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1. Identifying positive selection candidate loci for high-altitude adaptation in Andean populations

Author

Bigham Abigail W, Mao Xianyun, Mei Rui, Brutsaert Tom, Wilson Megan J, Julian Colleen, Parra Esteban J, Akey Joshua M, Moore Lorna G, and Shriver Mark D

Subjects
genome scan, positive selection, Native Americans, altitude adaptation, Medicine, Genetics, QH426-470
Abstract

Abstract High-altitude environments (>2,500 m) provide scientists with a natural laboratory to study the physiological and genetic effects of low ambient oxygen tension on human populations. One approach to understanding how life at high altitude has affected human metabolism is to survey genome-wide datasets for signatures of natural selection. In this work, we report on a study to identify selection-nominated candidate genes involved in adaptation to hypoxia in one highland group, Andeans from the South American Altiplano. We analysed dense microarray genotype data using four test statistics that detect departures from neutrality. Using a candidate gene, single nucleotide polymorphism-based approach, we identified genes exhibiting preliminary evidence of recent genetic adaptation in this population. These included genes that are part of the hypoxia-inducible transcription factor (HIF) pathway, a biochemical pathway involved in oxygen homeostasis, as well as three other genomic regions previously not known to be associated with high-altitude phenotypes. In addition to identifying selection-nominated candidate genes, we also tested whether the HIF pathway shows evidence of natural selection. Our results indicate that the genes of this biochemical pathway as a group show no evidence of having evolved in response to hypoxia in Andeans. Results from particular HIF-targeted genes, however, suggest that genes in this pathway could play a role in Andean adaptation to high altitude, even if the pathway as a whole does not show higher relative rates of evolution. These data suggest a genetic role in high-altitude adaptation and provide a basis for genotype/phenotype association studies that are necessary to confirm the role of putative natural selection candidate genes and gene regions in adaptation to altitude.

Published
2009
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2. Genome-wide scans for loci under selection in humans

Author

Ronald James and Akey Joshua M

Subjects
genetic variation, evolutionary genomics, natural selection, single nucleotide polymorphisms (SNPs), Medicine, Genetics, QH426-470
Abstract

Abstract Natural selection, which can be defined as the differential contribution of genetic variants to future generations, is the driving force of Darwinian evolution. Identifying regions of the human genome that have been targets of natural selection is an important step in clarifying human evolutionary history and understanding how genetic variation results in phenotypic diversity, it may also facilitate the search for complex disease genes. Technological advances in high-throughput DNA sequencing and single nucleotide polymorphism genotyping have enabled several genome-wide scans of natural selection to be undertaken. Here, some of the observations that are beginning to emerge from these studies will be reviewed, including evidence for geographically restricted selective pressures (ie local adaptation) and a relationship between genes subject to natural selection and human disease. In addition, the paper will highlight several important problems that need to be addressed in future genome-wide studies of natural selection.

Published
2005
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3. Large-scale SNP analysis reveals clustered and continuous patterns of human genetic variation

Author

Shriver Mark D, Mei Rui, Parra Esteban J, Sonpar Vibhor, Halder Indrani, Tishkoff Sarah A, Schurr Theodore G, Zhadanov Sergev I, Osipova Ludmila P, Brutsaert Tom D, Friedlaender Jonathan, Jorde Lynn B, Watkins W Scott, Bamshad Michael J, Gutierrez Gerardo, Loi Halina, Matsuzaki Hajime, Kittles Rick A, Argyropoulos George, Fernandez Jose R, Akey Joshua M, and Jones Keith W

Subjects
population genetics, population genomics, human evolution, migration, admixture, population stratification, Medicine, Genetics, QH426-470
Abstract

Abstract Understanding the distribution of human genetic variation is an important foundation for research into the genetics of common diseases. Some of the alleles that modify common disease risk are themselves likely to be common and, thus, amenable to identification using gene-association methods. A problem with this approach is that the large sample sizes required for sufficient statistical power to detect alleles with moderate effect make gene-association studies susceptible to false-positive findings as the result of population stratification 12. Such type I errors can be eliminated by using either family-based association tests or methods that sufficiently adjust for population stratification 345. These methods require the availability of genetic markers that can detect and, thus, control for sources of genetic stratification among populations. In an effort to investigate population stratification and identify appropriate marker panels, we have analysed 11,555 single nucleotide polymorphisms in 203 individuals from 12 diverse human populations. Individuals in each population cluster to the exclusion of individuals from other populations using two clustering methods. Higher-order branching and clustering of the populations are consistent with the geographic origins of populations and with previously published genetic analyses. These data provide a valuable resource for the definition of marker panels to detect and control for population stratification in population-based gene identification studies. Using three US resident populations (European-American, African-American and Puerto Rican), we demonstrate how such studies can proceed, quantifying proportional ancestry levels and detecting significant admixture structure in each of these populations.

Published
2005
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4. The genomic distribution of population substructure in four populations using 8,525 autosomal SNPs

Author

Shriver Mark D, Kennedy Giulia C, Parra Esteban J, Lawson Heather A, Sonpar Vibhor, Huang Jing, Akey Joshua M, and Jones Keith W

Subjects
population genomics, population genetics, microarray, genotyping, evolution, admixture, Medicine, Genetics, QH426-470
Abstract

Abstract Understanding the nature of evolutionary relationships among persons and populations is important for the efficient application of genome science to biomedical research. We have analysed 8,525 autosomal single nucleotide polymorphisms (SNPs) in 84 individuals from four populations: African-American, European-American, Chinese and Japanese. Individual relationships were reconstructed using the allele sharing distance and the neighbour-joining tree making method. Trees show clear clustering according to population, with the root branching from the African-American clade. The African-American cluster is much less star-like than European-American and East Asian clusters, primarily because of admixture. Furthermore, on the East Asian branch, all ten Chinese individuals cluster together and all ten Japanese individuals cluster together. Using positional information, we demonstrate strong correlations between inter-marker distance and both locus-specific FST (the proportion of total variation due to differentiation) levels and branch lengths. Chromosomal maps of the distribution of locus-specific branch lengths were constructed by combining these data with other published SNP markers (total of 33,704 SNPs). These maps clearly illustrate a non-uniform distribution of human genetic substructure, an instructional and useful paradigm for education and research.

Published
2004
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5. Evolution of Human-Specific Alleles Protecting Cognitive Function of Grandmothers

Author

Saha, Sudeshna, Khan, Naazneen, Comi, Troy, Verhagen, Andrea, Sasmal, Aniruddha, Diaz, Sandra, Yu, Hai, Chen, Xi, Akey, Joshua M, Frank, Martin, Gagneux, Pascal, and Varki, Ajit

Subjects
Genetics, Human Genome, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Alleles, Amino Acids, Animals, Cognition, Grandparents, Hominidae, Humans, CD33, pathogen, sialic acids, archaic genome, molecular dynamics simulation, phylogenetic analysis, Biochemistry and Cell Biology, Evolutionary Biology
Abstract

The myelomonocytic receptor CD33 (Siglec-3) inhibits innate immune reactivity by extracellular V-set domain recognition of sialic acid (Sia)-containing "self-associated molecular patterns" (SAMPs). We earlier showed that V-set domain-deficient CD33-variant allele, protective against late-onset Alzheimer's Disease (LOAD), is derived and specific to the hominin lineage. We now report multiple hominin-specific CD33 V-set domain mutations. Due to hominin-specific, fixed loss-of-function mutation in the CMAH gene, humans lack N-glycolylneuraminic acid (Neu5Gc), the preferred Sia-ligand of ancestral CD33. Mutational analysis and molecular dynamics (MD)-simulations indicate that fixed change in amino acid 21 of hominin V-set domain and conformational changes related to His45 corrected for Neu5Gc-loss by switching to N-acetylneuraminic acid (Neu5Ac)-recognition. We show that human-specific pathogens Neisseria gonorrhoeae and Group B Streptococcus selectively bind human CD33 (huCD33) as part of immune-evasive molecular mimicry of host SAMPs and that this binding is significantly impacted by amino acid 21 modification. In addition to LOAD-protective CD33 alleles, humans harbor derived, population-universal, cognition-protective variants at several other loci. Interestingly, 11 of 13 SNPs in these human genes (including CD33) are not shared by genomes of archaic hominins: Neanderthals and Denisovans. We present a plausible evolutionary scenario to compile, correlate, and comprehend existing knowledge about huCD33-evolution and suggest that grandmothering emerged in humans.

