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1. A high-quality human reference panel reveals the complexity and distribution of genomic structural variants

Author

Hehir-Kwa, Jayne Y, Marschall, Tobias, Kloosterman, Wigard P, Francioli, Laurent C, Baaijens, Jasmijn A, Dijkstra, Louis J, Abdellaoui, Abdel, Koval, Vyacheslav, Thung, Djie Tjwan, Wardenaar, René, Renkens, Ivo, Coe, Bradley P, Deelen, Patrick, de Ligt, Joep, Lameijer, Eric-Wubbo, van Dijk, Freerk, Hormozdiari, Fereydoun, Uitterlinden, André G, van Duijn, Cornelia M, Eichler, Evan E, de Bakker, Paul IW, Swertz, Morris A, Wijmenga, Cisca, van Ommen, Gert-Jan B, Slagboom, P Eline, Boomsma, Dorret I, Schönhuth, Alexander, Ye, Kai, and Guryev, Victor

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Epidemiology, Health Sciences, Human Genome, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, Algorithms, Chromosomes, Computational Biology, Gene Deletion, Genome, Human, Genomic Structural Variation, Genomics, Genotype, Haplotypes, Humans, INDEL Mutation, Linkage Disequilibrium, Netherlands, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, RNA, Sequence Analysis, DNA, Sequence Analysis, RNA, Software, Genome of the Netherlands Consortium
Abstract

Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals.

Published
2016

2. Transmission of human mtDNA heteroplasmy in the Genome of the Netherlands families: support for a variable-size bottleneck

Author

Li, Mingkun, Rothwell, Rebecca, Vermaat, Martijn, Wachsmuth, Manja, Schröder, Roland, Laros, Jeroen F J, Van Oven, Mannis, De Bakker, Paul I W, Bovenberg, Jasper A., Van Duijn, Cornelia M., Van Ommen, Gert Jan B, Slagboom, P. Eline, Swertz, Morris A., Wijmenga, Cisca, Kayser, Manfred, Boomsma, Dorret I., Zöllner, Sebastian, De Knijff, Peter, Stoneking, Mark, De Craen, Anton J M, Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Cao, Jeremy Sujie, Van Dijk, Freerk, Neerincx, Pieter B T, Deelen, Patrick, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Ye, Kai, Lameijer, Eric Wubbo, Den Dunnen, Johan T., Karssen, Lennart C., Van Leeuwen, Elisa M., Amin, Najaf, Koval, Vyacheslav, Rivadeneira, Fernando, Estrada, Karol, Hehir-Kwa, Jayne Y., De Ligt, Joep, Abdellaoui, Abdel, Hottenga, Jouke Jan, Kattenberg, V. Mathijs, Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D C, Handsaker, Robert E., McCarroll, Steven A., Eichler, Evan E., Ko, Arthur, Sudmant, Peter, Francioli, Laurent C., Kloosterman, Wigard P., Nijman, Isaac J., Guryev, Victor, Genetic Identification, Epidemiology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Biological Psychology, EMGO+ - Quality of Care, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep

Subjects
Male, Netherlands Twin Register (NTR), 0301 basic medicine, LEVEL, Inheritance Patterns, Twins, Twin Study, POINT MUTATIONS, Genome, Gene Frequency, Paternal mtDNA transmission, Genetics(clinical), Non-U.S. Gov't, Genetics (clinical), Netherlands, Genetics, Research Support, Non-U.S. Gov't, PURIFYING SELECTION, MITOCHONDRIAL-DNA MUTATIONS, RANDOM GENETIC DRIFT, HUMAN-DISEASE, Heteroplasmy, Female, Mitochondrial DNA, TISSUES, OOCYTES, Biology, Research Support, INHERITANCE, DNA, Mitochondrial, White People, Genetic Heterogeneity, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Journal Article, Humans, Family, Selection, Genetic, Allele, Allele frequency, Alleles, Models, Statistical, Polymorphism, Genetic, Models, Genetic, Research, Twin study, Minor allele frequency, 030104 developmental biology, Mutation, MELAS SYNDROME
Abstract

