systématique, adaptation, évolution (SAE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), This work was supported by grant to COC, JFB and CH (ANR-07-GANI-005) from ANR (Agence Nationale de la Recherche, France)., ANR-07-GANI-0005,PERCIMAP,Construction of a high-density Tilapia RH map(2007), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro), Wageningen University and Research Centre [Wageningen] (WUR), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), ANR-07-GANI-0005,GANI,Construction of a high-density Tilapia RH map(2007), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), De Villemeur, Hervé, and Genanimal - Construction of a high-density Tilapia RH map - - PERCIMAP2007 - ANR-07-GANI-0005 - GANI - VALID
Subjects: tetraodon-nigroviridis, 0106 biological sciences, Chromosomes, Artificial, Bacterial, oreochromis-niloticus, Genetic Linkage, tilapia, Polymorphisme génétique, sex determination, 01 natural sciences, Genome, Nile tilapia, poisson d'élevage, Marqueur génétique, évolution, Expressed Sequence Tags, Genetics, Comparative Genomic Hybridization, 0303 health sciences, Expressed sequence tag, biology, Oreochromis niloticus, Chromosome Mapping, Cichlids, genetic-linkage map, Oreochromis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Research Article, Biotechnology, construction, Locus des caractères quantitatifs, lcsh:QH426-470, Genotype, Perciformes (199XXXXXXX013), lcsh:Biotechnology, Fish farming, Animal Breeding and Genomics, Quantitative trait locus, Polymorphism, Single Nucleotide, 010603 evolutionary biology, 03 medical and health sciences, Fish physiology, lcsh:TP248.13-248.65, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], evolution, Animals, Fokkerij en Genomica, 14. Life underwater, 030304 developmental biology, Génie génétique, fish, Radiation Hybrid Mapping, génome, Microsatellite, sequence, L10 - Génétique et amélioration des animaux, biology.organism_classification, radiation hybrid map, Haplochromine, lcsh:Genetics, Evolutionary biology, cartographie du génome, Carte génétique, WIAS, M12 - Production de l'aquaculture, zebrafish genome, cichlidae, Microsatellite Repeats
Abstract: Background The Nile tilapia (Oreochromis niloticus) is the second most farmed fish species worldwide. It is also an important model for studies of fish physiology, particularly because of its broad tolerance to an array of environments. It is a good model to study evolutionary mechanisms in vertebrates, because of its close relationship to haplochromine cichlids, which have undergone rapid speciation in East Africa. The existing genomic resources for Nile tilapia include a genetic map, BAC end sequences and ESTs, but comparative genome analysis and maps of quantitative trait loci (QTL) are still limited. Results We have constructed a high-resolution radiation hybrid (RH) panel for the Nile tilapia and genotyped 1358 markers consisting of 850 genes, 82 markers corresponding to BAC end sequences, 154 microsatellites and 272 single nucleotide polymorphisms (SNPs). From these, 1296 markers could be associated in 81 RH groups, while 62 were not linked. The total size of the RH map is 34,084 cR3500 and 937,310 kb. It covers 88% of the entire genome with an estimated inter-marker distance of 742 Kb. Mapping of microsatellites enabled integration to the genetic map. We have merged LG8 and LG24 into a single linkage group, and confirmed that LG16-LG21 are also merged. The orientation and association of RH groups to each chromosome and LG was confirmed by chromosomal in situ hybridizations (FISH) of 55 BACs. Fifty RH groups were localized on the 22 chromosomes while 31 remained small orphan groups. Synteny relationships were determined between Nile tilapia, stickleback, medaka and pufferfish. Conclusion The RH map and associated FISH map provide a valuable gene-ordered resource for gene mapping and QTL studies. All genetic linkage groups with their corresponding RH groups now have a corresponding chromosome which can be identified in the karyotype. Placement of conserved segments indicated that multiple inter-chromosomal rearrangements have occurred between Nile tilapia and the other model fishes. These maps represent a valuable resource for organizing the forthcoming genome sequence of Nile tilapia, and provide a foundation for evolutionary studies of East African cichlid fishes.