Published
2022

6. A high-resolution integrated map of copy number polymorphisms within and between breeds of the modern domesticated dog

Author

Nicholas Thomas J, Baker Carl, Eichler Evan E, and Akey Joshua M

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Structural variation contributes to the rich genetic and phenotypic diversity of the modern domestic dog, Canis lupus familiaris, although compared to other organisms, catalogs of canine copy number variants (CNVs) are poorly defined. To this end, we developed a customized high-density tiling array across the canine genome and used it to discover CNVs in nine genetically diverse dogs and a gray wolf. Results In total, we identified 403 CNVs that overlap 401 genes, which are enriched for defense/immunity, oxidoreductase, protease, receptor, signaling molecule and transporter genes. Furthermore, we performed detailed comparisons between CNVs located within versus outside of segmental duplications (SDs) and find that CNVs in SDs are enriched for gene content and complexity. Finally, we compiled all known dog CNV regions and genotyped them with a custom aCGH chip in 61 dogs from 12 diverse breeds. These data allowed us to perform the first population genetics analysis of canine structural variation and identify CNVs that potentially contribute to breed specific traits. Conclusions Our comprehensive analysis of canine CNVs will be an important resource in genetically dissecting canine phenotypic and behavioral variation.

Published
2011
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7. Mapping gene expression quantitative trait loci by singular value decomposition and independent component analysis

Author

Storey John D, Biswas Shameek, and Akey Joshua M

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background The combination of gene expression profiling with linkage analysis has become a powerful paradigm for mapping gene expression quantitative trait loci (eQTL). To date, most studies have searched for eQTL by analyzing gene expression traits one at a time. As thousands of expression traits are typically analyzed, this can reduce power because of the need to correct for the number of hypothesis tests performed. In addition, gene expression traits exhibit a complex correlation structure, which is ignored when analyzing traits individually. Results To address these issues, we applied two different multivariate dimension reduction techniques, the Singular Value Decomposition (SVD) and Independent Component Analysis (ICA) to gene expression traits derived from a cross between two strains of Saccharomyces cerevisiae. Both methods decompose the data into a set of meta-traits, which are linear combinations of all the expression traits. The meta-traits were enriched for several Gene Ontology categories including metabolic pathways, stress response, RNA processing, ion transport, retro-transposition and telomeric maintenance. Genome-wide linkage analysis was performed on the top 20 meta-traits from both techniques. In total, 21 eQTL were found, of which 11 are novel. Interestingly, both cis and trans-linkages to the meta-traits were observed. Conclusion These results demonstrate that dimension reduction methods are a useful and complementary approach for probing the genetic architecture of gene expression variation.

Published
2008
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10. Tracing the peopling of the world through genomics

Author

Nielsen, Rasmus, Akey, Joshua M, Jakobsson, Mattias, Pritchard, Jonathan K, Tishkoff, Sarah, and Willerslev, Eske

Subjects
Biological Sciences, Genetics, History, Heritage and Archaeology, Human Society, Archaeology, Anthropology, Biotechnology, Human Genome, Acclimatization, Africa, Animals, Evolution, Molecular, Genome, Human, Genomics, Geography, History, Ancient, Human Migration, Humans, Neanderthals, Selection, Genetic, General Science & Technology
Abstract

Advances in the sequencing and the analysis of the genomes of both modern and ancient peoples have facilitated a number of breakthroughs in our understanding of human evolutionary history. These include the discovery of interbreeding between anatomically modern humans and extinct hominins; the development of an increasingly detailed description of the complex dispersal of modern humans out of Africa and their population expansion worldwide; and the characterization of many of the genetic adaptions of humans to local environmental conditions. Our interpretation of the evolutionary history and adaptation of humans is being transformed by analyses of these new genomic data.

Published
2017

11. The companion dog as a model for inflammaging: a cross-sectional pilot study.

Author

Schmid, Sarah M., Hoffman, Jessica M., Prescott, Jena, Ernst, Holley, Promislow, Daniel E. L., Akey, Joshua M., Benton, Brooke, Borenstein, Elhanan, Castelhano, Marta G., Coleman, Amanda E., Creevy, Kate E., Crowder, Kyle, Dunbar, Matthew D., Fajt, Virginia R., Fitzpatrick, Annette L., Jeffery, Unity, Jonlin, Erica C., Kaeberlein, Matt, Karlsson, Elinor K., and Kerr, Kathleen F.

Subjects
TUMOR necrosis factors, LYMPHOCYTE count, INFLAMMATORY mediators, INFLAMMATION, PLATELET count
Abstract

Inflammaging, the chronic, progressive proinflammatory state associated with aging, has been associated with multiple negative health outcomes in humans. The pathophysiology of inflammaging is complex; however, it is often characterized by high serum concentrations of inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and C-reactive protein (CRP). Few studies have evaluated the effects of age on inflammatory cytokines in companion dogs, and most of these studies included dogs of a single breed. In this cross-sectional study, we measured multiple circulating inflammatory markers and hematological parameters in banked serum samples from 47 healthy companion dogs of various breeds enrolled in the Dog Aging Project. Using univariate linear models, we investigated the association of each of these markers with age, sex, body weight, and body condition score (BCS), a measure of obesity in the dog. Serum IL-6, IL-8, and TNF-α concentrations were all positively associated with age. Lymphocyte count was negatively associated with age. Platelet count had a negative association with body weight. IL-2, albumin, cholesterol, triglyceride, bilirubin, S100A12, and NMH concentrations were not associated with age, weight, BCS, or sex after adjustment for multiple comparisons. Our findings replicate previous findings in humans, including increases in IL-6 and TNF-α with age, giving more evidence to the strength of the companion dog as a model for human aging. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility.