Although previous studies have documented a bottleneck in the transmission of mtDNA genomes from mothers to offspring, several aspects remain unclear, including the size and nature of the bottleneck. Here, we analyze the dynamics of mtDNA heteroplasmy transmission in the Genomes of the Netherlands (GoNL) data, which consists of complete mtDNA genome sequences from 228 trios, eight dizygotic (DZ) twin quartets, and 10 monozygotic (MZ) twin quartets. Using a minor allele frequency (MAF) threshold of 2%, we identified 189 heteroplasmies in the trio mothers, of which 59% were transmitted to offspring, and 159 heteroplasmies in the trio offspring, of which 70% were inherited from the mothers. MZ twin pairs exhibited greater similarity in MAF at heteroplasmic sites than DZ twin pairs, suggesting that the heteroplasmy MAF in the oocyte is the major determinant of the heteroplasmy MAF in the offspring. We used a likelihood method to estimate the effective number of mtDNA genomes transmitted to offspring under different bottleneck models; a variable bottleneck size model provided the best fit to the data, with an estimated mean of nine individual mtDNA genomes transmitted. We also found evidence for negative selection during transmission against novel heteroplasmies (in which the minor allele has never been observed in polymorphism data). These novel heteroplasmies are enhanced for tRNA and rRNA genes, and mutations associated with mtDNA diseases frequently occur in these genes. Our results thus suggest that the female germ line is able to recognize and select against deleterious heteroplasmies.

Published
2016
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3. Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome

Author

Vissers, Lisenka ELM, Bonetti, Monica, Paardekooper Overman, Jeroen, Nillesen, Willy M., Frints, Suzanna G M, de Ligt, Joep, Zampino, Giuseppe, Justino, Ana, Machado, José C., Schepens, Marga, Brunner, Han G., Veltman, Joris A., Scheffer, Hans, Gros, Piet, Costa, José L., Tartaglia, Marco, van der Burgt, Ineke, Yntema, Helger G., den Hertog, Jeroen, Sub Crystal and Structural Chemistry, Crystal and Structural Chemistry, Hubrecht Institute for Developmental Biology and Stem Cell Research, MUMC+: DA Klinische Genetica (5), Groei & Ontwikkeling, RS: GROW - Developmental Biology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Sub Crystal and Structural Chemistry, and Crystal and Structural Chemistry

Subjects
Male, Models, Molecular, Protein Conformation, DNA Mutational Analysis, Gene Expression, medicine.disease_cause, Models, Exome, Genetics(clinical), Non-U.S. Gov't, skin and connective tissue diseases, Zebrafish, Genetics (clinical), Genetics, Mutation, Research Support, Non-U.S. Gov't, Noonan Syndrome, High-Throughput Nucleotide Sequencing, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Pedigree, Phenotype, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Medical genetics, Female, musculoskeletal diseases, Heterozygote, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, animal structures, Other Research Donders Center for Medical Neuroscience [Radboudumc 0], Biology, Research Support, Article, Germline mutation, Molecular genetics, medicine, Journal Article, Animals, Humans, alpha-Macroglobulins, cardiovascular diseases, Sensory disorders Radboud Institute for Molecular Life Sciences [Radboudumc 12], Germ-Line Mutation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Cytogenetics, Facies, Molecular, Heterozygote advantage, medicine.disease, Amino Acid Substitution, Noonan syndrome
Abstract

Contains fulltext : 152975.pdf (Publisher’s version ) (Open Access) Noonan syndrome (NS) is a developmental disorder characterized by short stature, facial dysmorphisms and congenital heart defects. To date, all mutations known to cause NS are dominant, activating mutations in signal transducers of the RAS/mitogen-activated protein kinase (MAPK) pathway. In 25% of cases, however, the genetic cause of NS remains elusive, suggesting that factors other than those involved in the canonical RAS/MAPK pathway may also have a role. Here, we used family-based whole exome sequencing of a case-parent trio and identified a de novo mutation, p.(Arg802His), in A2ML1, which encodes the secreted protease inhibitor alpha-2-macroglobulin (A2M)-like-1. Subsequent resequencing of A2ML1 in 155 cases with a clinical diagnosis of NS led to the identification of additional mutations in two families, p.(Arg802Leu) and p.(Arg592Leu). Functional characterization of these human A2ML1 mutations in zebrafish showed NS-like developmental defects, including a broad head, blunted face and cardiac malformations. Using the crystal structure of A2M, which is highly homologous to A2ML1, we identified the intramolecular interaction partner of p.Arg802. Mutation of this residue, p.Glu906, induced similar developmental defects in zebrafish, strengthening our conclusion that mutations in A2ML1 cause a disorder clinically related to NS. This is the first report of the involvement of an extracellular factor in a disorder clinically related to RASopathies, providing potential new leads for better understanding of the molecular basis of this family of developmental diseases.