Published: 2012
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42. Centronuclear myopathy in Labrador retrievers: a recent founder mutation in the PTPLA gene has rapidly disseminated worldwide

Author: Jean-Laurent Thibaud, Marilyn Fender, G. Diane Shelton, Manuel Pelé, Jean-Jacques Panthier, Geneviève Aubin-Houzelstein, Jacques Penderis, Marie Maurer, Jérôme Mary, Laurent Guillaud, Natasha J. Olby, Inès Barthélémy, Christophe Hitte, Stéphane Blot, Thomas Bilzer, Laurent Tiret, École nationale vétérinaire d'Alfort (ENVA), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CNM Project, Institut fur Neuropathologie, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], College of Veterinary Medicine, North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC)-University of North Carolina System (UNC), College of Medical Veterinary and Life Sciences, University of Glasgow, Department of Pathology [San Diego], University of California [San Diego] (UC San Diego), University of California-University of California, Génétique Moléculaire et Cellulaire (UGMC), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Génétique Fonctionnelle de la Souris, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), This work was funded by the CNM Project (www.labradorcnm.com), the French Association against Myopathies (AFM), a FP6 EuroTransBio Grant from the European Commission (Biomarks), the American Kennel Club-Canine Health Foundation and the Centre National de la Recherche Scientifique (CNRS), École nationale vétérinaire - Alfort (ENVA), Department of Pathology [Univ California San Diego] (UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Heinrich-Heine-Universität Düsseldorf [Düsseldorf], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), and Tiret, Laurent
Subjects: Myotubularin, MESH: Founder Effect, medicine.disease_cause, Muscular Dystrophies, MESH: Dogs, 0302 clinical medicine, Autosomal Recessive, MESH: Animals, Dog Diseases, Small Animals, Genetics, 0303 health sciences, Mutation, Multidisciplinary, myopathy, skeletal-muscle, domestic dog, Genomics, Animal Models, Neuromuscular Diseases, Veterinary Diagnostics, Founder Effect, Phenotype, Neurology, Medicine, Research Article, Myopathies, Structural, Congenital, Veterinary Medicine, medicine.medical_specialty, MESH: Mutation, MESH: Myopathies, Structural, Congenital, Science, Animal Types, MESH: Dog Diseases, Genes, Recessive, MESH: Protein Tyrosine Phosphatases, Biology, MESH: Phenotype, Veterinary Neurology, 03 medical and health sciences, Model Organisms, Dogs, Genomic Medicine, Genetic Mutation, Molecular genetics, Heredity, medicine, Animals, Allele, Centronuclear myopathy, Alleles, MESH: Genes, Recessive, 030304 developmental biology, Congenital Hereditary Myopathies, Clinical Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, MESH: Alleles, Haplotype, medicine.disease, myopathie centronucléaire, chien, Genetics of Disease, Veterinary Science, Gene Function, Protein Tyrosine Phosphatases, gène ptpla, Animal Genetics, 030217 neurology & neurosurgery, Founder effect
Abstract: Centronuclear myopathies (CNM) are inherited congenital disorders characterized by an excessive number of internalized nuclei. In humans, CNM results from ~70 mutations in three major genes from the myotubularin, dynamin and amphiphysin families. Analysis of animal models with altered expression of these genes revealed common defects in all forms of CNM, paving the way for unified pathogenic and therapeutic mechanisms. Despite these efforts, some CNM cases remain genetically unresolved. We previously identified an autosomal recessive form of CNM in French Labrador retrievers from an experimental pedigree, and showed that a loss-of-function mutation in the protein tyrosine phosphatase-like A (PTPLA) gene segregated with CNM. Around the world, client-owned Labrador retrievers with a similar clinical presentation and histopathological changes in muscle biopsies have been described. We hypothesized that these Labradors share the same PTPLAcnm mutation. Genotyping of an international panel of 7,426 Labradors led to the identification of PTPLAcnm carriers in 13 countries. Haplotype analysis demonstrated that the PTPLAcnm allele resulted from a single and recent mutational event that may have rapidly disseminated through the extensive use of popular sires. PTPLA-deficient Labradors will help define the integrated role of PTPLA in the existing CNM gene network. They will be valuable complementary large animal models to test innovative therapies in CNM.