Author

Nuttle, Xander, Giannuzzi, Giuliana, Duyzend, Michael H, Schraiber, Joshua G, Narvaiza, Iñigo, Sudmant, Peter H, Penn, Osnat, Chiatante, Giorgia, Malig, Maika, Huddleston, John, Benner, Chris, Camponeschi, Francesca, Ciofi-Baffoni, Simone, Stessman, Holly AF, Marchetto, Maria CN, Denman, Laura, Harshman, Lana, Baker, Carl, Raja, Archana, Penewit, Kelsi, Janke, Nicolette, Tang, W Joyce, Ventura, Mario, Banci, Lucia, Antonacci, Francesca, Akey, Joshua M, Amemiya, Chris T, Gage, Fred H, Reymond, Alexandre, and Eichler, Evan E

Subjects
Chromosomes, Human, Pair 16, Animals, Humans, Pan troglodytes, Chromosome Breakage, Genetic Predisposition to Disease, Iron, Proteins, Autistic Disorder, Evolution, Molecular, Species Specificity, Gene Duplication, Recombination, Genetic, Homeostasis, Time Factors, DNA Copy Number Variations, Pongo, Human Genome, Genetics, Biotechnology, General Science & Technology
Abstract

Genetic differences that specify unique aspects of human evolution have typically been identified by comparative analyses between the genomes of humans and closely related primates, including more recently the genomes of archaic hominins. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for approximately 1% of cases of autism and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution. Here we reconstruct the evolutionary history of the locus and identify bolA family member 2 (BOLA2) as a gene duplicated exclusively in Homo sapiens. We estimate that a 95-kilobase-pair segment containing BOLA2 duplicated across the critical region approximately 282 thousand years ago (ka), one of the latest among a series of genomic changes that dramatically restructured the locus during hominid evolution. All humans examined carried one or more copies of the duplication, which nearly fixed early in the human lineage--a pattern unlikely to have arisen so rapidly in the absence of selection (P

Published
2016

13. Extreme selective sweeps independently targeted the X chromosomes of the great apes

Author

Nam, Kiwoong, Munch, Kasper, Hobolth, Asger, Dutheil, Julien Yann, Veeramah, Krishna R, Woerner, August E, Hammer, Michael F, Mailund, Thomas, Schierup, Mikkel Heide, Prado-Martinez, Javier, Sudmant, Peter H, Kidd, Jeffrey M, Li, Heng, Kelley, Joanna L, Lorente-Galdos, Belen, O’Connor, Timothy D, Santpere, Gabriel, Cagan, Alexander, Theunert, Christoph, Casals, Ferran, Laayouni, Hafid, Halager, Anders E, Malig, Maika, Hernandez-Rodriguez, Jessica, Hernando-Herraez, Irene, Prüfer, Kay, Pybus, Marc, Johnstone, Laurel, Lachmann, Michael, Alkan, Can, Twigg, Dorina, Petit, Natalia, Baker, Carl, Hormozdiari, Fereydoun, Fernandez-Callejo, Marcos, Dabad, Marc, Wilson, Michael L, Stevison, Laurie, Camprubí, Cristina, Carvalho, Tiago, Ruiz-Herrera, Aurora, Vives, Laura, Mele, Marta, Abello, Teresa, Kondova, Ivanela, Bontrop, Ronald E, Pusey, Anne, Lankester, Felix, Kiyang, John A, Bergl, Richard A, Lonsdorf, Elizabeth, Myers, Simon, Ventura, Mario, Gagneux, Pascal, Comas, David, Siegismund, Hans, Blanc, Julie, Agueda-Calpena, Lidia, Gut, Marta, Fulton, Lucinda, Tishkoff, Sarah A, Mullikin, James C, Wilson, Richard K, Gut, Ivo G, Gonder, Mary Katherine, Ryder, Oliver A, Hahn, Beatrice H, Navarro, Arcadi, Akey, Joshua M, Bertranpetit, Jaume, Reich, David, Schierup, Mikkel H, Hvilsom, Christina, Andrés, Aida M, Wall, Jeffrey D, Bustamante, Carlos D, Eichler, Evan E, and Marques-Bonet, Tomas

Subjects
Human Genome, Genetics, Animals, Computational Biology, Databases, Genetic, Genetic Variation, Genetics, Population, Hominidae, Models, Genetic, Polymorphism, Genetic, Selection, Genetic, Species Specificity, X Chromosome, Great Ape Genome Diversity Project, X-chromosome evolution, ampliconic genes, great apes, meiotic drive, selective sweeps
Abstract

The unique inheritance pattern of the X chromosome exposes it to natural selection in a way that is different from that of the autosomes, potentially resulting in accelerated evolution. We perform a comparative analysis of X chromosome polymorphism in 10 great ape species, including humans. In most species, we identify striking megabase-wide regions, where nucleotide diversity is less than 20% of the chromosomal average. Such regions are found exclusively on the X chromosome. The regions overlap partially among species, suggesting that the underlying targets are partly shared among species. The regions have higher proportions of singleton SNPs, higher levels of population differentiation, and a higher nonsynonymous-to-synonymous substitution ratio than the rest of the X chromosome. We show that the extent to which diversity is reduced is incompatible with direct selection or the action of background selection and soft selective sweeps alone, and therefore, we suggest that very strong selective sweeps have independently targeted these specific regions in several species. The only genomic feature that we can identify as strongly associated with loss of diversity is the location of testis-expressed ampliconic genes, which also have reduced diversity around them. We hypothesize that these genes may be responsible for selective sweeps in the form of meiotic drive caused by an intragenomic conflict in male meiosis.

Published
2015

16. Great ape genetic diversity and population history.

Author

Prado-Martinez, Javier, Sudmant, Peter H, Kidd, Jeffrey M, Li, Heng, Kelley, Joanna L, Lorente-Galdos, Belen, Veeramah, Krishna R, Woerner, August E, O'Connor, Timothy D, Santpere, Gabriel, Cagan, Alexander, Theunert, Christoph, Casals, Ferran, Laayouni, Hafid, Munch, Kasper, Hobolth, Asger, Halager, Anders E, Malig, Maika, Hernandez-Rodriguez, Jessica, Hernando-Herraez, Irene, Prüfer, Kay, Pybus, Marc, Johnstone, Laurel, Lachmann, Michael, Alkan, Can, Twigg, Dorina, Petit, Natalia, Baker, Carl, Hormozdiari, Fereydoun, Fernandez-Callejo, Marcos, Dabad, Marc, Wilson, Michael L, Stevison, Laurie, Camprubí, Cristina, Carvalho, Tiago, Ruiz-Herrera, Aurora, Vives, Laura, Mele, Marta, Abello, Teresa, Kondova, Ivanela, Bontrop, Ronald E, Pusey, Anne, Lankester, Felix, Kiyang, John A, Bergl, Richard A, Lonsdorf, Elizabeth, Myers, Simon, Ventura, Mario, Gagneux, Pascal, Comas, David, Siegismund, Hans, Blanc, Julie, Agueda-Calpena, Lidia, Gut, Marta, Fulton, Lucinda, Tishkoff, Sarah A, Mullikin, James C, Wilson, Richard K, Gut, Ivo G, Gonder, Mary Katherine, Ryder, Oliver A, Hahn, Beatrice H, Navarro, Arcadi, Akey, Joshua M, Bertranpetit, Jaume, Reich, David, Mailund, Thomas, Schierup, Mikkel H, Hvilsom, Christina, Andrés, Aida M, Wall, Jeffrey D, Bustamante, Carlos D, Hammer, Michael F, Eichler, Evan E, and Marques-Bonet, Tomas

Subjects
Animals, Animals, Wild, Animals, Zoo, Hominidae, Gorilla gorilla, Humans, Pan paniscus, Pan troglodytes, Inbreeding, Genetics, Population, Population Density, Evolution, Molecular, Phylogeny, Polymorphism, Single Nucleotide, Genome, Africa, Asia, Southeastern, Gene Flow, Genetic Variation, General Science & Technology
Abstract

Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria-Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.

Published
2013

17. Telomere length as a quantitative trait: genome-wide survey and genetic mapping of telomere length-control genes in yeast.

