301 results on '"Gregory S Barsh"'
Search Results
2. Endless microbes most beautiful and most wonderful.
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Gregory S Barsh, Geraldine Butler, Gregory P Copenhaver, Sean Crosson, Lotte Søgaard-Andersen, and Eva H Stukenbrock
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Genetics ,QH426-470 - Published
- 2023
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3. Expanding human variation at PLOS Genetics.
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Gregory S Barsh, Gregory P Copenhaver, Hua Tang, and Scott M Williams
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Genetics ,QH426-470 - Published
- 2022
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4. Aberrant regulation of a poison exon caused by a non-coding variant in a mouse model of Scn1a-associated epileptic encephalopathy.
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Yuliya Voskobiynyk, Gopal Battu, Stephanie A Felker, J Nicholas Cochran, Megan P Newton, Laura J Lambert, Robert A Kesterson, Richard M Myers, Gregory M Cooper, Erik D Roberson, and Gregory S Barsh
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Genetics ,QH426-470 - Abstract
Dravet syndrome (DS) is a developmental and epileptic encephalopathy that results from mutations in the Nav1.1 sodium channel encoded by SCN1A. Most known DS-causing mutations are in coding regions of SCN1A, but we recently identified several disease-associated SCN1A mutations in intron 20 that are within or near to a cryptic and evolutionarily conserved "poison" exon, 20N, whose inclusion is predicted to lead to transcript degradation. However, it is not clear how these intron 20 variants alter SCN1A expression or DS pathophysiology in an organismal context, nor is it clear how exon 20N is regulated in a tissue-specific and developmental context. We address those questions here by generating an animal model of our index case, NM_006920.4(SCN1A):c.3969+2451G>C, using gene editing to create the orthologous mutation in laboratory mice. Scn1a heterozygous knock-in (+/KI) mice exhibited an ~50% reduction in brain Scn1a mRNA and Nav1.1 protein levels, together with characteristics observed in other DS mouse models, including premature mortality, seizures, and hyperactivity. In brain tissue from adult Scn1a +/+ animals, quantitative RT-PCR assays indicated that ~1% of Scn1a mRNA included exon 20N, while brain tissue from Scn1a +/KI mice exhibited an ~5-fold increase in the extent of exon 20N inclusion. We investigated the extent of exon 20N inclusion in brain during normal fetal development in RNA-seq data and discovered that levels of inclusion were ~70% at E14.5, declining progressively to ~10% postnatally. A similar pattern exists for the homologous sodium channel Nav1.6, encoded by Scn8a. For both genes, there is an inverse relationship between the level of functional transcript and the extent of poison exon inclusion. Taken together, our findings suggest that poison exon usage by Scn1a and Scn8a is a strategy to regulate channel expression during normal brain development, and that mutations recapitulating a fetal-like pattern of splicing cause reduced channel expression and epileptic encephalopathy.
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- 2021
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5. PEA15 loss of function and defective cerebral development in the domestic cat.
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Emily C Graff, J Nicholas Cochran, Christopher B Kaelin, Kenneth Day, Heather L Gray-Edwards, Rie Watanabe, Jey W Koehler, Rebecca A Falgoust, Jeremy W Prokop, Richard M Myers, Nancy R Cox, Gregory S Barsh, Douglas R Martin, and Lives Consortium
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Genetics ,QH426-470 - Abstract
Cerebral cortical size and organization are critical features of neurodevelopment and human evolution, for which genetic investigation in model organisms can provide insight into developmental mechanisms and the causes of cerebral malformations. However, some abnormalities in cerebral cortical proliferation and folding are challenging to study in laboratory mice due to the absence of gyri and sulci in rodents. We report an autosomal recessive allele in domestic cats associated with impaired cerebral cortical expansion and folding, giving rise to a smooth, lissencephalic brain, and that appears to be caused by homozygosity for a frameshift in PEA15 (phosphoprotein expressed in astrocytes-15). Notably, previous studies of a Pea15 targeted mutation in mice did not reveal structural brain abnormalities. Affected cats, however, present with a non-progressive hypermetric gait and tremors, develop dissociative behavioral defects and aggression with age, and exhibit profound malformation of the cerebrum, with a 45% average decrease in overall brain weight, and reduction or absence of the ectosylvian, sylvian and anterior cingulate gyrus. Histologically, the cerebral cortical layers are disorganized, there is substantial loss of white matter in tracts such as the corona radiata and internal capsule, but the cerebellum is relatively spared. RNA-seq and immunohistochemical analysis reveal astrocytosis. Fibroblasts cultured from affected cats exhibit increased TNFα-mediated apoptosis, and increased FGFb-induced proliferation, consistent with previous studies implicating PEA15 as an intracellular adapter protein, and suggesting an underlying pathophysiology in which increased death of neurons accompanied by increased proliferation of astrocytes gives rise to abnormal organization of neuronal layers and loss of white matter. Taken together, our work points to a new role for PEA15 in development of a complex cerebral cortex that is only apparent in gyrencephalic species.
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- 2020
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6. By what name shall I call thee?
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Gregory S Barsh and Gregory P Copenhaver
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Genetics ,QH426-470 - Published
- 2020
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7. Mixed methods.
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David J Balding, Gregory S Barsh, Gregory P Copenhaver, and Chengqi Yi
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Genetics ,QH426-470 - Published
- 2020
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8. Evaluating the strength of genetic results: Risks and responsibilities.
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Gregory S Barsh, Gregory M Cooper, Gregory P Copenhaver, Giorgio Sirugo, Hua Tang, and Scott M Williams
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Genetics ,QH426-470 - Published
- 2019
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9. 2019 PLOS Genetics Research Prize: Fruit fly school - language and dialects for communicating a threat.
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Gregory S Barsh, Gregory P Copenhaver, Elapulli Sankaranarayanan Prakash, and Daniela C Zarnescu
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Genetics ,QH426-470 - Published
- 2019
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10. The Plight of Muntaser Ibrahim.
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Giorgio Sirugo, Scott M Williams, Sarah A Tishkoff, Heather J Cordell, Jonathan Marchini, Gregory S Barsh, and Gregory P Copenhaver
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Genetics ,QH426-470 - Published
- 2019
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11. Making room for opinions.
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Gregory P Copenhaver and Gregory S Barsh
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Genetics ,QH426-470 - Published
- 2019
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12. Doubling down on forensic twin studies.
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Gregory P Copenhaver, Bruce Weir, Mark Rothstein, Hua Tang, Scott M Williams, and Gregory S Barsh
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Genetics ,QH426-470 - Published
- 2018
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13. De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay.