Published: 2011
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43. LUPA: a European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs

Author: Michel Georges, Christophe Hitte, Anne-Sophie Lequarré, Merete Fredholm, Tosso Leeb, Catherine André, Hannes Lohi, Leif Andersson, Kerstin Lindblad-Toh, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), Université de Liège, Science for Life Laboratory, Uppsala University-Department of Medical Biochemistry and Microbiology, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Faculty of Life Sciences, Division of Genetics and Bioinformatics, Faculty of Life Science [Copenhagen], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Institute of Genetics, Vetsuisse Faculty-University of Bern, Folkhälsan Institute of Genetics, HMNC Brain Health-Department of Veterinary Biosciences-Program in Molecular Medicine-Biomedicum Helsinki, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], European Project: 201370,EC:FP7:HEALTH,FP7-HEALTH-2007-A,LUPA(2008), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), De Villemeur, Hervé, Unravelling the molecular basis of common complex human disorders using the dog as a model system - LUPA - - EC:FP7:HEALTH2008-01-01 - 2012-06-30 - 201370 - VALID, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)
Subjects: International Cooperation, ved/biology.organism_classification_rank.species, [SDV.GEN] Life Sciences [q-bio]/Genetics, Disease, Canine, 0403 veterinary science, MESH: Dogs, Human health, Single nucleotide polymorphism arrays, MESH: Animals, Dog Diseases, Genetics, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Polymorphism, Single Nucleotide, MESH: DNA, Chromosome Mapping, 04 agricultural and veterinary sciences, Pedigree, Europe, LUPA, Canine genome, 040301 veterinary sciences, MESH: Pedigree, MESH: Dog Diseases, High density, Single-nucleotide polymorphism, Computational biology, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Dogs, Animals, Humans, SNP, Inherited disorders, Model organism, 030304 developmental biology, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, General Veterinary, ved/biology, DNA, Disease Models, Animal, MESH: International Cooperation, MESH: Genome-Wide Association Study, Animal Science and Zoology, MESH: Europe, MESH: Disease Models, Animal, MESH: Chromosome Mapping, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract: International audience; The domestic dog offers a unique opportunity to explore the genetic basis of disease, morphology and behaviour. Humans share many diseases with our canine companions, making dogs an ideal model organism for comparative disease genetics. Using newly developed resources, genome-wide association studies in dog breeds are proving to be exceptionally powerful. Towards this aim, veterinarians and geneticists from 12 European countries are collaborating to collect and analyse the DNA from large cohorts of dogs suffering from a range of carefully defined diseases of relevance to human health. This project, named LUPA, has already delivered considerable results. The consortium has collaborated to develop a new high density single nucleotide polymorphism (SNP) array. Mutations for four monogenic diseases have been identified and the information has been utilised to find mutations in human patients. Several complex diseases have been mapped and fine mapping is underway. These findings should ultimately lead to a better understanding of the molecular mechanisms underlying complex diseases in both humans and their best friend.