Author

Gatbonton, Tonibelle, Imbesi, Maria, Nelson, Melisa, Akey, Joshua M, Ruderfer, Douglas M, Kruglyak, Leonid, Simon, Julian A, and Bedalov, Antonio

Subjects
Chromosomes, Fungal, Telomere, Saccharomyces cerevisiae, Fungal Proteins, Silent Information Regulator Proteins, Saccharomyces cerevisiae, Chromosome Mapping, Gene Deletion, Sister Chromatid Exchange, Polymorphism, Genetic, Genes, Fungal, Genome, Fungal, Quantitative Trait Loci, Chromosomes, Fungal, Genes, Genome, Polymorphism, Genetic, Silent Information Regulator Proteins, Genetics, Developmental Biology
Abstract

Telomere length-variation in deletion strains of Saccharomyces cerevisiae was used to identify genes and pathways that regulate telomere length. We found 72 genes that when deleted confer short telomeres, and 80 genes that confer long telomeres relative to those of wild-type yeast. Among identified genes, 88 have not been previously implicated in telomere length control. Genes that regulate telomere length span a variety of functions that can be broadly separated into telomerase-dependent and telomerase-independent pathways. We also found 39 genes that have an important role in telomere maintenance or cell proliferation in the absence of telomerase, including genes that participate in deoxyribonucleotide biosynthesis, sister chromatid cohesion, and vacuolar protein sorting. Given the large number of loci identified, we investigated telomere lengths in 13 wild yeast strains and found substantial natural variation in telomere length among the isolates. Furthermore, we crossed a wild isolate to a laboratory strain and analyzed telomere length in 122 progeny. Genome-wide linkage analysis among these segregants revealed two loci that account for 30%-35% of telomere length-variation between the strains. These findings support a general model of telomere length-variation in outbred populations that results from polymorphisms at a large number of loci. Furthermore, our results laid the foundation for studying genetic determinants of telomere length-variation and their roles in human disease.

Published
2006

18. Multiple locus linkage analysis of genomewide expression in yeast.

Author

Storey, John D, Akey, Joshua M, and Kruglyak, Leonid

Subjects
Saccharomyces cerevisiae, Probability, Chromosome Mapping, Gene Expression Profiling, Epistasis, Genetic, Phenotype, Genome, Fungal, Quantitative Trait Loci, Genetic Linkage, Epistasis, Genetic, Genome, Fungal, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Developmental Biology
Abstract

With the ability to measure thousands of related phenotypes from a single biological sample, it is now feasible to genetically dissect systems-level biological phenomena. The genetics of transcriptional regulation and protein abundance are likely to be complex, meaning that genetic variation at multiple loci will influence these phenotypes. Several recent studies have investigated the role of genetic variation in transcription by applying traditional linkage analysis methods to genomewide expression data, where each gene expression level was treated as a quantitative trait and analyzed separately from one another. Here, we develop a new, computationally efficient method for simultaneously mapping multiple gene expression quantitative trait loci that directly uses all of the available data. Information shared across gene expression traits is captured in a way that makes minimal assumptions about the statistical properties of the data. The method produces easy-to-interpret measures of statistical significance for both individual loci and the overall joint significance of multiple loci selected for a given expression trait. We apply the new method to a cross between two strains of the budding yeast Saccharomyces cerevisiae, and estimate that at least 37% of all gene expression traits show two simultaneous linkages, where we have allowed for epistatic interactions. Pairs of jointly linking quantitative trait loci are identified with high confidence for 170 gene expression traits, where it is expected that both loci are true positives for at least 153 traits. In addition, we are able to show that epistatic interactions contribute to gene expression variation for at least 14% of all traits. We compare the proposed approach to an exhaustive two-dimensional scan over all pairs of loci. Surprisingly, we demonstrate that an exhaustive two-dimensional scan is less powerful than the sequential search used here. In addition, we show that a two-dimensional scan does not truly allow one to test for simultaneous linkage, and the statistical significance measured from this existing method cannot be interpreted among many traits.

Published
2005

19. Population History and Natural Selection Shape Patterns of Genetic Variation in 132 Genes

Author

Akey, Joshua M, Eberle, Michael A, Rieder, Mark J, Carlson, Christopher S, Shriver, Mark D, Nickerson, Deborah A, and Kruglyak, Leonid

Subjects
Genetics, Human Genome, Blacks, Chromosomes, Human, Pair 7, Computational Biology, Evolution, Molecular, Genetic Variation, Genetics, Population, Genome, Human, Humans, Models, Genetic, Models, Statistical, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Population Groups, Selection, Genetic, Sequence Analysis, DNA, Whites, White People, Black People, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Identifying regions of the human genome that have been targets of natural selection will provide important insights into human evolutionary history and may facilitate the identification of complex disease genes. Although the signature that natural selection imparts on DNA sequence variation is difficult to disentangle from the effects of neutral processes such as population demographic history, selective and demographic forces can be distinguished by analyzing multiple loci dispersed throughout the genome. We studied the molecular evolution of 132 genes by comprehensively resequencing them in 24 African-Americans and 23 European-Americans. We developed a rigorous computational approach for taking into account multiple hypothesis tests and demographic history and found that while many apparent selective events can instead be explained by demography, there is also strong evidence for positive or balancing selection at eight genes in the European-American population, but none in the African-American population. Our results suggest that the migration of modern humans out of Africa into new environments was accompanied by genetic adaptations to emergent selective forces. In addition, a region containing four contiguous genes on Chromosome 7 showed striking evidence of a recent selective sweep in European-Americans. More generally, our results have important implications for mapping genes underlying complex human diseases.

Published
2004

21. Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals

Author

Vernot, Benjamin, Tucci, Serena, Kelso, Janet, Schraiber, Joshua G., Wolf, Aaron B., Gittelman, Rachel M., Dannemann, Michael, Grote, Steffi, McCoy, Rajiv C., Norton, Heather, Scheinfeldt, Laura B., Merriwether, David A., Koki, George, Friedlaender, Jonathan S., Wakefield, Jon, Pääbo, Svante, and Akey, Joshua M.

Published
2016

22. The phenotypic legacy of admixture between modern humans and Neandertals

Author

Simonti, Corinne N., Vernot, Benjamin, Bastarache, Lisa, Bottinger, Erwin, Carrell, David S., Chisholm, Rex L., Crosslin, David R., Hebbring, Scott J., Jarvik, Gail P., Kullo, Iftikhar J., Li, Rongling, Pathak, Jyotishman, Ritchie, Marylyn D., Roden, Dan M., Verma, Shefali S., Tromp, Gerard, Prato, Jeffrey D., Bush, William S., Akey, Joshua M., Denny, Joshua C., and Capra, John A.