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Susan M Hiatt, Matthew B Neu, Ryne C Ramaker, Andrew A Hardigan, Jeremy W Prokop, Miroslava Hancarova, Darina Prchalova, Marketa Havlovicova, Jan Prchal, Viktor Stranecky, Dwight K C Yim, Zöe Powis, Boris Keren, Caroline Nava, Cyril Mignot, Marlene Rio, Anya Revah-Politi, Parisa Hemati, Nicholas Stong, Alejandro D Iglesias, Sharon F Suchy, Rebecca Willaert, Ingrid M Wentzensen, Patricia G Wheeler, Lauren Brick, Mariya Kozenko, Anna C E Hurst, James W Wheless, Yves Lacassie, Richard M Myers, Gregory S Barsh, Zdenek Sedlacek, and Gregory M Cooper
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Genetics ,QH426-470 - Abstract
Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p = 4.93 x 10(-11)) than expected from the estimated random mutation rate. Further, all de novo variants described here affect residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. The affected residues are highly conserved across both RAL- and RAS-family genes, are devoid of variation in large human population datasets, and several are homologous to positions at which disease-associated variants have been observed in other GTPase genes. We directly assayed GTP hydrolysis and RALA effector-protein binding of the observed variants, and found that all but one tested variant significantly reduced both activities compared to wild-type. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases.
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- 2018
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14. 2018 PLOS Genetics Research Prize: Bundling, stabilizing, organizing-The orchestration of acentriolar spindle assembly by microtubule motor proteins.
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Gregory S Barsh, Needhi Bhalla, Francesca Cole, Gregory P Copenhaver, Soni Lacefield, and Diana E Libuda
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Genetics ,QH426-470 - Published
- 2018
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15. Bringing PLOS Genetics Editors to Preprint Servers.
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Gregory S Barsh, Casey M Bergman, Christopher D Brown, Nadia D Singh, and Gregory P Copenhaver
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Genetics ,QH426-470 - Published
- 2016
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16. A Hox-Embedded Long Noncoding RNA: Is It All Hot Air?
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Licia Selleri, Marisa S Bartolomei, Wendy A Bickmore, Lin He, Lisa Stubbs, Wolf Reik, and Gregory S Barsh
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Genetics ,QH426-470 - Published
- 2016
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17. The Language of Genetics In the Interviews of Jane Gitschier.
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Gregory S Barsh and Gregory P Copenhaver
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Genetics ,QH426-470 - Published
- 2016
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18. How the zebrafish got its stripes
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Kelly A McGowan and Gregory S Barsh
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pigment pattern ,melanophore ,xanthophore ,evolution ,danio ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Live-cell imaging and genetic tools reveal a new way in which pigment cells communicate in zebrafish
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- 2016
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19. PLOS Genetics Data Sharing Policy: In Pursuit of Functional Utility.
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Gregory S Barsh, Gregory M Cooper, Gregory P Copenhaver, Greg Gibson, Mark I McCarthy, Hua Tang, and Scott M Williams
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Genetics ,QH426-470 - Published
- 2015
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20. A Decad(e) of Reasons to Contribute to a PLOS Community-Run Journal.
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Gregory P Copenhaver and Gregory S Barsh
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Genetics ,QH426-470 - Published
- 2015
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21. Recurrent evolution of melanism in South American felids.
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Alexsandra Schneider, Corneliu Henegar, Kenneth Day, Devin Absher, Constanza Napolitano, Leandro Silveira, Victor A David, Stephen J O'Brien, Marilyn Menotti-Raymond, Gregory S Barsh, and Eduardo Eizirik
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Genetics ,QH426-470 - Abstract
Morphological variation in natural populations is a genomic test bed for studying the interface between molecular evolution and population genetics, but some of the most interesting questions involve non-model organisms that lack well annotated reference genomes. Many felid species exhibit polymorphism for melanism but the relative roles played by genetic drift, natural selection, and interspecies hybridization remain uncertain. We identify mutations of Agouti signaling protein (ASIP) or the Melanocortin 1 receptor (MC1R) as independent causes of melanism in three closely related South American species: the pampas cat (Leopardus colocolo), the kodkod (Leopardus guigna), and Geoffroy's cat (Leopardus geoffroyi). To assess population level variation in the regions surrounding the causative mutations we apply genomic resources from the domestic cat to carry out clone-based capture and targeted resequencing of 299 kb and 251 kb segments that contain ASIP and MC1R, respectively, from 54 individuals (13-21 per species), achieving enrichment of ~500-2500-fold and ~150x coverage. Our analysis points to unique evolutionary histories for each of the three species, with a strong selective sweep in the pampas cat, a distinctive but short melanism-specific haplotype in the Geoffroy's cat, and reduced nucleotide diversity for both ancestral and melanism-bearing chromosomes in the kodkod. These results reveal an important role for natural selection in a trait of longstanding interest to ecologists, geneticists, and the lay community, and provide a platform for comparative studies of morphological variation in other natural populations.
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- 2015
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22. Dominant Red Coat Color in Holstein Cattle Is Associated with a Missense Mutation in the Coatomer Protein Complex, Subunit Alpha (COPA) Gene.
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Ben Dorshorst, Corneliu Henegar, Xiaoping Liao, Markus Sällman Almén, Carl-Johan Rubin, Shosuke Ito, Kazumasa Wakamatsu, Paul Stothard, Brian Van Doormaal, Graham Plastow, Gregory S Barsh, and Leif Andersson
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Medicine ,Science - Abstract
Coat color in Holstein dairy cattle is primarily controlled by the melanocortin 1 receptor (MC1R) gene, a central determinant of black (eumelanin) vs. red/brown pheomelanin synthesis across animal species. The major MC1R alleles in Holsteins are Dominant Black (MC1RD) and Recessive Red (MC1Re). A novel form of dominant red coat color was first observed in an animal born in 1980. The mutation underlying this phenotype was named Dominant Red and is epistatic to the constitutively activated MC1RD. Here we show that a missense mutation in the coatomer protein complex, subunit alpha (COPA), a gene with previously no known role in pigmentation synthesis, is completely associated with Dominant Red in Holstein dairy cattle. The mutation results in an arginine to cysteine substitution at an amino acid residue completely conserved across eukaryotes. Despite this high level of conservation we show that both heterozygotes and homozygotes are healthy and viable. Analysis of hair pigment composition shows that the Dominant Red phenotype is similar to the MC1R Recessive Red phenotype, although less effective at reducing eumelanin synthesis. RNA-seq data similarly show that Dominant Red animals achieve predominantly pheomelanin synthesis by downregulating genes normally required for eumelanin synthesis. COPA is a component of the coat protein I seven subunit complex that is involved with retrograde and cis-Golgi intracellular coated vesicle transport of both protein and RNA cargo. This suggests that Dominant Red may be caused by aberrant MC1R protein or mRNA trafficking within the highly compartmentalized melanocyte, mimicking the effect of the Recessive Red loss of function MC1R allele.