Published: 2011
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44. Toward understanding dog evolutionary and domestication history

Author: Pascale Quignon, Francis Galibert, Christophe Hitte, Catherine André, Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), and De Villemeur, Hervé
Subjects: MESH: Selection, Genetic, MESH: Wolves, Breeding, MESH: History, Ancient, Domestication, MESH: Dogs, Dna genetics, MESH: Behavior, Animal, Dog, MESH: Animals, History, Ancient, 0303 health sciences, education.field_of_study, Genome, Behavior, Animal, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], 05 social sciences, MESH: DNA, General Medicine, Biological Evolution, Breed, Phenotype, Animals, Domestic, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], General Agricultural and Biological Sciences, Evolution, Population, MESH: Biological Evolution, MESH: Breeding, Biology, MESH: Phenotype, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Dogs, Species Specificity, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BID.EVO] Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Animals, Humans, MESH: Species Specificity, 0501 psychology and cognitive sciences, MESH: Animals, Domestic, 050102 behavioral science & comparative psychology, Selection, Genetic, education, 030304 developmental biology, Wolves, MESH: Humans, General Immunology and Microbiology, [SDV.EE.IEO] Life Sciences [q-bio]/Ecology, environment/Symbiosis, Biological evolution, DNA, MESH: Population, Evolutionary biology, Upper Paleolithic, [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis
Abstract: International audience; Dog domestication was probably started very early during the Upper paleolithic period (~35,000 BP), thus well before any other animal or plant domestication. This early process, probably unconscious, is called proto-domestication to distinguish it from the real domestication process that has been dated around 14,000 BC. Genomic DNA analyses have shown recently that domestication started in the Middle East and rapidly expanded into all human populations. Nowadays, the dog population is fragmented in several hundreds of breeds well characterized by their phenotypes that offer a unique spectrum of polymorphism. More recent studies detect genetic signatures that will be useful to highlight breed history as well as the impact of domestication at the DNA level.
Published: 2011
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45. A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis

Author: Françoise Gray, Natasha J. Olby, Sandra Brahimi, Jean-Laurent Thibaud, Fanny Pilot-Storck, Marie Abitbol, Benoit Hedan, Catherine Caillaud, Jean-Philippe Puech, Marie Maurer, Stéphane Dréano, Christophe Hitte, Delphine Delattre, Françoise Delisle, Laurent Tiret, Stéphane Blot, Catherine André, Geneviève Aubin-Houzelstein, Jean-Jacques Panthier, Florence Bernex, Génétique Moléculaire et Cellulaire (UGMC), École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Laboratoire de neurobiologie, École nationale vétérinaire - Alfort (ENVA), Department of Clinical Sciences, North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC)-University of North Carolina System (UNC), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie et génétique moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Antagene, Service d'anatomie et cytologie pathologiques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre de radiothérapie-Scanner, De Villemeur, Hervé, École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), École nationale vétérinaire d'Alfort (ENVA), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre d'Etudes et de Recherche Thérapeutique en Ophtalmologie (CERTO), Association RETINA France, Partenaires INRAE-Partenaires INRAE, MICEN-Vet, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Ecole Natl Vet Alfort, Fonctions et dysfonctions épithéliales - UFC (EA 4267) (FDE), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Alcatel-Thales III-V Lab (III-V Lab), THALES, Génétique fonctionnelle et médicale (GFM - ENVA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Génétique Moléculaire et Cellulaire ( UGMC ), Institut National de la Recherche Agronomique ( INRA ) -Ecole Nationale Vétérinaire d'Alfort, Ecole Nationale Vétérinaire d'Alfort, North Carolina State University [Raleigh] ( NCSU ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 ( UPD7 ), CERTO, sans affiliation, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and THALES [France]
Subjects: Male, Candidate gene, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.GEN] Life Sciences [q-bio]/Genetics, 0403 veterinary science, Gene Frequency, Catalytic Domain, Missense mutation, Dog Diseases, ComputingMilieux_MISCELLANEOUS, Arylsulfatases, Genetics, 0303 health sciences, Multidisciplinary, Reverse Transcriptase Polymerase Chain Reaction, Sulfatase, Age Factors, Chromosome Mapping, 04 agricultural and veterinary sciences, Biological Sciences, 3. Good health, Pedigree, Cerebellar cortex, dog, lysosome, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Genotype, 040301 veterinary sciences, Molecular Sequence Data, Mutation, Missense, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Cell Line, 03 medical and health sciences, Cerebellar Cortex, Dogs, Microscopy, Electron, Transmission, Neuronal Ceroid-Lipofuscinoses, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic heterogeneity, Gene Expression Profiling, animal model, Haplotype, ataxia, medicine.disease, Molecular biology, Chromosomes, Mammalian, Haplotypes, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], neurodegenerative, Neuronal ceroid lipofuscinosis, ATP-Binding Cassette Transporters, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Neuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motor deterioration, epileptic seizures, and premature death. Rare adult forms of NCL with late onset are known as Kufs’ disease. Loci underlying these adult forms remain unknown due to the small number of patients and genetic heterogeneity. Here we confirm that a late-onset form of NCL recessively segregates in US and French pedigrees of American Staffordshire Terrier (AST) dogs. Through combined association, linkage, and haplotype analyses, we mapped the disease locus to a single region of canine chromosome 9. We eventually identified a worldwide breed-specific variant in exon 2 of the Arylsulfatase G ( ARSG ) gene, which causes a p.R99H substitution in the vicinity of the catalytic domain of the enzyme. In transfected cells or leukocytes from affected dogs, the missense change leads to a 75% decrease in sulfatase activity, providing a functional confirmation that the variant might be the NCL-causing mutation. Our results uncover a protein involved in neuronal homeostasis, identify a family of candidate genes to be screened in patients with Kufs' disease, and suggest that a deficiency in sulfatase is part of the NCL pathogenesis.