Published
2016

25. The impact of rare variation on gene expression across tissues

Author

Li, Xin, Kim, Yungil, Tsang, Emily K., Davis, Joe R., Damani, Farhan N., Chiang, Colby, Hess, Gaelen T., Zappala, Zachary, Strober, Benjamin J., Scott, Alexandra J., Li, Amy, Ganna, Andrea, Bassik, Michael C., Merker, Jason D., Aguet, Franois, Ardlie, Kristin G., Cummings, Beryl B., Gelfand, Ellen T., Getz, Gad, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, Karczewski, Konrad J., Lek, Monkol, Li, Xiao, MacArthur, Daniel G., Nedzel, Jared L., Nguyen, Duyen T., Noble, Michael S., Segr, Ayellet V., Trowbridge, Casandra A., Tukiainen, Taru, Abell, Nathan S., Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K., Brown, Andrew, Brown, Christopher D., Castel, Stephane E., Chen, Lin S., Conrad, Donald F., Cox, Nancy J., Delaneau, Olivier, Dermitzakis, Emmanouil T., Engelhardt, Barbara E., Eskin, Eleazar, Ferreira, Pedro G., Frsard, Laure, Gamazon, Eric R., Garrido-Martn, Diego, Gewirtz, Ariel D.H., Gliner, Genna, Gloudemans, Michael J., Guigo, Roderic, Hall, Ira M., Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I., McDowell, Ian C., Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B., Muoz-Aguirre, Manuel, Ndungu, Anne W., Nicolae, Dan L., Nobel, Andrew B., Oliva, Meritxell, Ongen, Halit, Palowitch, John J., Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J., Peterson, Christine B., Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Shabalin, Andrey A., Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E., Sul, Jae Hoon, Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A., Xi, Hualin S., Yeger-Lotem, Esti, Zaugg, Judith B., Zhou, Yi-Hui, Akey, Joshua M., Bates, Daniel, Chan, Joanne, Claussnitzer, Melina, Demanelis, Kathryn, Diegel, Morgan, Doherty, Jennifer A., Feinberg, Andrew P., Fernando, Marian S., Halow, Jessica, Hansen, Kasper D., Haugen, Eric, Hickey, Peter F., Hou, Lei, Jasmine, Farzana, Jian, Ruiqi, Jiang, Lihua, Johnson, Audra, Kaul, Rajinder, Kellis, Manolis, Kibriya, Muhammad G., Lee, Kristen, Billy Li, Jin, Li, Qin, Lin, Jessica, Lin, Shin, Linder, Sandra, Linke, Caroline, Liu, Yaping, Maurano, Matthew T., Molinie, Benoit, Nelson, Jemma, Neri, Fidencio J., Park, Yongjin, Pierce, Brandon L., Rinaldi, Nicola J., Rizzardi, Lindsay F., Sandstrom, Richard, Skol, Andrew, Smith, Kevin S., Snyder, Michael P., Stamatoyannopoulos, John, Tang, Hua, Wang, Li, Wang, Meng, Van Wittenberghe, Nicholas, Wu, Fan, Zhang, Rui, Nierras, Concepcion R., Branton, Philip A., Carithers, Latarsha J., Guan, Ping, Moore, Helen M., Rao, Abhi, Vaught, Jimmie B., Gould, Sarah E., Lockart, Nicole C., Martin, Casey, Struewing, Jeffery P., Volpi, Simona, Addington, Anjene M., Koester, Susan E., Little, A. Roger, Brigham, Lori E., Hasz, Richard, Hunter, Marcus, Johns, Christopher, Johnson, Mark, Kopen, Gene, Leinweber, William F., Lonsdale, John T., McDonald, Alisa, Mestichelli, Bernadette, Myer, Kevin, Roe, Brian, Salvatore, Michael, Shad, Saboor, Thomas, Jeffrey A., Walters, Gary, Washington, Michael, Wheeler, Joseph, Bridge, Jason, Foster, Barbara A., Gillard, Bryan M., Karasik, Ellen, Kumar, Rachna, Miklos, Mark, Moser, Michael T., Jewell, Scott D., Montroy, Robert G., Rohrer, Daniel C., Valley, Dana R., Davis, David A., Mash, Deborah C., Undale, Anita H., Smith, Anna M., Tabor, David E., Roche, Nancy V., McLean, Jeffrey A., Vatanian, Negin, Robinson, Karna L., Sobin, Leslie, Barcus, Mary E., Valentino, Kimberly M., Qi, Liqun, Hunter, Steven, Hariharan, Pushpa, Singh, Shilpi, Um, Ki Sung, Matose, Takunda, Tomaszewski, Maria M., Barker, Laura K., Mosavel, Maghboeba, Siminoff, Laura A., Traino, Heather M., Flicek, Paul, Juettemann, Thomas, Ruffier, Magali, Sheppard, Dan, Taylor, Kieron, Trevanion, Stephen J., Zerbino, Daniel R., Craft, Brian, Goldman, Mary, Haeussler, Maximilian, Kent, W. James, Lee, Christopher M., Paten, Benedict, Rosenbloom, Kate R., Vivian, John, and Zhu, Jingchun

Subjects
Disease susceptibility -- Genetic aspects, Genetic variation -- Observations, Gene expression -- Observations, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Xin Li [1]; Yungil Kim [2]; Emily K. Tsang [1, 3]; Joe R. Davis [1, 4]; Farhan N. Damani [2]; Colby Chiang [5]; Gaelen T. Hess [4]; Zachary Zappala [...]

Published
2017
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26. Dynamic landscape and regulation of RNA editing in mammals

Author

Tan, Meng How, Li, Qin, Shanmugam, Raghuvaran, Piskol, Robert, Kohler, Jennefer, Young, Amy N., Liu, Kaiwen Ivy, Zhang, Rui, Ramaswami, Gokul, Ariyoshi, Kentaro, Gupte, Ankita, Keegan, Liam P., George, Cyril X., Ramu, Avinash, Huang, Ni, Pollina, Elizabeth A., Leeman, Dena S., Rustighi, Alessandra, Goh, Y. P. Sharon, Aguet, Franois, Ardlie, Kristin G., Cummings, Beryl B., Gelfand, Ellen T., Getz, Gad, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, Karczewski, Konrad J., Lek, Monkol, Li, Xiao, MacArthur, Daniel G., Nedzel, Jared L., Nguyen, Duyen T., Noble, Michael S., Segr, Ayellet V., Trowbridge, Casandra A., Tukiainen, Taru, Abell, Nathan S., Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K., Brown, Andrew, Brown, Christopher D., Castel, Stephane E., Chen, Lin S., Chiang, Colby, Conrad, Donald F., Cox, Nancy J., Damani, Farhan N., Davis, Joe R., Delaneau, Olivier, Dermitzakis, Emmanouil T., Engelhardt, Barbara E., Eskin, Eleazar, Ferreira, Pedro G., Frsard, Laure, Gamazon, Eric R., Garrido-Martn, Diego, Gewirtz, Ariel D. H., Gliner, Genna, Gloudemans, Michael J., Guigo, Roderic, Hall, Ira M., Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I., McDowell, Ian C., Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B., Muoz-Aguirre, Manuel, Ndungu, Anne W., Nicolae, Dan L., Nobel, Andrew B., Oliva, Meritxell, Ongen, Halit, Palowitch, John J., Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J., Peterson, Christine B., Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J., Shabalin, Andrey A., Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E., Strober, Benjamin J., Sul, Jae Hoon, Tsang, Emily K., Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A., Xi, Hualin S., Yeger-Lotem, Esti, Zappala, Zachary, Zaugg, Judith B., Zhou, Yi-Hui, Akey, Joshua M., Bates, Daniel, Chan, Joanne, Claussnitzer, Melina, Demanelis, Kathryn, Diegel, Morgan, Doherty, Jennifer A., Feinberg, Andrew P., Fernando, Marian S., Halow, Jessica, Hansen, Kasper D., Haugen, Eric, Hickey, Peter F., Hou, Lei, Jasmine, Farzana, Jian, Ruiqi, Jiang, Lihua, Johnson, Audra, Kaul, Rajinder, Kellis, Manolis, Kibriya, Muhammad G., Lee, Kristen, Li, Jin Billy, Lin, Jessica, Lin, Shin, Linder, Sandra, Linke, Caroline, Liu, Yaping, Maurano, Matthew T., Molinie, Benoit, Nelson, Jemma, Neri, Fidencio J., Park, Yongjin, Pierce, Brandon L., Rinaldi, Nicola J., Rizzardi, Lindsay F., Sandstrom, Richard, Skol, Andrew, Smith, Kevin S., Snyder, Michael P., Stamatoyannopoulos, John, Tang, Hua, Wang, Li, Wang, Meng, Van Wittenberghe, Nicholas, Wu, Fan, Nierras, Concepcion R., Branton, Philip A., Carithers, Latarsha J., Guan, Ping, Moore, Helen M., Rao, Abhi, Vaught, Jimmie B., Gould, Sarah E., Lockart, Nicole C., Martin, Casey, Struewing, Jeffery P., Volpi, Simona, Addington, Anjene M., Koester, Susan E., Little, A. Roger, Brigham, Lori E., Hasz, Richard, Hunter, Marcus, Johns, Christopher, Johnson, Mark, Kopen, Gene, Leinweber, William F., Lonsdale, John T., McDonald, Alisa, Mestichelli, Bernadette, Myer, Kevin, Roe, Brian, Salvatore, Michael, Shad, Saboor, Thomas, Jeffrey A., Walters, Gary, Washington, Michael, Wheeler, Joseph, Bridge, Jason, Foster, Barbara A., Gillard, Bryan M., Karasik, Ellen, Kumar, Rachna, Miklos, Mark, Moser, Michael T., Jewell, Scott D., Montroy, Robert G., Rohrer, Daniel C., Valley, Dana R., Davis, David A., Mash, Deborah C., Undale, Anita H., Smith, Anna M., Tabor, David E., Roche, Nancy V., McLean, Jeffrey A., Vatanian, Negin, Robinson, Karna L., Sobin, Leslie, Barcus, Mary E., Valentino, Kimberly M., Qi, Liqun, Hunter, Steven, Hariharan, Pushpa, Singh, Shilpi, Um, Ki Sung, Matose, Takunda, Tomaszewski, Maria M., Barker, Laura K., Mosavel, Maghboeba, Siminoff, Laura A., Traino, Heather M., Flicek, Paul, Juettemann, Thomas, Ruffier, Magali, Sheppard, Dan, Taylor, Kieron, Trevanion, Stephen J., Zerbino, Daniel R., Craft, Brian, Goldman, Mary, Haeussler, Maximilian, Kent, W. James, Lee, Christopher M., Paten, Benedict, Rosenbloom, Kate R., Vivian, John, Zhu, Jingchun, Chawla, Ajay, Del Sal, Giannino, Peltz, Gary, Brunet, Anne, Samuel, Charles E., OConnell, Mary A., Walkley, Carl R., and Nishikura, Kazuko