Published
2015
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4. Erratum : Next-generation sequencing-based genome diagnostics across clinical genetics centers: Implementation choices and their effects (European Journal of Human Genetics (2015) 23 (1142-1150) DOI:10.1038/ejhg.2014.279)

Author

Vrijenhoek, Terry, Kraaijeveld, Ken, Elferink, Martin, De Ligt, Joep, Kranendonk, Elcke, Santen, Gijs, Nijman, Isaac J., Butler, Derek, Claes, Godelieve, Costessi, Adalberto, Dorlijn, Wim, Van Eyndhoven, Winfried, Halley, Dicky J J, Van Den Hout, Mirjam C G N, Van Hove, Steven, Johansson, Lennart F., Jongbloed, Jan D H, Kamps, Rick, Kockx, Christel E M, De Koning, Bart, Kriek, Marjolein, Deprez, Ronald Lekanne Dit, Lunstroo, Hans, Mannens, Marcel, Mook, Olaf R., Nelen, Marcel, Ploem, Corrette, Rijnen, Marco, Saris, Jasper J., Sinke, Richard, Sistermans, Erik, Van Slegtenhorst, Marjon, Sleutels, Frank, Van Der Stoep, Nienke, Van Tienhoven, Marianne, Vermaat, Martijn, Vogel, Maartje, Waisfisz, Quinten, Weiss, Janneke Marjan, Van Den Wijngaard, Arthur, Van Workum, Wilbert, Ijntema, Helger, Van Der Zwaag, Bert, Van Ijcken, Wilfred F J, Den Dunnen, Johan T., Veltman, Joris A., Hennekam, Raoul, and Cuppen, Edwin

Subjects
Published Erratum, Genetics, Genetics(clinical)
Published
2015

5. Characteristics of de novo structural changes in the human genome

Author

Kloosterman, Wigard P., Francioli, Laurent C., Hormozdiari, Fereydoun, Marschall, Tobias, Hehir-Kwa, Jayne Y., Abdellaoui, Abdel, Lameijer, Eric Wubbo, Moed, Matthijs H., Koval, Vyacheslav, Renkens, Ivo, Van Roosmalen, Markus J., Arp, Pascal, Karssen, Lennart C., Coe, Bradley P., Handsaker, Robert E., Suchiman, Eka D., Cuppen, Edwin, Thung, Djie Tjwan, McVey, Mitch, Wendl, Michael C., Uitterlinden, André, Van Duijn, Cornelia M., Swertz, Morris A., Wijmenga, Cisca, Van Ommen, Gert Jan B, Slagboom, P. Eline, Boomsma, Dorret I., Schönhuth, Alexander, Eichler, Evan E., De Bakker, Paul I W, Ye, Kai, Guryev, Victor, Bovenberg, Jasper A., De Craen, Anton J M, Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Cao, Jeremy Sujie, Van Dijk, Freerk, Neerincx, Pieter B T, Deelen, Patrick, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Vermaat, Martijn, Laros, Jeroen F J, Den Dunnen, Johan T., De Knijff, Peter, Van Leeuwen, Elisa M., Amin, Najaf, Rivadeneira, Fernando, Estrada, Karol, De Ligt, Joep, Hottenga, Jouke Jan, Kattenberg, V. Mathijs, Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D C, McCarroll, Steven A., Ko, Arthur, Sudmant, Peter, Nijman, Isaac J., Adult Psychiatry, Epidemiology and Data Science, ACS - Amsterdam Cardiovascular Sciences, AII - Amsterdam institute for Infection and Immunity, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ANS - Amsterdam Neuroscience, CCA -Cancer Center Amsterdam, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Internal Medicine, Epidemiology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Male, Netherlands Twin Register (NTR), Mutation rate, INTELLECTUAL DISABILITY, Retrotransposon, Genome of Netherlands Consortium, VARIANTS, Medical and Health Sciences, Genome, 0302 clinical medicine, INDEL Mutation, Mutation Rate, Genetics(clinical), Copy-number variation, Genetics (clinical), Genetics, 0303 health sciences, education.field_of_study, food and beverages, Genomics, Single Nucleotide, Biological Sciences, Female, Sequence Analysis, Human, Retroelements, SEQUENCING DATA, Bioinformatics, Molecular Sequence Data, Population, MUTATION-RATES, POPULATION-SCALE, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Humans, Amino Acid Sequence, Polymorphism, Indel, education, Alleles, 030304 developmental biology, COPY NUMBER VARIATION, INDIVIDUAL HUMAN, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], IDENTIFICATION, Genome, Human, Research, Human Genome, Genetic Variation, Sequence Analysis, DNA, DNA, GENE, Haplotypes, DISCOVERY, Human genome, Sequence Alignment, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 154750.pdf (Publisher’s version ) (Open Access) Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions, and interchromosomal events. These data indicate a mutation rate of 2.94 indels (1-20 bp) and 0.16 SVs (>20 bp) per generation. De novo structural changes affect on average 4.1 kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a nonuniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations. 01 juni 2015