Published: 2010
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46. MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers

Author: G. Diane Shelton, Susan M. Taylor, Alan H. Beggs, Johann Böhm, Katie M. Minor, Laurent Tiret, Marie Maurer, Andrew P. Mizisin, Ling T. Guo, Elizabeth C R Snead, Jocelyn Laporte, James R. Mickelson, M. Kozlowski, Martin K. Childers, Christophe Hitte, Anna Buj-Bello, Manton Center for Orphan Disease Research, Harvard Medical School [Boston] (HMS)-Boston Children's Hospital, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Western College of Veterinary Medicine, University of Saskatchewan [Saskatoon] (U of S), Génétique Moléculaire et Cellulaire (UGMC), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), School of Veterinary Medicine, University of Minnesota [Twin Cities] (UMN), University of Minnesota System-University of Minnesota System, Wake Forest University, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology [San Diego], University of California [San Diego] (UC San Diego), University of California-University of California, Généthon, University of Minnesota [Twin Cities], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Genethon, Boston Children's Hospital-Harvard Medical School [Boston] (HMS), De Villemeur, Hervé, École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology [Univ California San Diego] (UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), and University of California (UC)-University of California (UC)
Subjects: Male, Pathology, Myotubularin, necklace fibers, canine myopathy, [SDV.GEN] Life Sciences [q-bio]/Genetics, Exon, Mice, 0302 clinical medicine, congenital myopathy, Chlorocebus aethiops, Missense mutation, Dog Diseases, Fluorescent Antibody Technique, Indirect, Genetics, Mice, Knockout, 0303 health sciences, Multidisciplinary, Genetic Diseases, X-Linked, SDV:GEN, Biological Sciences, myotubularin, animal model, Protein Tyrosine Phosphatases, Non-Receptor, X-linked myotubular myopathy, Muscle atrophy, Pedigree, COS Cells, Female, medicine.symptom, Myopathies, Structural, Congenital, medicine.medical_specialty, Genotype, Green Fluorescent Proteins, Molecular Sequence Data, Biology, 03 medical and health sciences, Dogs, Genetic model, medicine, Animals, Humans, Amino Acid Sequence, Centronuclear myopathy, Muscle, Skeletal, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, Sequence Homology, Amino Acid, medicine.disease, Congenital myopathy, Microscopy, Electron, Haplotypes, Mutation, 030217 neurology & neurosurgery
Abstract: Mutations in the MTM1 gene encoding myotubularin cause X-linked myotubular myopathy (XLMTM), a well-defined subtype of human centronuclear myopathy. Seven male Labrador Retrievers, age 14–26 wk, were clinically evaluated for generalized weakness and muscle atrophy. Muscle biopsies showed variability in fiber size, centrally placed nuclei resembling fetal myotubes, and subsarcolemmal ringed and central dense areas highlighted with mitochondrial specific reactions. Ultrastructural studies confirmed the centrally located nuclei, abnormal perinuclear structure, and mitochondrial accumulations. Wild-type triads were infrequent, with most exhibiting an abnormal orientation of T tubules. MTM1 gene sequencing revealed a unique exon 7 variant in all seven affected males, causing a nonconservative missense change, p.N155K, which haplotype data suggest derives from a recent founder in the local population. Analysis of a worldwide panel of 237 unaffected Labrador Retrievers and 59 additional control dogs from 25 other breeds failed to identify this variant, supporting it as the pathogenic mutation. Myotubularin protein levels and localization were abnormal in muscles from affected dogs, and expression of GFP-MTM1 p.N155K in COS-1 cells showed that the mutant protein was sequestered in proteasomes, where it was presumably misfolded and prematurely degraded. These data demonstrate that XLMTM in Labrador Retrievers is a faithful genetic model of the human condition.