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- 2015
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23. Enhanced stability and polyadenylation of select mRNAs support rapid thermogenesis in the brown fat of a hibernator
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Katharine R Grabek, Cecilia Diniz Behn, Gregory S Barsh, Jay R Hesselberth, and Sandra L Martin
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Ictidomys tridecemlineatus ,non-shivering thermogenesis ,biological oscillation ,digital transcriptome ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
During hibernation, animals cycle between torpor and arousal. These cycles involve dramatic but poorly understood mechanisms of dynamic physiological regulation at the level of gene expression. Each cycle, Brown Adipose Tissue (BAT) drives periodic arousal from torpor by generating essential heat. We applied digital transcriptome analysis to precisely timed samples to identify molecular pathways that underlie the intense activity cycles of hibernator BAT. A cohort of transcripts increased during torpor, paradoxical because transcription effectively ceases at these low temperatures. We show that this increase occurs not by elevated transcription but rather by enhanced stabilization associated with maintenance and/or extension of long poly(A) tails. Mathematical modeling further supports a temperature-sensitive mechanism to protect a subset of transcripts from ongoing bulk degradation instead of increased transcription. This subset was enriched in a C-rich motif and genes required for BAT activation, suggesting a model and mechanism to prioritize translation of key proteins for thermogenesis.
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- 2015
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24. Modeling 3D facial shape from DNA.
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Peter Claes, Denise K Liberton, Katleen Daniels, Kerri Matthes Rosana, Ellen E Quillen, Laurel N Pearson, Brian McEvoy, Marc Bauchet, Arslan A Zaidi, Wei Yao, Hua Tang, Gregory S Barsh, Devin M Absher, David A Puts, Jorge Rocha, Sandra Beleza, Rinaldo W Pereira, Gareth Baynam, Paul Suetens, Dirk Vandermeulen, Jennifer K Wagner, James S Boster, and Mark D Shriver
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Genetics ,QH426-470 - Abstract
Human facial diversity is substantial, complex, and largely scientifically unexplained. We used spatially dense quasi-landmarks to measure face shape in population samples with mixed West African and European ancestry from three locations (United States, Brazil, and Cape Verde). Using bootstrapped response-based imputation modeling (BRIM), we uncover the relationships between facial variation and the effects of sex, genomic ancestry, and a subset of craniofacial candidate genes. The facial effects of these variables are summarized as response-based imputed predictor (RIP) variables, which are validated using self-reported sex, genomic ancestry, and observer-based facial ratings (femininity and proportional ancestry) and judgments (sex and population group). By jointly modeling sex, genomic ancestry, and genotype, the independent effects of particular alleles on facial features can be uncovered. Results on a set of 20 genes showing significant effects on facial features provide support for this approach as a novel means to identify genes affecting normal-range facial features and for approximating the appearance of a face from genetic markers.
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- 2014
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25. Genetic architecture of skin and eye color in an African-European admixed population.
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Sandra Beleza, Nicholas A Johnson, Sophie I Candille, Devin M Absher, Marc A Coram, Jailson Lopes, Joana Campos, Isabel Inês Araújo, Tovi M Anderson, Bjarni J Vilhjálmsson, Magnus Nordborg, António Correia E Silva, Mark D Shriver, Jorge Rocha, Gregory S Barsh, and Hua Tang
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Genetics ,QH426-470 - Abstract
Variation in human skin and eye color is substantial and especially apparent in admixed populations, yet the underlying genetic architecture is poorly understood because most genome-wide studies are based on individuals of European ancestry. We study pigmentary variation in 699 individuals from Cape Verde, where extensive West African/European admixture has given rise to a broad range in trait values and genomic ancestry proportions. We develop and apply a new approach for measuring eye color, and identify two major loci (HERC2[OCA2] P = 2.3 × 10(-62), SLC24A5 P = 9.6 × 10(-9)) that account for both blue versus brown eye color and varying intensities of brown eye color. We identify four major loci (SLC24A5 P = 5.4 × 10(-27), TYR P = 1.1 × 10(-9), APBA2[OCA2] P = 1.5 × 10(-8), SLC45A2 P = 6 × 10(-9)) for skin color that together account for 35% of the total variance, but the genetic component with the largest effect (~44%) is average genomic ancestry. Our results suggest that adjacent cis-acting regulatory loci for OCA2 explain the relationship between skin and eye color, and point to an underlying genetic architecture in which several genes of moderate effect act together with many genes of small effect to explain ~70% of the estimated heritability.
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- 2013
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26. Levels of the Mahogunin Ring Finger 1 E3 ubiquitin ligase do not influence prion disease.
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Derek Silvius, Rose Pitstick, Misol Ahn, Delisha Meishery, Abby Oehler, Gregory S Barsh, Stephen J DeArmond, George A Carlson, and Teresa M Gunn
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Medicine ,Science - Abstract
Prion diseases are rare but invariably fatal neurodegenerative disorders. They are associated with spongiform encephalopathy, a histopathology characterized by the presence of large, membrane-bound vacuolar structures in the neuropil of the brain. While the primary cause is recognized as conversion of the normal form of prion protein (PrP(C)) to a conformationally distinct, pathogenic form (PrP(Sc)), the cellular pathways and mechanisms that lead to spongiform change, neuronal dysfunction and death are not known. Mice lacking the Mahogunin Ring Finger 1 (MGRN1) E3 ubiquitin ligase develop spongiform encephalopathy by 9 months of age but do not become ill. In cell culture, PrP aberrantly present in the cytosol was reported to interact with and sequester MGRN1. This caused endo-lysosomal trafficking defects similar to those observed when Mgrn1 expression is knocked down, implicating disrupted MGRN1-dependent trafficking in the pathogenesis of prion disease. As these defects were rescued by over-expression of MGRN1, we investigated whether reduced or elevated Mgrn1 expression influences the onset, progression or pathology of disease in mice inoculated with PrP(Sc). No differences were observed, indicating that disruption of MGRN1-dependent pathways does not play a significant role in the pathogenesis of transmissible spongiform encephalopathy.
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- 2013
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27. Guidelines for genome-wide association studies.
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Gregory S Barsh, Gregory P Copenhaver, Greg Gibson, and Scott M Williams
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Genetics ,QH426-470 - Published
- 2012
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28. Genome-wide association studies of quantitatively measured skin, hair, and eye pigmentation in four European populations.