Subjects
Genetic research, Mammals -- Genetic aspects, RNA processing -- Research, Genetic regulation, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Meng How Tan (corresponding author) [1, 2, 3]; Qin Li [1]; Raghuvaran Shanmugam [2, 3]; Robert Piskol [1]; Jennefer Kohler [1]; Amy N. Young [1]; Kaiwen Ivy Liu [3]; [...]

Published
2017
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27. Landscape of X chromosome inactivation across human tissues

Author

Tukiainen, Taru, Villani, Alexandra-Chlo, Yen, Angela, Rivas, Manuel A., Marshall, Jamie L., Satija, Rahul, Aguirre, Matt, Gauthier, Laura, Fleharty, Mark, Kirby, Andrew, Cummings, Beryl B., Castel, Stephane E., Karczewski, Konrad J., Aguet, Franois, Byrnes, Andrea, Ardlie, Kristin G., Gelfand, Ellen T., Getz, Gad, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, Lek, Monkol, Li, Xiao, MacArthur, Daniel G., Nedzel, Jared L., Nguyen, Duyen T., Noble, Michael S., Segr, Ayellet V., Trowbridge, Casandra A., Abell, Nathan S., Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K., Brown, Andrew, Brown, Christopher D., Chen, Lin S., Chiang, Colby, Conrad, Donald F., Cox, Nancy J., Damani, Farhan N., Davis, Joe R., Delaneau, Olivier, Dermitzakis, Emmanouil T., Engelhardt, Barbara E., Eskin, Eleazar, Ferreira, Pedro G., Frsard, Laure, Gamazon, Eric R., Garrido-Martn, Diego, Gewirtz, Ariel D. H., Gliner, Genna, Gloudemans, Michael J., Guigo, Roderic, Hall, Ira M., Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I., McDowell, Ian C., Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B., Muoz-Aguirre, Manuel, Ndungu, Anne W., Nicolae, Dan L., Nobel, Andrew B., Oliva, Meritxell, Ongen, Halit, Palowitch, John J., Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J., Peterson, Christine B., Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J., Shabalin, Andrey A., Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E., Strober, Benjamin J., Sul, Jae Hoon, Tsang, Emily K., Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A., Xi, Hualin S., Yeger-Lotem, Esti, Zappala, Zachary, Zaugg, Judith B., Zhou, Yi-Hui, Akey, Joshua M., Bates, Daniel, Chan, Joanne, Claussnitzer, Melina, Demanelis, Kathryn, Diegel, Morgan, Doherty, Jennifer A., Feinberg, Andrew P., Fernando, Marian S., Halow, Jessica, Hansen, Kasper D., Haugen, Eric, Hickey, Peter F., Hou, Lei, Jasmine, Farzana, Jian, Ruiqi, Jiang, Lihua, Johnson, Audra, Kaul, Rajinder, Kellis, Manolis, Kibriya, Muhammad G., Lee, Kristen, Li, Jin Billy, Li, Qin, Lin, Jessica, Lin, Shin, Linder, Sandra, Linke, Caroline, Liu, Yaping, Maurano, Matthew T., Molinie, Benoit, Nelson, Jemma, Neri, Fidencio J., Park, Yongjin, Pierce, Brandon L., Rinaldi, Nicola J., Rizzardi, Lindsay F., Sandstrom, Richard, Skol, Andrew, Smith, Kevin S., Snyder, Michael P., Stamatoyannopoulos, John, Tang, Hua, Wang, Li, Wang, Meng, Van Wittenberghe, Nicholas, Wu, Fan, Zhang, Rui, Nierras, Concepcion R., Branton, Philip A., Carithers, Latarsha J., Guan, Ping, Moore, Helen M., Rao, Abhi, Vaught, Jimmie B., Gould, Sarah E., Lockart, Nicole C., Martin, Casey, Struewing, Jeffery P., Volpi, Simona, Addington, Anjene M., Koester, Susan E., Little, A. Roger, Brigham, Lori E., Hasz, Richard, Hunter, Marcus, Johns, Christopher, Johnson, Mark, Kopen, Gene, Leinweber, William F., Lonsdale, John T., McDonald, Alisa, Mestichelli, Bernadette, Myer, Kevin, Roe, Brian, Salvatore, Michael, Shad, Saboor, Thomas, Jeffrey A., Walters, Gary, Washington, Michael, Wheeler, Joseph, Bridge, Jason, Foster, Barbara A., Gillard, Bryan M., Karasik, Ellen, Kumar, Rachna, Miklos, Mark, Moser, Michael T., Jewell, Scott D., Montroy, Robert G., Rohrer, Daniel C., Valley, Dana R., Davis, David A., Mash, Deborah C., Undale, Anita H., Smith, Anna M., Tabor, David E., Roche, Nancy V., McLean, Jeffrey A., Vatanian, Negin, Robinson, Karna L., Sobin, Leslie, Barcus, Mary E., Valentino, Kimberly M., Qi, Liqun, Hunter, Steven, Hariharan, Pushpa, Singh, Shilpi, Um, Ki Sung, Matose, Takunda, Tomaszewski, Maria M., Barker, Laura K., Mosavel, Maghboeba, Siminoff, Laura A., Traino, Heather M., Flicek, Paul, Juettemann, Thomas, Ruffier, Magali, Sheppard, Dan, Taylor, Kieron, Trevanion, Stephen J., Zerbino, Daniel R., Craft, Brian, Goldman, Mary, Haeussler, Maximilian, Kent, W. James, Lee, Christopher M., Paten, Benedict, Rosenbloom, Kate R., Vivian, John, Zhu, Jingchun, Regev, Aviv, and Hacohen, Nir

Subjects
Chromosomes -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Taru Tukiainen (corresponding author) [1, 2]; Alexandra-Chlo Villani [2, 3]; Angela Yen [2, 4]; Manuel A. Rivas [1, 2, 5]; Jamie L. Marshall [1, 2]; Rahul Satija [2, 6, [...]