Published: 2010
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47. Drosophila translational elongation factor-1{gamma} is modified in response to DOA kinase activity and is essential for cellular viability

Author: Yujie Fan, Emeline Sarot, Arlette Kpebe, Ana Cuervo Gaspar, Mark Horn, Catherine Dreux, Aurélie Mathieu, Yunlong Zhao, Linda Chaney, Terri Goss Kinzy, Leonard Rabinow, Michael Schlierf, Christophe Hitte, Olivier Grémy, Développement et évolution (DE), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), East China Normal University [Shangaï] (ECNU), Department of Biochemistry and Molecular Biology, University of Nebraska System, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Genetics, Microbiology and Immunology, De Villemeur, Hervé, Bioénergétique et Ingénierie des Protéines (BIP ), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), The Institute for Genomic Research (TIGR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Azzopardi, Laure, and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Transcription, Genetic, Cell Survival, Movement, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Protein Serine-Threonine Kinases, Investigations, Biology, Conserved sequence, 03 medical and health sciences, Peptide Elongation Factor 1, Genetics, Animals, Drosophila Proteins, Humans, RNA, Messenger, Transgenes, Phosphorylation, Kinase activity, Protein kinase A, Conserved Sequence, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Kinase, 030302 biochemistry & molecular biology, Gene Expression Regulation, Developmental, biology.organism_classification, [SDV] Life Sciences [q-bio], Drosophila melanogaster, Larva, Female, Genes, Lethal, Translational elongation, Protein Kinases, Sequence Alignment, Drosophila Protein, Transcription Factors
Abstract: Drosophila translational elongation factor-1γ (EF1γ) interacts in the yeast two-hybrid system with DOA, the LAMMER protein kinase of Drosophila. Analysis of mutant EF1γ alleles reveals that the locus encodes a structurally conserved protein essential for both organismal and cellular survival. Although no genetic interactions were detected in combinations with mutations in EF1α, an EF1γ allele enhanced mutant phenotypes of Doa alleles. A predicted LAMMER kinase phosphorylation site conserved near the C terminus of all EF1γ orthologs is a phosphorylation site in vitro for both Drosophila DOA and tobacco PK12 LAMMER kinases. EF1γ protein derived from Doa mutant flies migrates with altered mobility on SDS gels, consistent with it being an in vivo substrate of DOA kinase. However, the aberrant mobility appears to be due to a secondary protein modification, since the mobility of EF1γ protein obtained from wild-type Drosophila is unaltered following treatment with several nonspecific phosphatases. Expression of a construct expressing a serine-to-alanine substitution in the LAMMER kinase phosphorylation site into the fly germline rescued null EF1γ alleles but at reduced efficiency compared to a wild-type construct. Our data suggest that EF1γ functions in vital cellular processes in addition to translational elongation and is a LAMMER kinase substrate in vivo.