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Sophie I Candille, Devin M Absher, Sandra Beleza, Marc Bauchet, Brian McEvoy, Nanibaa' A Garrison, Jun Z Li, Richard M Myers, Gregory S Barsh, Hua Tang, and Mark D Shriver
- Subjects
Medicine ,Science - Abstract
Pigmentation of the skin, hair, and eyes varies both within and between human populations. Identifying the genes and alleles underlying this variation has been the goal of many candidate gene and several genome-wide association studies (GWAS). Most GWAS for pigmentary traits to date have been based on subjective phenotypes using categorical scales. But skin, hair, and eye pigmentation vary continuously. Here, we seek to characterize quantitative variation in these traits objectively and accurately and to determine their genetic basis. Objective and quantitative measures of skin, hair, and eye color were made using reflectance or digital spectroscopy in Europeans from Ireland, Poland, Italy, and Portugal. A GWAS was conducted for the three quantitative pigmentation phenotypes in 176 women across 313,763 SNP loci, and replication of the most significant associations was attempted in a sample of 294 European men and women from the same countries. We find that the pigmentation phenotypes are highly stratified along axes of European genetic differentiation. The country of sampling explains approximately 35% of the variation in skin pigmentation, 31% of the variation in hair pigmentation, and 40% of the variation in eye pigmentation. All three quantitative phenotypes are correlated with each other. In our two-stage association study, we reproduce the association of rs1667394 at the OCA2/HERC2 locus with eye color but we do not identify new genetic determinants of skin and hair pigmentation supporting the lack of major genes affecting skin and hair color variation within Europe and suggesting that not only careful phenotyping but also larger cohorts are required to understand the genetic architecture of these complex quantitative traits. Interestingly, we also see that in each of these four populations, men are more lightly pigmented in the unexposed skin of the inner arm than women, a fact that is underappreciated and may vary across the world.
- Published
- 2012
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29. How the leopard hides its spots: ASIP mutations and melanism in wild cats.
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Alexsandra Schneider, Victor A David, Warren E Johnson, Stephen J O'Brien, Gregory S Barsh, Marilyn Menotti-Raymond, and Eduardo Eizirik
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Medicine ,Science - Abstract
The occurrence of melanism (darkening of the background coloration) is documented in 13 felid species, in some cases reaching high frequencies at the population level. Recent analyses have indicated that it arose multiple times in the Felidae, with three different species exhibiting unique mutations associated with this trait. The causative mutations in the remaining species have so far not been identified, precluding a broader assessment of the evolutionary dynamics of melanism in the Felidae. Among these, the leopard (Panthera pardus) is a particularly important target for research, given the iconic status of the 'black panther' and the extremely high frequency of melanism observed in some Asian populations. Another felid species from the same region, the Asian golden cat (Pardofelis temminckii), also exhibits frequent records of melanism in some areas. We have sequenced the coding region of the Agouti Signaling Protein (ASIP) gene in multiple leopard and Asian golden cat individuals, and identified distinct mutations strongly associated with melanism in each of them. The single nucleotide polymorphism (SNP) detected among the P. pardus individuals was caused by a nonsense mutation predicted to completely ablate ASIP function. A different SNP was identified in P. temminckii, causing a predicted amino acid change that should also induce loss of function. Our results reveal two additional cases of species-specific mutations implicated in melanism in the Felidae, and indicate that ASIP mutations may play an important role in naturally-occurring coloration polymorphism.
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- 2012
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30. Ancestral components of admixed genomes in a Mexican cohort.
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Nicholas A Johnson, Marc A Coram, Mark D Shriver, Isabelle Romieu, Gregory S Barsh, Stephanie J London, and Hua Tang
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Genetics ,QH426-470 - Abstract
For most of the world, human genome structure at a population level is shaped by interplay between ancient geographic isolation and more recent demographic shifts, factors that are captured by the concepts of biogeographic ancestry and admixture, respectively. The ancestry of non-admixed individuals can often be traced to a specific population in a precise region, but current approaches for studying admixed individuals generally yield coarse information in which genome ancestry proportions are identified according to continent of origin. Here we introduce a new analytic strategy for this problem that allows fine-grained characterization of admixed individuals with respect to both geographic and genomic coordinates. Ancestry segments from different continents, identified with a probabilistic model, are used to construct and study "virtual genomes" of admixed individuals. We apply this approach to a cohort of 492 parent-offspring trios from Mexico City. The relative contributions from the three continental-level ancestral populations-Africa, Europe, and America-vary substantially between individuals, and the distribution of haplotype block length suggests an admixing time of 10-15 generations. The European and Indigenous American virtual genomes of each Mexican individual can be traced to precise regions within each continent, and they reveal a gradient of Amerindian ancestry between indigenous people of southwestern Mexico and Mayans of the Yucatan Peninsula. This contrasts sharply with the African roots of African Americans, which have been characterized by a uniform mixing of multiple West African populations. We also use the virtual European and Indigenous American genomes to search for the signatures of selection in the ancestral populations, and we identify previously known targets of selection in other populations, as well as new candidate loci. The ability to infer precise ancestral components of admixed genomes will facilitate studies of disease-related phenotypes and will allow new insight into the adaptive and demographic history of indigenous people.
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- 2011
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31. A nervous origin for fish stripes.
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Robert N Kelsh and Gregory S Barsh
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Genetics ,QH426-470 - Published
- 2011
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32. PDK1-Foxo1 in agouti-related peptide neurons regulates energy homeostasis by modulating food intake and energy expenditure.
- Author
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Yongheng Cao, Masanori Nakata, Shiki Okamoto, Eisuke Takano, Toshihiko Yada, Yasuhiko Minokoshi, Yukio Hirata, Kazunori Nakajima, Kristy Iskandar, Yoshitake Hayashi, Wataru Ogawa, Gregory S Barsh, Hiroshi Hosoda, Kenji Kangawa, Hiroshi Itoh, Tetsuo Noda, Masato Kasuga, and Jun Nakae
- Subjects
Medicine ,Science - Abstract
Insulin and leptin intracellular signaling pathways converge and act synergistically on the hypothalamic phosphatidylinositol-3-OH kinase/3-phosphoinositide-dependent protein kinase 1 (PDK1). However, little is known about whether PDK1 in agouti-related peptide (AGRP) neurons contributes to energy homeostasis. We generated AGRP neuron-specific PDK1 knockout (AGRPPdk1(-/-)) mice and mice with selective expression of transactivation-defective Foxo1 (Δ256Foxo1(AGRP)Pdk1(-/-)). The AGRPPdk1(-/-) mice showed reductions in food intake, body length, and body weight. The Δ256Foxo1(AGRP)Pdk1(-/-) mice showed increased body weight, food intake, and reduced locomotor activity. After four weeks of calorie-restricted feeding, oxygen consumption and locomotor activity were elevated in AGRPPdk1(-/-) mice and reduced in Δ256Foxo1(AGRP)Pdk1(-/-) mice. In vitro, ghrelin-induced changes in [Ca(2+)](i) and inhibition of ghrelin by leptin were significantly attenuated in AGRPPdk1(-/-) neurons compared to control neurons. However, ghrelin-induced [Ca(2+)](i) changes and leptin inhibition were restored in Δ256Foxo1(AGRP)Pdk1(-/-) mice. These results suggested that PDK1 and Foxo1 signaling pathways play important roles in the control of energy homeostasis through AGRP-independent mechanisms.