Published
2015
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6. The Genomic Scrapheap Challenge; Extracting Relevant Data from Unmapped Whole Genome Sequencing Reads, Including Strain Specific Genomic Segments, in Rats.

Author

van der Weide, Robin H., Simonis, Marieke, Hermsen, Roel, Toonen, Pim, Cuppen, Edwin, and de Ligt, Joep

Subjects
GENOMICS, NUCLEOTIDE sequencing, PHYLOGENY, GENE libraries, GENOTYPE-environment interaction, LABORATORY rats
Abstract

Unmapped next-generation sequencing reads are typically ignored while they contain biologically relevant information. We systematically analyzed unmapped reads from whole genome sequencing of 33 inbred rat strains. High quality reads were selected and enriched for biologically relevant sequences; similarity-based analysis revealed clustering similar to previously reported phylogenetic trees. Our results demonstrate that on average 20% of all unmapped reads harbor sequences that can be used to improve reference genomes and generate hypotheses on potential genotype-phenotype relationships. Analysis pipelines would benefit from incorporating the described methods and reference genomes would benefit from inclusion of the genomic segments obtained through these efforts. [ABSTRACT FROM AUTHOR]

Published
2016
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7. Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing.

Author

Schuurs-Hoeijmakers, Janneke H. M., Vulto-van Silfhout, Anneke T., Vissers, Lisenka E. L. M., van de Vondervoort, Ilse I. G. M., van Bon, Bregje W. M., de Ligt, Joep, Gilissen, Christian, Hehir-Kwa, Jayne Y., Neveling, Kornelia, del Rosario, Marisol, Hira, Gausiya, Reitano, Santina, Vitello, Aurelio, Failla, Pinella, Greco, Donatella, Fichera, Marco, Galesi, Ornella, Kleefstra, Tjitske, Greally, Marie T., and Ockeloen, Charlotte W.

Subjects
GENETICS, GENETIC mutation, PHENOTYPES, CHROMOSOME abnormalities, GENE mapping
Abstract

Background Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown. Objectives We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Nonconsanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect. Methods and results Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes. Conclusions We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes. [ABSTRACT FROM AUTHOR]

Published
2013
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8. Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects.

Author

Willemsen, Marjolein H., Vissers, Lisenka E. L., Willemsen, Michèl A. A. P., van Bon, Bregje W. M., Kroes, Thessa, de Ligt, Joep, de Vries, Bert B., Schoots, Jeroen, Lugtenberg, Dorien, Hamel, Ben C. J., van Bokhoven, Hans, Brunner, Han G., Veltman, Joris A., and Kleefstra, Tjitske

Subjects
NEURONS, GENETIC mutation, MOLECULAR motor proteins, DYNEIN, FAMILIAL diseases, NEUROPATHY, GENETICS
Abstract