Published: 2010
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48. Intrabreed Stratification Related to Divergent Selection Regimes in Purebred Dogs May Affect the Interpretation of Genetic Association Studies

Author: Jennifer S. Yokoyama, Nicholas Branson, Donna J. Dyer, Melanie L. Chang, Karen L. Overall, Christophe Hitte, Steven P. Hamilton, Institute for Human Genetics, University of California [San Francisco] (UCSF), University of California-University of California, Center for Neurobiology and Behavior, University of Pennsylvania [Philadelphia], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), University of Pennsylvania, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), and De Villemeur, Hervé
Subjects: 0106 biological sciences, Breeding program, Population, Single-nucleotide polymorphism, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Population stratification, 010603 evolutionary biology, 01 natural sciences, 03 medical and health sciences, Genetics, SNP, education, Molecular Biology, Genetics (clinical), Selection (genetic algorithm), 030304 developmental biology, Genetic association, 0303 health sciences, education.field_of_study, [SDV.GEN]Life Sciences [q-bio]/Genetics, Original Articles, Evolutionary biology, Purebred, Biotechnology
Abstract: International audience; Until recently, canine genetic research has not focused on population structure within breeds, which may confound the results of case-control studies by introducing spurious correlations between phenotype and genotype that reflect population history. Intrabreed structure may exist when geographical origin or divergent selection regimes influence the choices of potential mates for breeding dogs. We present evidence for intrabreed stratification from a genome-wide marker survey in a sample of unrelated dogs. We genotyped 76 Border Collies, 49 Australian Shepherds, 17 German Shepherd Dogs, and 17 Portuguese Water Dogs for our primary analyses using Affymetrix Canine v2.0 single-nucleotide polymorphism (SNP) arrays. Subsets of autosomal markers were examined using clustering algorithms to facilitate assignment of individuals to populations and estimation of the number of populations represented in the sample. SNPs passing stringent quality control filters were employed for explicitly phylogenetic analyses reconstructing relationships between individuals using maximum parsimony and Bayesian methods. We used simulation studies to explore the possible effects of intrabreed stratification on genome-wide association studies. These analyses demonstrate significant stratification in at least one of our primary breeds of interest, the Border Collie. Demographic and pedigree data suggest that this population substructure may result from geographic isolation or divergent selection regimes practiced by breeders with different breeding program goals. Simulation studies indicate that such stratification could result in false discovery rates significant enough to confound genome-wide association analyses. Intrabreed stratification should be accounted for when designing and interpreting the results of case-control association studies using purebred dogs.
Published: 2009
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49. Genetic diversity of canine olfactory receptors

Author: Catherine André, Maud Rimbault, Stéphanie Robin, Stéphane Dréano, Francis Galibert, Christophe Hitte, Amaury Vaysse, Sandrine Tacher, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Systèmes d'Elevage, Nutrition Animale et Humaine (SENAH), Ecole Nationale Supérieure Agronomique de Rennes-Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Supérieure Agronomique de Rennes, and De Villemeur, Hervé
Subjects: Olfactory system, Linkage disequilibrium, lcsh:QH426-470, Sequence analysis, lcsh:Biotechnology, variabilité génétique, récepteur olfactif, polymorphisme snp, Single-nucleotide polymorphism, polymorphisme, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, modèle, Receptors, Odorant, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 03 medical and health sciences, Dogs, 0302 clinical medicine, lcsh:TP248.13-248.65, Genetics, medicine, Animals, Gene family, SNP, Alleles, 030304 developmental biology, évolution biologique, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Olfactory receptor, gène, Haplotype, DNA, Sequence Analysis, DNA, lcsh:Genetics, medicine.anatomical_structure, Amino Acid Substitution, Haplotypes, chien, 030217 neurology & neurosurgery, olfaction, Research Article, Biotechnology
Abstract: Background Evolution has resulted in large repertoires of olfactory receptor (OR) genes, forming the largest gene families in mammalian genomes. Knowledge of the genetic diversity of olfactory receptors is essential if we are to understand the differences in olfactory sensory capability between individuals. Canine breeds constitute an attractive model system for such investigations. Results We sequenced 109 OR genes considered representative of the whole OR canine repertoire, which consists of more than 800 genes, in a cohort of 48 dogs of six different breeds. SNP frequency showed the overall level of polymorphism to be high. However, the distribution of SNP was highly heterogeneous among OR genes. More than 50% of OR genes were found to harbour a large number of SNP, whereas the rest were devoid of SNP or only slightly polymorphic. Heterogeneity was also observed across breeds, with 25% of the SNP breed-specific. Linkage disequilibrium within OR genes and OR clusters suggested a gene conversion process, consistent with a mean level of polymorphism higher than that observed for introns and intergenic sequences. A large proportion (47%) of SNP induced amino-acid changes and the Ka/Ks ratio calculated for all alleles with a complete ORF indicated a low selective constraint with respect to the high level of redundancy of the olfactory combinatory code and an ongoing pseudogenisation process, which affects dog breeds differently. Conclusion Our demonstration of a high overall level of polymorphism, likely to modify the ligand-binding capacity of receptors distributed differently within the six breeds tested, is the first step towards understanding why Labrador Retrievers and German Shepherd Dogs have a much greater potential for use as sniffer dogs than Pekingese dogs or Greyhounds. Furthermore, the heterogeneity in OR polymorphism observed raises questions as to why, in a context in which most OR genes are highly polymorphic, a subset of these genes is not? This phenomenon may be related to the nature of their ligands and their importance in everyday life.