- Published
- 2011
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33. Scientists
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Gregory S Barsh and Gregory P Copenhaver
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Genetics ,QH426-470 - Published
- 2009
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34. PLoS Genetics turns three: looking back, looking ahead.
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Wayne N Frankel and Gregory S Barsh
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Genetics ,QH426-470 - Published
- 2008
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35. Mammalian comparative sequence analysis of the Agrp locus.
- Author
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Christopher B Kaelin, Gregory M Cooper, Arend Sidow, and Gregory S Barsh
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Medicine ,Science - Abstract
Agouti-related protein encodes a neuropeptide that stimulates food intake. Agrp expression in the brain is restricted to neurons in the arcuate nucleus of the hypothalamus and is elevated by states of negative energy balance. The molecular mechanisms underlying Agrp regulation, however, remain poorly defined. Using a combination of transgenic and comparative sequence analysis, we have previously identified a 760 bp conserved region upstream of Agrp which contains STAT binding elements that participate in Agrp transcriptional regulation. In this study, we attempt to improve the specificity for detecting conserved elements in this region by comparing genomic sequences from 10 mammalian species. Our analysis reveals a symmetrical organization of conserved sequences upstream of Agrp, which cluster into two inverted repeat elements. Conserved sequences within these elements suggest a role for homeodomain proteins in the regulation of Agrp and provide additional targets for functional evaluation.
- Published
- 2007
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36. Distinct pigmentary and melanocortin 1 receptor-dependent components of cutaneous defense against ultraviolet radiation.
- Author
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Craig S April and Gregory S Barsh
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Genetics ,QH426-470 - Abstract
Genetic variation at the melanocortin 1 receptor (MC1R) is an important risk factor for developing ultraviolet (UV) radiation-induced skin cancer, the most common form of cancer in humans. The underlying mechanisms by which the MC1R defends against UV-induced skin cancer are not known. We used neonatal mouse skin (which, like human skin, contains a mixture of melanocytes and keratinocytes) to study how pigment cells and Mc1r genotype affect the genome-level response to UV radiation. Animals without viable melanocytes (Kit(W-v)/Kit(W-v)) or animals lacking a functional Mc1r (Mc1r(e)/Mc1r(e)) were exposed to sunburn-level doses of UVB radiation, and the patterns of large-scale gene expression in the basal epidermis were compared to each other and to nonmutant animals. Our analysis revealed discrete Kit- and Mc1r-dependent UVB transcriptional responses in the basal epidermis. The Kit-dependent UVB response was characterized largely by an enrichment of oxidative and endoplasmic reticulum stress genes, highlighting a distinctive role for pigmented melanocytes in mediating antioxidant defenses against genotoxic stresses within the basal epidermal environment. By contrast, the Mc1r-dependent UVB response contained an abundance of genes associated with regulating the cell cycle and oncogenesis. To test the clinical relevance of these observations, we analyzed publicly available data sets for primary melanoma and melanoma metastases and found that the set of genes specific for the Mc1r-dependent UVB response was able to differentiate between different clinical subtypes. Our analysis also revealed that the classes of genes induced by UVB differ from those repressed by UVB with regard to their biological functions, their overall number, and their size. The findings described here offer new insights into the transcriptional nature of the UV response in the skin and provide a molecular framework for the underlying mechanisms by which melanocytes and the Mc1r independently mediate and afford protection against UV radiation.
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- 2007
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37. Effects of hypothalamic neurodegeneration on energy balance.
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Allison Wanting Xu, Christopher B Kaelin, Gregory J Morton, Kayoko Ogimoto, Kimber Stanhope, James Graham, Denis G Baskin, Peter Havel, Michael W Schwartz, and Gregory S Barsh
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Biology (General) ,QH301-705.5 - Abstract
Normal aging in humans and rodents is accompanied by a progressive increase in adiposity. To investigate the role of hypothalamic neuronal circuits in this process, we used a Cre-lox strategy to create mice with specific and progressive degeneration of hypothalamic neurons that express agouti-related protein (Agrp) or proopiomelanocortin (Pomc), neuropeptides that promote positive or negative energy balance, respectively, through their opposing effects on melanocortin receptor signaling. In previous studies, Pomc mutant mice became obese, but Agrp mutant mice were surprisingly normal, suggesting potential compensation by neuronal circuits or genetic redundancy. Here we find that Pomc-ablation mice develop obesity similar to that described for Pomc knockout mice, but also exhibit defects in compensatory hyperphagia similar to what occurs during normal aging. Agrp-ablation female mice exhibit reduced adiposity with normal compensatory hyperphagia, while animals ablated for both Pomc and Agrp neurons exhibit an additive interaction phenotype. These findings provide new insight into the roles of hypothalamic neurons in energy balance regulation, and provide a model for understanding defects in human energy balance associated with neurodegeneration and aging.
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- 2005
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38. Dorsoventral patterning of the mouse coat by Tbx15.
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Sophie I Candille, Catherine D Van Raamsdonk, Changyou Chen, Sanne Kuijper, Yanru Chen-Tsai, Andreas Russ, Frits Meijlink, and Gregory S Barsh
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Biology (General) ,QH301-705.5 - Abstract
Many members of the animal kingdom display coat or skin color differences along their dorsoventral axis. To determine the mechanisms that control regional differences in pigmentation, we have studied how a classical mouse mutation, droopy ear (de(H)), affects dorsoventral skin characteristics, especially those under control of the Agouti gene. Mice carrying the Agouti allele black-and-tan (a(t)) normally have a sharp boundary between dorsal black hair and yellow ventral hair; the de(H) mutation raises the pigmentation boundary, producing an apparent dorsal-to-ventral transformation. We identify a 216 kb deletion in de(H) that removes all but the first exon of the Tbx15 gene, whose embryonic expression in developing mesenchyme correlates with pigmentary and skeletal malformations observed in de(H)/de(H) animals. Construction of a targeted allele of Tbx15 confirmed that the de(H) phenotype was caused by Tbx15 loss of function. Early embryonic expression of Tbx15 in dorsal mesenchyme is complementary to Agouti expression in ventral mesenchyme; in the absence of Tbx15, expression of Agouti in both embryos and postnatal animals is displaced dorsally. Transplantation experiments demonstrate that positional identity of the skin with regard to dorsoventral pigmentation differences is acquired by E12.5, which is shortly after early embryonic expression of Tbx15. Fate-mapping studies show that the dorsoventral pigmentation boundary is not in register with a previously identified dermal cell lineage boundary, but rather with the limb dorsoventral boundary. Embryonic expression of Tbx15 in dorsolateral mesenchyme provides an instructional cue required to establish the future positional identity of dorsal dermis. These findings represent a novel role for T-box gene action in embryonic development, identify a previously unappreciated aspect of dorsoventral patterning that is widely represented in furred mammals, and provide insight into the mechanisms that underlie region-specific differences in body morphology.