Background DYNC1H1 encodes the heavy chain protein of the cytoplasmic dynein 1 motor protein complex that plays a key role in retrograde axonal transport in neurons. Furthermore, it interacts with the LIS1 gene of which haploinsufficiency causes a severe neuronal migration disorder in humans, known as classical lissencephaly or Miller-Dieker syndrome. Aim To describe the clinical spectrum and molecular characteristics of DYNC1H1 mutations Methods A family based exome sequencing approach was used to identify de novo mutations in patients with severe intellectual disability. Results In this report the identification of two de novo missense mutations in DYNC1H1 (p.Glu1518Lys and p.His3822Pro) in two patients with severe intellectual disability and variable neuronal migration defects is described Conclusion Since an autosomal dominant mutation in DYNC1H1 was previously identified in a family with the axonal (type 2) form of Charcot- Marie-Tooth (CMT2) disease and mutations in Dync1h1 in mice also cause impaired neuronal migration in addition to neuropathy, these data together suggest that mutations in DYNC1H1 can lead to a broad phenotypic spectrum and confirm the importance of DYNC1H1 in both central and peripheral neuronal functions. [ABSTRACT FROM AUTHOR]

Published
2012
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9. A de novo paradigm for mental retardation.

Author

Vissers, Lisenka E. L. M., de Ligt, Joep, Gilissen, Christian, Janssen, Irene, Steehouwer, Marloes, de Vries, Petra, van Lier, Bart, Arts, Peer, Wieskamp, Nienke, del Rosario, Marisol, van Bon, Bregje W. M., Hoischen, Alexander, de Vries, Bert B. A., Brunner, Han G., and Veltman, Joris A.

Subjects
*GENETIC mutation, *FERTILITY, *BIOLOGICAL evolution, *GENETICS, *INTELLECTUAL disabilities, *EXONS (Genetics), *GENE frequency
Abstract

The per-generation mutation rate in humans is high. De novo mutations may compensate for allele loss due to severely reduced fecundity in common neurodevelopmental and psychiatric diseases, explaining a major paradox in evolutionary genetic theory. Here we used a family based exome sequencing approach to test this de novo mutation hypothesis in ten individuals with unexplained mental retardation. We identified and validated unique non-synonymous de novo mutations in nine genes. Six of these, identified in six different individuals, are likely to be pathogenic based on gene function, evolutionary conservation and mutation impact. Our findings provide strong experimental support for a de novo paradigm for mental retardation. Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population. [ABSTRACT FROM AUTHOR]

Published
2010
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10. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer.

Author

Drost, Jarno, van Boxtel, Ruben, Blokzijl, Francis, Mizutani, Tomohiro, Sasaki, Nobuo, Sasselli, Valentina, de Ligt, Joep, Behjati, Sam, Grolleman, Judith E., van Wezel, Tom, Nik-Zainal, Serena, Kuiper, Roland P., Cuppen, Edwin, and Clevers, Hans

Subjects
*CANCER genetics, *GENETIC mutation, *CRISPRS, *ORGANOIDS, *GENETICS
Abstract

Mutational processes underlie cancer initiation and progression. Signatures of these processes in cancer genomes may explain cancer etiology and could hold diagnostic and prognostic value. We developed a strategy that can be used to explore the origin of cancer-associated mutational signatures. We used CRISPR-Cas9 technology to delete key DNA repair genes in human colon organoids, followed by delayed subcloning and whole-genome sequencing. We found that mutation accumulation in organoids deficient in the mismatch repair gene MLH1 is driven by replication errors and accurately models the mutation profiles observed in mismatch repair–deficient colorectal cancers. Application of this strategy to the cancer predisposition gene NTHL1, which encodes a base excision repair protein, revealed a mutational footprint (signature 30) previously observed in a breast cancer cohort. We show that signature 30 can arise from germline NTHL1 mutations. [ABSTRACT FROM AUTHOR]

Published
2017
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11. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer

Author

Ruben van Boxtel, Hans Clevers, Sam Behjati, Jarno Drost, Judith E. Grolleman, Tom van Wezel, Nobuo Sasaki, Valentina Sasselli, Joep de Ligt, Francis Blokzijl, Edwin Cuppen, Tomohiro Mizutani, Serena Nik-Zainal, Roland P. Kuiper, Hubrecht Institute for Developmental Biology and Stem Cell Research, Drost, Jarno [0000-0002-2941-6179], van Boxtel, Ruben [0000-0003-1285-2836], Blokzijl, Francis [0000-0002-8084-8444], Mizutani, Tomohiro [0000-0002-8373-7969], Sasaki, Nobuo [0000-0002-8798-7244], Sasselli, Valentina [0000-0002-7118-0067], de Ligt, Joep [0000-0002-0348-419X], Behjati, Sam [0000-0002-6600-7665], Grolleman, Judith E [0000-0001-8841-503X], van Wezel, Tom [0000-0001-5773-7730], Nik-Zainal, Serena [0000-0001-5054-1727], Kuiper, Roland P [0000-0003-4928-3809], Cuppen, Edwin [0000-0002-0400-9542], Clevers, Hans [0000-0002-3077-5582], and Apollo - University of Cambridge Repository

Subjects
DNA Replication, 0301 basic medicine, DNA Repair, Colon, DNA repair, Breast Neoplasms, Biology, Research Support, MLH1, medicine.disease_cause, DNA Mismatch Repair, Article, Deoxyribonuclease (Pyrimidine Dimer), 03 medical and health sciences, Germline mutation, INDEL Mutation, Neoplasms, Journal Article, medicine, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Humans, CRISPR, Non-U.S. Gov't, Germ-Line Mutation, Genetics, Mutation, Multidisciplinary, Stem Cells, Research Support, Non-U.S. Gov't, Cancer, Base excision repair, medicine.disease, 3. Good health, Organoids, 030104 developmental biology, Mutagenesis, Female, DNA mismatch repair, CRISPR-Cas Systems, Colorectal Neoplasms, MutL Protein Homolog 1
Abstract

A signature event for organoids Human cancer genomes harbor cryptic mutational signatures that represent the cumulative effects of DNA damage and defects in DNA repair processes. Knowledge of how specific signatures originate could have a major impact on cancer diagnosis and prevention. One approach to address this question is to reproduce the signatures in experimental systems by genetic engineering and then match the signatures to those found in naturally occurring cancers. Drost et al. used CRISPR-Cas9 to delete certain DNA repair enzymes from human colon organoids. In a proof-of-concept study, they show that deficiency in base excision repair is responsible for a mutational signature previously identified in cancer genome sequencing projects. Science , this issue p. 234

Published
2017

12. A de novo paradigm for mental retardation

Author

Marisol del Rosario, Bart van Lier, Christian Gilissen, Bert B.A. de Vries, Peer Arts, Petra de Vries, Joep de Ligt, Lisenka E.L.M. Vissers, Nienke Wieskamp, Marloes Steehouwer, Joris A. Veltman, Bregje W.M. van Bon, Irene M. Janssen, Alexander Hoischen, Han G. Brunner, Vissers, Lisenka E L M, De Ligt, Joep, Gilissen, Christian, Janssen, Irene, Steehouwer, Marloes, De Vries, Petra, Van Lier, Bart, Arts, Peer, Wieskamp, Nienke, Del Rosario, Marisol, Van Bon, Bregje W M, Hoischen, Alexander, De Vries, Bert B A, Brunner, Han G, and Veltman, Joris A

Subjects
Male, Mutation rate, medicine.medical_specialty, Genetics and epigenetic pathways of disease [NCMLS 6], Population, Neurogenetics, Biology, mental retardation, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Genetics, medicine, Humans, gene mutation, Copy-number variation, education, Exome sequencing, 030304 developmental biology, 0303 health sciences, education.field_of_study, Base Sequence, Point mutation, Exons, Sequence Analysis, DNA, Mutation (genetic algorithm), Mutation, Medical genetics, Female, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 89284.pdf (Publisher’s version ) (Closed access) The per-generation mutation rate in humans is high. De novo mutations may compensate for allele loss due to severely reduced fecundity in common neurodevelopmental and psychiatric diseases, explaining a major paradox in evolutionary genetic theory. Here we used a family based exome sequencing approach to test this de novo mutation hypothesis in ten individuals with unexplained mental retardation. We identified and validated unique non-synonymous de novo mutations in nine genes. Six of these, identified in six different individuals, are likely to be pathogenic based on gene function, evolutionary conservation and mutation impact. Our findings provide strong experimental support for a de novo paradigm for mental retardation. Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population. 01 december 2010

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