Published: 2009
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50. Survey sequencing and radiation hybrid mapping to construct comparative maps

Author: Ewen F. Kirkness, Francis Galibert, Christophe Hitte, Elaine A. Ostrander, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ), The Institute for Genomic Research ( TIGR ), JCVI J. Craig Venter Institute, Cancer Genetics Branch, National Institute of Health (NIH)-National Human Genome Research Institute, U.S. Army Grant DAAD19-01-1-0658 (E.A.O. and F.G.), NIH R01CA-92167 (E.A.O, E.K. and F.G.), Conseil Regional de Bretagne (FG and CH), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), The Institute for Genomic Research (TIGR), National Institute of Health (NIH)-National Human Genome Research Institute (NHGRI), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Genetic Markers, Male, MESH: Sequence Analysis, DNA, Genotype, MESH : Male, MESH: Radiation Hybrid Mapping, Hybrid genome assembly, MESH : Genotype, Computational biology, Biology, MESH: Genetic Markers, Genome, MESH: Sequence Homology, Nucleic Acid, Article, DNA sequencing, MESH: Dogs, MESH: Genotype, 03 medical and health sciences, MESH : Radiation Hybrid Mapping, Dogs, 0302 clinical medicine, MESH : Dogs, Sequence Homology, Nucleic Acid, Animals, MESH : Genetic Markers, Radiation hybrid mapping, MESH: Animals, MESH : Sequence Homology, Nucleic Acid, Gene, 030304 developmental biology, Genetics, Radiation Hybrid Mapping, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Gene map, Sequence Analysis, DNA, Genome project, MESH: Male, MESH : Animals, Chromosome breakage, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery, MESH : Sequence Analysis, DNA
Abstract: In MURPHY WJ (ed.) Phylogenomics, Humana Press. (Methods in Molecular Biology, 422); International audience; Radiation hybrid (RH) mapping has become one of the most well-established techniques for economically and efficiently navigating genomes of interest. The success of the technique relies on random chromosome breakage of a target genome, which is then captured by recipient cells missing a preselected marker. Selection for hybrid cells that have DNA fragments bearing the marker of choice, plus a random set of DNA fragments from the initial irradiation, generates a set of cell lines that recapitulates the genome of the target organism several-fold. Markers or genes of interest are analyzed by PCR using DNA isolated from each cell line. Statistical tools are applied to determine both the linear order of markers on each chromosome, and the confidence of each placement. The resolution of the resulting map relies on many factors, most notably the degree of breakage from the initial radiation as well as the number of hybrid clones and mean retention value.A high-resolution RH map of a genome derived from low pass or survey sequencing (coverage from 1 to 2 times) can provide essentially the same comparative data on gene order that is derived from high-coverage (greater than x7) genome sequencing. When combined with fluorescence in situ hybridization, RH maps are complete and ordered blueprints for each chromosome. They give information about the relative order and spacing of genes and markers, and allow investigators to move between target and reference genomes, such as those of mouse or human, with ease although the approach is not limited to mammal genomes.
Published: 2008
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