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- 2004
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39. In PLoS Biology, volume 1, issue 1:: What Controls Variation in Human Skin Color?
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Gregory S Barsh
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Biology (General) ,QH301-705.5 - Published
- 2003
40. What controls variation in human skin color?
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Gregory S Barsh
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Biology (General) ,QH301-705.5 - Published
- 2003
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41. Parents’ Perspectives on the Utility of Genomic Sequencing in the Neonatal Intensive Care Unit
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Brothers, Amy A. Lemke, Michelle L. Thompson, Emily C. Gimpel, Katelyn C. McNamara, Carla A. Rich, Candice R. Finnila, Meagan E. Cochran, James M. J. Lawlor, Kelly M. East, Kevin M. Bowling, Donald R. Latner, Susan M. Hiatt, Michelle D. Amaral, Whitley V. Kelley, Veronica Greve, David E. Gray, Stephanie A. Felker, Hannah Meddaugh, Ashley Cannon, Amanda Luedecke, Kelly E. Jackson, Laura G. Hendon, Hillary M. Janani, Marla Johnston, Lee Ann Merin, Sarah L. Deans, Carly Tuura, Trent Hughes, Heather Williams, Kelly Laborde, Matthew B. Neu, Jessica Patrick-Esteve, Anna C. E. Hurst, Brian M. Kirmse, Renate Savich, Steven B. Spedale, Sara J. Knight, Gregory S. Barsh, Bruce R. Korf, Gregory M. Cooper, and Kyle B.
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genome sequencing ,parent–infant bonding ,timing of disclosure of results ,parental guilt ,utility - Abstract
Background: It is critical to understand the wide-ranging clinical and non-clinical effects of genome sequencing (GS) for parents in the NICU context. We assessed parents’ experiences with GS as a first-line diagnostic tool for infants with suspected genetic conditions in the NICU. Methods: Parents of newborns (N = 62) suspected of having a genetic condition were recruited across five hospitals in the southeast United States as part of the SouthSeq study. Semi-structured interviews (N = 78) were conducted after parents received their child’s sequencing result (positive, negative, or variants of unknown significance). Thematic analysis was performed on all interviews. Results: Key themes included that (1) GS in infancy is important for reproductive decision making, preparing for the child’s future care, ending the diagnostic odyssey, and sharing results with care providers; (2) the timing of disclosure was acceptable for most parents, although many reported the NICU environment was overwhelming; and (3) parents deny that receiving GS results during infancy exacerbated parent–infant bonding, and reported variable impact on their feelings of guilt. Conclusion: Parents reported that GS during the neonatal period was useful because it provided a “backbone” for their child’s care. Parents did not consistently endorse negative impacts like interference with parent–infant bonding.
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- 2023
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42. Endless microbes most beautiful and most wonderful
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Gregory S. Barsh, Geraldine Butler, Gregory P. Copenhaver, Sean Crosson, Lotte Søgaard-Andersen, and Eva H. Stukenbrock
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Cancer Research ,Genetics ,Molecular Biology ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics - Abstract
Since Antonie van Leeuwenhoek first observed microbes, we have come to learn that life on our planet includes not only the macroscopic lifeforms visible to the unaided eye that Charles Darwin studied but also an immense diversity of microbes (Fig 1). We have learned that microorganisms influence nearly every aspect of human existence with beneficial or detrimental effects. With their pivotal roles in biomass conversion, biogeochemical cycles, photosynthesis, and in promoting plant growth, life on this planet ultimately depends on the activities of microorganisms. On the other hand, microorganisms are the etiological agents of many diseases in humans, animals, and plants, causing massive economic losses yearly. Microorganisms also contribute significantly to the production of greenhouse gases such as CO2 and CH4 and, thus, contribute to global warming. In the past decade, we have also learned that microorganisms inhabiting the human body, i.e., the human microbiome, have profound effects on human physiology. Not to forget, some of our most delicious food products and beverages get their distinct qualities from microorganisms, and the pharmaceutical and biotechnological industry relies heavily on microbes. In terms of research, many technological breakthroughs in molecular biology, such as DNA cloning, PCR, and CRISPR-Cas technologies have their origin in microbes. Therefore, research in microbiology is as important now as it ever was.
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- 2023
43. Genome sequencing as a first-line diagnostic test for hospitalized infants
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Kevin M. Bowling, Michelle L. Thompson, Candice R. Finnila, Susan M. Hiatt, Donald R. Latner, Michelle D. Amaral, James M.J. Lawlor, Kelly M. East, Meagan E. Cochran, Veronica Greve, Whitley V. Kelley, David E. Gray, Stephanie A. Felker, Hannah Meddaugh, Ashley Cannon, Amanda Luedecke, Kelly E. Jackson, Laura G. Hendon, Hillary M. Janani, Marla Johnston, Lee Ann Merin, Sarah L. Deans, Carly Tuura, Heather Williams, Kelly Laborde, Matthew B. Neu, Jessica Patrick-Esteve, Anna C.E. Hurst, Jegen Kandasamy, Wally Carlo, Kyle B. Brothers, Brian M. Kirmse, Renate Savich, Duane Superneau, Steven B. Spedale, Sara J. Knight, Gregory S. Barsh, Bruce R. Korf, and Gregory M. Cooper
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Base Sequence ,Diagnostic Tests, Routine ,First line ,Chromosome Mapping ,Humans ,Diagnostic test ,Genetic Testing ,Genomics ,Computational biology ,Biology ,Article ,Genetics (clinical) ,DNA sequencing - Abstract
PURPOSE: SouthSeq is a translational research study that performed genome sequencing (GS) for infants with symptoms suggestive of a genetic disorder. Recruitment targeted racial/ethnic minorities and rural, medically underserved areas in the Southeastern US that are historically under-represented in genomic medicine research. METHODS: GS and analysis were performed for 367 infants to detect disease-causal variation concurrent with standard of care evaluation and testing. RESULTS: Definitive diagnostic (DD) or likely diagnostic (LD) genetic findings were identified in 30% of infants and 14% harbored an uncertain result. Only 43% of DD/LD findings were identified via concurrent clinical genetic testing suggesting that GS testing is better for obtaining early genetic diagnosis. We also identified phenotypes that correlate with the likelihood of receiving a DD/LD finding, such as craniofacial, ophthalmologic, auditory, skin, and hair abnormalities. We did not observe any differences in diagnostic rates between racial/ethnic groups. CONCLUSION: We describe one of the largest-to-date GS cohorts of ill infants, enriched for African American and rural patients. Our results demonstrate the utility of GS as it provides early in life detection of clinically relevant genetic variation not identified via current clinical genetic testing, particularly for infants exhibiting certain phenotypic features.