Published
2017
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32. Banking on a new understanding: translational opportunities from veterinary biobanks.

Author

LaLonde-Paul, D., Mouttham, L., Dog Aging Project Consortium, Akey, Joshua M., Benton, Brooke, Borenstein, Elhanan, Coleman, Amanda E., Creevy, Kate E., Crowder, Kyle, Dunbar, Matthew D., Fajt, Virginia R., Fitzpatrick, Annette L., Jeffery, Unity, Jonlin, Erica C., Kaeberlein, Matt, Karlsson, Elinor K., Kerr, Kathleen F., Levine, Jonathan M., Ma, Jing, and McClelland, Robyn L.

Subjects
LABORATORY mice, HUMAN physiology, DOGS, LOW-calorie diet, BIOBANKS, TRANSLATIONAL research, DOG behavior
Abstract

Current advances in geroscience are due in part to the discovery of biomarkers with high predictive ability in short-lived laboratory animals such as flies and mice. These model species, however, do not always adequately reflect human physiology and disease, highlighting the need for a more comprehensive and relevant model of human aging. Domestic dogs offer a solution to this obstacle, as they share many aspects not only of the physiological and pathological trajectories of their human counterpart, but also of their environment. Furthermore, they age at a considerably faster rate. Studying aging in the companion dog provides an opportunity to better understand the biological and environmental determinants of healthy lifespan in our pets, and to translate those findings to human aging. Biobanking, the systematic collection, processing, storage, and distribution of biological material and associated data has contributed to basic, clinical, and translational research by streamlining the management of high-quality biospecimens for biomarker discovery and validation. In this review, we discuss how veterinary biobanks can support research on aging, particularly when integrated into large-scale longitudinal studies. As an example of this concept, we introduce the Dog Aging Project Biobank. [ABSTRACT FROM AUTHOR]

Published
2023
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34. Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

Author

O'Roak, Brian J., Vives, Laura, Fu, Wenqing, Egertson, Jarrett D., Stanaway, Ian B., Phelps, Ian G., Carvill, Gemma, Kumar, Akash, Lee, Choli, Ankenman, Katy, Munson, Jeff, Hiatt, Joseph B., Turner, Emily H., Levy, Roie, O'Day, Diana R., Krumm, Niklas, Coe, Bradley P., Martin, Beth K., Borenstein, Elhanan, Nickerson, Deborah A., Mefford, Heather C., Doherty, Dan, Akey, Joshua M., Bernier, Raphael, Eichler, Evan E., and Shendure, Jay

Published
2012
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35. Genetic effects on gene expression across human tissues

Author

Aguet, François, Ardlie, Kristin G., Cummings, Beryl B., Gelfand, Ellen T., Getz, Gad, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, Karczewski, Konrad J., Lek, Monkol, Li, Xiao, MacArthur, Daniel G., Nedzel, Jared L., Nguyen, Duyen T., Noble, Michael S., Segrè, Ayellet V., Trowbridge, Casandra A., Tukiainen, Taru, Abell, Nathan S., Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K., Brown, Andrew, Brown, Christopher D., Castel, Stephane E., Chen, Lin S., Chiang, Colby, Conrad, Donald F., Cox, Nancy J., Damani, Farhan N., Davis, Joe R., Delaneau, Olivier, Dermitzakis, Emmanouil T., Engelhardt, Barbara E., Eskin, Eleazar, Ferreira, Pedro G., Frésard, Laure, Gamazon, Eric R., Garrido-Martín, Diego, Gewirtz, Ariel D.H., Gliner, Genna, Gloudemans, Michael J., Guigo, Roderic, Hall, Ira M., Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Im, Hae Kyung, Jo, Brian, Kang, Eun Yong, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I., McDowell, Ian C., Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B., Muñoz-Aguirre, Manuel, Ndungu, Anne W., Nicolae, Dan L., Nobel, Andrew B., Oliva, Meritxell, Ongen, Halit, Palowitch, John J., Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J., Peterson, Christine B., Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J., Shabalin, Andrey A., Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E., Strober, Benjamin J., Sul, Jae Hoon, Tsang, Emily K., Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A., Xi, Hualin S., Yeger-Lotem, Esti, Zappala, Zachary, Zaugg, Judith B., Zhou, Yi-Hui, Akey, Joshua M., Bates, Daniel, Chan, Joanne, Claussnitzer, Melina, Demanelis, Kathryn, Diegel, Morgan, Doherty, Jennifer A., Feinberg, Andrew P., Fernando, Marian S., Halow, Jessica, Hansen, Kasper D., Haugen, Eric, Hickey, Peter F., Hou, Lei, Jasmine, Farzana, Jian, Ruiqi, Jiang, Lihua, Johnson, Audra, Kaul, Rajinder, Kellis, Manolis, Kibriya, Muhammad G., Lee, Kristen, Li, Jin Billy, Li, Qin, Lin, Jessica, Lin, Shin, Linder, Sandra, Linke, Caroline, Liu, Yaping, Maurano, Matthew T., Molinie, Benoit, Nelson, Jemma, Neri, Fidencio J., Park, Yongjin, Pierce, Brandon L., Rinaldi, Nicola J., Rizzardi, Lindsay F., Sandstrom, Richard, Skol, Andrew, Smith, Kevin S., Snyder, Michael P., Stamatoyannopoulos, John, Tang, Hua, Wang, Li, Wang, Meng, Van Wittenberghe, Nicholas, Wu, Fan, Zhang, Rui, Nierras, Concepcion R., Branton, Philip A., Carithers, Latarsha J., Guan, Ping, Moore, Helen M., Rao, Abhi, Vaught, Jimmie B., Gould, Sarah E., Lockart, Nicole C., Martin, Casey, Struewing, Jeffery P., Volpi, Simona, Addington, Anjene M., Koester, Susan E., Little, Roger A., Brigham, Lori E., Hasz, Richard, Hunter, Marcus, Johns, Christopher, Johnson, Mark, Kopen, Gene, Leinweber, William F., Lonsdale, John T., McDonald, Alisa, Mestichelli, Bernadette, Myer, Kevin, Roe, Brian, Salvatore, Michael, Shad, Saboor, Thomas, Jeffrey A., Walters, Gary, Washington, Michael, Wheeler, Joseph, Bridge, Jason, Foster, Barbara A., Gillard, Bryan M., Karasik, Ellen, Kumar, Rachna, Miklos, Mark, Moser, Michael T., Jewell, Scott D., Montroy, Robert G., Rohrer, Daniel C., Valley, Dana R., Davis, David A., Mash, Deborah C., Undale, Anita H., Smith, Anna M., Tabor, David E., Roche, Nancy V., McLean, Jeffrey A., Vatanian, Negin, Robinson, Karna L., Sobin, Leslie, Barcus, Mary E., Valentino, Kimberly M., Qi, Liqun, Hunter, Steven, Hariharan, Pushpa, Singh, Shilpi, Um, Ki Sung, Matose, Takunda, Tomaszewski, Maria M., Barker, Laura K., Mosavel, Maghboeba, Siminoff, Laura A., Traino, Heather M., Flicek, Paul, Juettemann, Thomas, Ruffier, Magali, Sheppard, Dan, Taylor, Kieron, Trevanion, Stephen J., Zerbino, Daniel R., Craft, Brian, Goldman, Mary, Haeussler, Maximilian, Kent, James W., Lee, Christopher M., Paten, Benedict, Rosenbloom, Kate R., Vivian, John, Zhu, Jingchun, Brown, Andrew A., Nguyen, Duyen Y., Sullivan, Timothy J., Addington, Anjene, Koester, Susan, Lockhart, Nicole C., Roe, Bryan, Valley, Dana, Gewirtz, Ariel D. H., He, Amy Z., Quon, Gerald, Ripke, Stephan, Shimko, Tyler C., Teran, Nicole A., Zhang, Hailei, Bustamante, Carlos D., and Guigó, Roderic

Published
2017
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37. Associations between physical activity and cognitive dysfunction in older companion dogs: results from the Dog Aging Project.