- Published
- 2022
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- View/download PDF
44. Whole-genome sequences shed light on the demographic history and contemporary genetic erosion of free-ranging jaguar (Panthera onca) populations
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Gustavo P. Lorenzana, Oliver A. Ryder, Leandro Silveira, Dênis A. Sana, Eduardo Eizirik, William J. Murphy, Jeremy Johnson, Laury Cullen, Joares A. May, Daniel Luis Zanella Kantek, Henrique V. Figueiró, Ronaldo Gonçalves Morato, Elinor K. Karlsson, Christopher B. Kaelin, Gregory S. Barsh, and Edsel Amorim Moraes Jr.
- Subjects
Conservation of Natural Resources ,Free ranging ,Jaguar ,Demographic history ,Panthera onca ,Biology ,Genome ,Evolutionary biology ,biology.animal ,Genetics ,Animals ,Panthera ,Genetic erosion ,Molecular Biology ,Demography - Published
- 2022
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- View/download PDF
45. Ancestry dynamics and trait selection in a designer cat breed
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Christopher B. Kaelin, Kelly A. McGowan, Anthony D. Hutcherson, John M. Delay, and Gregory S. Barsh
- Abstract
SummaryThe Bengal cat breed was developed from intercrosses between the Asian leopard cat,Prionailurus bengalensis, and the domestic cat,Felis silvestris catus, with a last common ancestor 6 million years ago. Predicted to contain ~95% of their genome from domestic cats, regions of the leopard cat genome are thought to account for unique pelage traits and ornate color patterns of the Bengal breed, which are similar to those of ocelots and jaguars. We explore ancestry distribution and selection signatures in the Bengal breed using reduced representation and whole genome sequencing from 905 cats. Overall, leopard cat introgressions are reduced twofold from expectation and include examples of genetic incompatibility—reduced expression of a leopard cat gene in a domestic cat background—underlying the color traitsCharcoaland contributing to coat color variation. Leopard cat introgressions do not show strong signatures of selection; instead, selective sweeps in Bengal cats are associated with domestic, rather than leopard cat haplotypes, and harbor candidate genes for pelage and color pattern. We identify the molecular and phenotypic basis of one selective sweep as reduced expression of theFgfr2gene, which underliesGlitter, a desirable trait that affects hair texture and light reflectivity.
- Published
- 2022
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46. Developmental genetics of color pattern establishment in cats
- Author
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Gregory S. Barsh, Kelly A. McGowan, and Christopher B. Kaelin
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Keratinocytes ,Genotype ,Science ,Epidermal thickness ,General Physics and Astronomy ,Evolutionary biology ,Biology ,Development ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Article ,Wnt inhibitor ,Gene expression ,medicine ,Animals ,Author Correction ,Gene ,Wnt Signaling Pathway ,Skin ,Regulation of gene expression ,Mutation ,Multidisciplinary ,CATS ,Pigmentation ,Wnt signaling pathway ,Gene Expression Regulation, Developmental ,RNA sequencing ,Cat ,General Chemistry ,Hair follicle ,Phenotype ,medicine.anatomical_structure ,Developmental genetics ,Animals, Domestic ,Cats ,Pattern formation ,Intercellular Signaling Peptides and Proteins ,Pattern type ,Epidermis ,Single-Cell Analysis - Abstract
Intricate color patterns are a defining aspect of morphological diversity in the Felidae. We applied morphological and single-cell gene expression analysis to fetal skin of domestic cats to identify when, where, and how, during fetal development, felid color patterns are established. Early in development, we identify stripe-like alterations in epidermal thickness preceded by a gene expression pre-pattern. The secreted Wnt inhibitor encoded by Dickkopf 4 plays a central role in this process, and is mutated in cats with the Ticked pattern type. Our results bring molecular understanding to how the leopard got its spots, suggest that similar mechanisms underlie periodic color pattern and periodic hair follicle spacing, and identify targets for diverse pattern variation in other mammals., Intricate color patterns are a defining aspect of morphological diversity in the Felidae. Here the authors apply morphological and single-cell gene expression analysis to fetal skin of domestic cats to identify when, where, and how, during fetal development, felid color patterns are established.
- Published
- 2021
47. Genetic architecture and evolution of color variation in American black bears
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Emily E. Puckett, Isis S. Davis, Dawn C. Harper, Kazumasa Wakamatsu, Gopal Battu, Jerrold L. Belant, Dean E. Beyer, Colin Carpenter, Anthony P. Crupi, Maria Davidson, Christopher S. DePerno, Nicholas Forman, Nicholas L. Fowler, David L. Garshelis, Nicholas Gould, Kerry Gunther, Mark Haroldson, Shosuke Ito, David Kocka, Carl Lackey, Ryan Leahy, Caitlin Lee-Roney, Tania Lewis, Ashley Lutto, Kelly McGowan, Colleen Olfenbuttel, Mike Orlando, Alexander Platt, Matthew D. Pollard, Megan Ramaker, Heather Reich, Jaime L. Sajecki, Stephanie K. Sell, Jennifer Strules, Seth Thompson, Frank van Manen, Craig Whitman, Ryan Williamson, Frederic Winslow, Christopher B. Kaelin, Michael S. Marks, and Gregory S. Barsh
- Subjects
General Agricultural and Biological Sciences ,General Biochemistry, Genetics and Molecular Biology - Abstract
SUMMARYColor variation is a frequent evolutionary substrate for camouflage in small mammals but the underlying genetics and evolutionary forces that drive color variation in natural populations of large mammals are mostly unexplained. The American black bear, Ursus americanus, exhibits a range of colors including the cinnamon morph which has a similar color to the brown bear, U. arctos, and is found at high frequency in the American southwest. Reflectance and chemical melanin measurements showed little distinction between U. arctos and cinnamon U. americanus individuals. We used a genome-wide association for hair color as a quantitative trait in 151 U. americanus individuals and identified a single major locus (P < 10−13). Additional genomic and functional studies identified a missense alteration (R153C) in Tyrosinase-related protein 1 (TYRP1) that impaired protein localization and decreased pigment production. Population genetic analyses and demographic modeling indicated that the R153C variant arose 9.36kya in a southwestern population where it likely provided a selective advantage, spreading both northwards and eastwards by gene flow. A different TYRP1 allele, R114C, contributes to the characteristic brown color of U. arctos, but is not fixed across the range.HIGHLIGHTSThe cinnamon morph of American black bears and brown bears have different missense mutations in TYRP1 that account for their similar colorationTYRP1 variants in American black bears and brown bears are loss-of-function alleles associated with impaired protein localization to melanosomesIn American black bears, the variant causing the cinnamon morph arose 9,360 years ago in the western lineage where it provides an adaptive advantage, and has spread northwards and eastwards by migration
- Published
- 2022
- Full Text
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48. The Therapeutic Odyssey: Positioning Genomic Sequencing in the Search for a Child’s Best Possible Life