Author

Bray, Emily E., Raichlen, David A., Forsyth, Kiersten K., Promislow, Daniel E. L., Alexander, Gene E., MacLean, Evan L., Dog Aging Project Consortium, Akey, Joshua M., Benton, Brooke, Borenstein, Elhanan, Castelhano, Marta G., Coleman, Amanda E., Creevy, Kate E., Crowder, Kyle, Dunbar, Matthew D., Fajt, Virginia R., Fitzpatrick, Annette L., Jeffrey, Unity, Jonlin, Erica C., and Kaeberlein, Matt

Subjects
PHYSICAL activity, COGNITION disorders, DISEASE risk factors, COGNITIVE aging, ALZHEIMER'S disease, DOG bites
Abstract

Canine cognitive dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimer's disease. Given that physical activity is believed to reduce risk of Alzheimer's disease in humans, we explored the association between physical activity and cognitive health in a cohort of companion dogs, aged 6–18 years. We hypothesized that higher levels of physical activity would be associated with lower (i.e., better) scores on a cognitive dysfunction rating instrument and lower prevalence of dementia, and that this association would be robust when controlling for age, comorbidities, and other potential confounders. Our sample included 11,574 companion dogs enrolled through the Dog Aging Project, of whom 287 had scores over the clinical threshold for CCD. In this observational, cross-sectional study, we used owner-reported questionnaire data to quantify dog cognitive health (via a validated scale), physical activity levels, health conditions, training history, and dietary supplements. We fit regression models with measures of cognitive health as the outcome, and physical activity—with several important covariates—as predictors. We found a significant negative relationship between physical activity and current severity of cognitive dysfunction symptoms (estimate = − 0.10, 95% CI: − 0.11 to − 0.08, p < 0.001), extent of symptom worsening over a 6-month interval (estimate = − 0.07, 95% CI: − 0.09 to − 0.05, p < 0.001), and whether a dog reached a clinical level of CCD (odds ratio = 0.53, 95% CI: 0.45 to 0.63, p < 0.001). Physical activity was robustly associated with better cognitive outcomes in dogs. Our findings illustrate the value of companion dogs as a model for investigating relationships between physical activity and cognitive aging, including aspects of dementia that may have translational potential for Alzheimer's disease. While the current study represents an important first step in identifying a relationship between physical activity and cognitive function, it cannot determine causality. Future studies are needed to rule out reverse causation by following the same dogs prospectively over time, and to evaluate causality by administering physical activity interventions. [ABSTRACT FROM AUTHOR]

Published
2023
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39. Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes

Author

Tennessen, Jacob A., Bigham, Abigail W., O'Connor, Timothy D., Fu, Wenqing, Kenny, Eimear E., Gravel, Simon, McGee, Sean, Do, Ron, Liu, Xiaoming, Jun, Goo, Kang, Hyun Min, Jordan, Daniel, Leal, Suzanne M., Gabriel, Stacey, Rieder, Mark J., Abecasis, Goncalo, Altshuler, David, Nickerson, Deborah A., Boerwinkle, Eric, Sunyaev, Shamil, Bustamante, Carlos D., Bamshad, Michael J., and Akey, Joshua M.

Published
2012
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42. Purpose, Partnership, and Possibilities: The Implementation of the Dog Aging Project Biobank

Author

Mouttham, Lara, primary, Castelhano, Marta G, additional, Akey, Joshua M, additional, Benton, Brooke, additional, Borenstein, Elhanan, additional, Coleman, Amanda E, additional, Creevy, Kate E, additional, Crowder, Kyle, additional, Dunbar, Matthew D, additional, Ernst, Holley R, additional, Fajt, Virginia R, additional, Fitzpatrick, Annette L, additional, Garrison, Susan J, additional, Herndon, Reba S, additional, Jaramilla, Debra, additional, Jeffery, Unity, additional, Jonlin, Erica C, additional, Kaeberlein, Matt, additional, Karlsson, Elinor K, additional, Kerr, Kathleen F, additional, Levine, Jonathan M, additional, Ma, Jing, additional, McClelland, Robyn L, additional, Prescott, Jena O, additional, Promislow, Daniel EL, additional, Ruple, Audrey, additional, Schwartz, Stephen M, additional, Shrager, Sandi, additional, Snyder-Mackler, Noah, additional, Tinkle, Amanda K, additional, Tolbert, M Katherine, additional, Urfer, Silvan R, additional, and Wilfond, Benjamin S, additional

Published
2022
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44. HUMAN GENOMICS: The phenotypic legacy of admixture between modern humans and Neandertals

Author

Simonti, Corinne N., Vernot, Benjamin, Bastarache, Lisa, Bottinger, Erwin, Carrell, David S., Chisholm, Rex L., Crosslin, David R., Hebbring, Scott J., Jarvik, Gail P., Kullo, Iftikhar J., Li, Rongling, Pathak, Jyotishman, Ritchie, Marylyn D., Roden, Dan M., Verma, Shefali S., Tromp, Gerard, Prato, Jeffrey D., Bush, William S., Akey, Joshua M., Denny, Joshua C., and Capra, John A.

Published
2016
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49. Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants

Author

Fu, Wenqing, O'Connor, Timothy D., Jun, Goo, Kang, Hyun Min, Abecasis, Goncalo, Leal, Suzanne M., Gabriel, Stacey, Altshuler, David, Shendure, Jay, Nickerson, Deborah A., Bamshad, Michael J., and Akey, Joshua M.

Subjects
Gene mutations -- Physiological aspects -- Research, Population genetics -- Research, Genetic variation -- Physiological aspects -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Establishing the age of each mutation segregating in contemporary human populations is important to fully understand our evolutionary history (1,2) and will help to facilitate the development of new approaches [...]

Published
2013

50. Deep sequencing of 1320 genes reveals the landscape of protein-truncating variants and their contribution to psoriasis in 19,973 Chinese individuals

Author

Xu, Huixin, primary, Zhen, Qi, additional, Bai, Mingzhou, additional, Fang, Lin, additional, Zhang, Yong, additional, Li, Bao, additional, Ge, Huiyao, additional, Moon, Sunjin, additional, Chen, Weiwei, additional, Fu, Wenqing, additional, Xu, Qiongqiong, additional, Zhou, Yuwen, additional, Yu, Yafeng, additional, Lin, Long, additional, Yong, Liang, additional, Zhang, Tao, additional, Chen, Shirui, additional, Liu, Siyang, additional, Zhang, Hui, additional, Chen, Ruoyan, additional, Cao, Lu, additional, Zhang, Yuanwei, additional, Zhang, Ruixue, additional, Yang, Huanjie, additional, Hu, Xia, additional, Akey, Joshua M., additional, Jin, Xin, additional, and Sun, Liangdan, additional

Published
2021
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