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Janet Elizabeth Childerhose, Carla Rich, Kelly M. East, Whitley V. Kelley, Shirley Simmons, Candice R. Finnila, Kevin Bowling, Michelle Amaral, Susan M. Hiatt, Michelle Thompson, David E. Gray, James M. J. Lawlor, Richard M. Myers, Gregory S. Barsh, Edward J. Lose, Martina E. Bebin, Greg M. Cooper, and Kyle Bertram Brothers
- Subjects
Parents ,Motivation ,Health (social science) ,Base Sequence ,Health Policy ,Genomic sequencing ,Genomics ,Computational biology ,medicine.disease ,Article ,DNA sequencing ,Philosophy ,Intellectual disability ,medicine ,Humans ,Family ,Child ,Genetic diagnosis ,Psychology ,human activities - Abstract
BACKGROUND: The desire of parents to obtain a genetic diagnosis for their child with intellectual disability and associated symptoms has long been framed as a diagnostic odyssey, an arduous and sometimes perilous journey focused on the goal of identifying a cause for the child’s condition. METHODS: Semi-structured interviews (N=60) were conducted with parents of children (N=59, aged 2–24 years) with intellectual disability and/or developmental delay (IDD) who underwent genome sequencing at a single pediatric multispecialty clinic. Interviews were conducted after parents received their child’s sequencing result (positive findings, negative findings, or variants of unknown significance). Thematic analysis was performed on all interviews. RESULTS: Parents reported that obtaining a genetic diagnosis was one important step in their overall goal of helping their child live their best life possible life. They intended to use the result as a tool to help their child by seeking the correct school placement and obtaining benefits and therapeutic services. CONCLUSIONS: For the parents of children with IDD, the search for a genetic diagnosis is best conceptualized as a part of parents’ ongoing efforts to leverage various diagnoses to obtain educational and therapeutic services for their children. Cleaving parents’ search for a genetic diagnosis from these broader efforts obscures the value that some parents place on a sequencing result in finding and tailoring therapies and services beyond the clinic. Interviews with parents reveal, therefore, that genomic sequencing is best understood as one important stage of an ongoing therapeutic odyssey that largely takes place outside the clinic. Findings suggest the need to expand translational research efforts to contextualize a genetic diagnosis within parents’ broader efforts to obtain educational and therapeutic services outside clinical contexts.
- Published
- 2021
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49. Identifying rare, medically relevant variation via population-based genomic screening in Alabama: opportunities and pitfalls
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Kelly M. East, Whitley V. Kelley, James M.J. Lawlor, Kelly Williams, Irene P. Moss, Gregory S. Barsh, Michelle L. Thompson, Devin Absher, Jeffrey C. Edberg, Gregory M. Cooper, Kevin M. Bowling, E. Christopher Partridge, David E. Gray, Bruce R. Korf, and Anna C.E. Hurst
- Subjects
0301 basic medicine ,Genetics ,Disease gene ,Sanger sequencing ,education.field_of_study ,Population ,Population based ,030105 genetics & heredity ,Biology ,Genomic screening ,03 medical and health sciences ,symbols.namesake ,030104 developmental biology ,False positive paradox ,symbols ,Allele ,education ,Return of results ,Genetics (clinical) - Abstract
Purpose To evaluate the effectiveness and specificity of population-based genomic screening in Alabama. Methods The Alabama Genomic Health Initiative (AGHI) has enrolled and evaluated 5369 participants for the presence of pathogenic/likely pathogenic (P/LP) variants using the Illumina Global Screening Array (GSA), with validation of all P/LP variants via Sanger sequencing in a CLIA-certified laboratory before return of results. Results Among 131 variants identified by the GSA that were evaluated by Sanger sequencing, 67 (51%) were false positives (FP). For 39 of the 67 FP variants, a benign/likely benign variant was present at or near the targeted P/LP variant. Variants detected within African American individuals were significantly enriched for FPs, likely due to a higher rate of nontargeted alternative alleles close to array-targeted P/LP variants. Conclusion In AGHI, we have implemented an array-based process to screen for highly penetrant genetic variants in actionable disease genes. We demonstrate the need for clinical validation of array-identified variants in direct-to-consumer or population testing, especially for diverse populations.
- Published
- 2021
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50. Long live the king: chromosome-level assembly of the lion (Panthera leo) using linked-read, Hi-C, and long-read data
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Ryan W. Taylor, Gregory S. Barsh, Ellie E. Armstrong, Elizabeth A. Hadly, Christopher B. Kaelin, Danny E. Miller, and Dmitri A. Petrov
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Lions ,0106 biological sciences ,Physiology ,Demographic history ,Population ,Endangered species ,Plant Science ,Runs of Homozygosity ,Panthera leo ,Synteny ,010603 evolutionary biology ,01 natural sciences ,Reference bias ,General Biochemistry, Genetics and Molecular Biology ,Dovetail Hi-C ,03 medical and health sciences ,Structural Biology ,biology.animal ,Animals ,education ,lcsh:QH301-705.5 ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,Genome ,Genome assembly ,biology ,Population size ,Cell Biology ,biology.organism_classification ,Asiatic lion ,Oxford Nanopore ,lcsh:Biology (General) ,Evolutionary biology ,Conservation genomics ,10x Genomics Chromium ,Female ,Panthera ,General Agricultural and Biological Sciences ,Inbreeding ,Research Article ,Developmental Biology ,Biotechnology ,African lion - Abstract
Background The lion (Panthera leo) is one of the most popular and iconic feline species on the planet, yet in spite of its popularity, the last century has seen massive declines for lion populations worldwide. Genomic resources for endangered species represent an important way forward for the field of conservation, enabling high-resolution studies of demography, disease, and population dynamics. Here, we present a chromosome-level assembly from a captive African lion from the Exotic Feline Rescue Center (Center Point, IN) as a resource for current and subsequent genetic work of the sole social species of the Panthera clade. Results Our assembly is composed of 10x Genomics Chromium data, Dovetail Hi-C, and Oxford Nanopore long-read data. Synteny is highly conserved between the lion, other Panthera genomes, and the domestic cat. We find variability in the length of runs of homozygosity across lion genomes, indicating contrasting histories of recent and possibly intense inbreeding and bottleneck events. Demographic analyses reveal similar ancient histories across all individuals during the Pleistocene except the Asiatic lion, which shows a more rapid decline in population size. We show a substantial influence on the reference genome choice in the inference of demographic history and heterozygosity. Conclusions We demonstrate that the choice of reference genome is important when comparing heterozygosity estimates across species and those inferred from different references should not be compared to each other. In addition, estimates of heterozygosity or the amount or length of runs of homozygosity should not be taken as reflective of a species, as these can differ substantially among individuals. This high-quality genome will greatly aid in the continuing research and conservation efforts for the lion, which is rapidly moving towards becoming a species in danger of extinction.
- Published
- 2020
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