132 research outputs found
Joint analysis of functional genomic data and genome-wide association studies of 18 human traits
Annotations of gene structures and regulatory elements can inform genome-wide
association studies (GWAS). However, choosing the relevant annotations for
interpreting an association study of a given trait remains challenging. We
describe a statistical model that uses association statistics computed across
the genome to identify classes of genomic element that are enriched or depleted
for loci that influence a trait. The model naturally incorporates multiple
types of annotations. We applied the model to GWAS of 18 human traits,
including red blood cell traits, platelet traits, glucose levels, lipid levels,
height, BMI, and Crohn's disease. For each trait, we evaluated the relevance of
450 different genomic annotations, including protein-coding genes, enhancers,
and DNase-I hypersensitive sites in over a hundred tissues and cell lines. We
show that the fraction of phenotype-associated SNPs that influence protein
sequence ranges from around 2% (for platelet volume) up to around 20% (for LDL
cholesterol); that repressed chromatin is significantly depleted for SNPs
associated with several traits; and that cell type-specific DNase-I
hypersensitive sites are enriched for SNPs associated with several traits (for
example, the spleen in platelet volume). Finally, by re-weighting each GWAS
using information from functional genomics, we increase the number of loci with
high-confidence associations by around 5%.Comment: Fixed typos, included minor clarification
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Inference of Population Splits and Mixtures from Genome-Wide Allele Frequency Data
Many aspects of the historical relationships between populations in a species are reflected in genetic data. Inferring these relationships from genetic data, however, remains a challenging task. In this paper, we present a statistical model for inferring the patterns of population splits and mixtures in multiple populations. In our model, the sampled populations in a species are related to their common ancestor through a graph of ancestral populations. Using genome-wide allele frequency data and a Gaussian approximation to genetic drift, we infer the structure of this graph. We applied this method to a set of 55 human populations and a set of 82 dog breeds and wild canids. In both species, we show that a simple bifurcating tree does not fully describe the data; in contrast, we infer many migration events. While some of the migration events that we find have been detected previously, many have not. For example, in the human data, we infer that Cambodians trace approximately 16% of their ancestry to a population ancestral to other extant East Asian populations. In the dog data, we infer that both the boxer and basenji trace a considerable fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to domestication and that East Asian toy breeds (the Shih Tzu and the Pekingese) result from admixture between modern toy breeds and “ancient” Asian breeds. Software implementing the model described here, called TreeMix, is available at http://treemix.googlecode.com.</p
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Noisy Splicing Drives mRNA Isoform Diversity in Human Cells
While the majority of multiexonic human genes show some evidence of alternative splicing, it is unclear what fraction of observed splice forms is functionally relevant. In this study, we examine the extent of alternative splicing in human cells using deep RNA sequencing and de novo identification of splice junctions. We demonstrate the existence of a large class of low abundance isoforms, encompassing approximately 150,000 previously unannotated splice junctions in our data. Newly-identified splice sites show little evidence of evolutionary conservation, suggesting that the majority are due to erroneous splice site choice. We show that sequence motifs involved in the recognition of exons are enriched in the vicinity of unconserved splice sites. We estimate that the average intron has a splicing error rate of approximately 0.7% and show that introns in highly expressed genes are spliced more accurately, likely due to their shorter length. These results implicate noisy splicing as an important property of genome evolution.</p
Ancient west Eurasian ancestry in southern and eastern Africa
The history of southern Africa involved interactions between indigenous
hunter-gatherers and a range of populations that moved into the region. Here we
use genome-wide genetic data to show that there are at least two admixture
events in the history of Khoisan populations (southern African hunter-gatherers
and pastoralists who speak non-Bantu languages with click consonants). One
involved populations related to Niger-Congo-speaking African populations, and
the other introduced ancestry most closely related to west Eurasian (European
or Middle Eastern) populations. We date this latter admixture event to
approximately 900-1,800 years ago, and show that it had the largest demographic
impact in Khoisan populations that speak Khoe-Kwadi languages. A similar signal
of west Eurasian ancestry is present throughout eastern Africa. In particular,
we also find evidence for two admixture events in the history of Kenyan,
Tanzanian, and Ethiopian populations, the earlier of which involved populations
related to west Eurasians and which we date to approximately 2,700 - 3,300
years ago. We reconstruct the allele frequencies of the putative west Eurasian
population in eastern Africa, and show that this population is a good proxy for
the west Eurasian ancestry in southern Africa. The most parsimonious
explanation for these findings is that west Eurasian ancestry entered southern
Africa indirectly through eastern Africa.Comment: Added additional simulations, some additional discussio
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Identifying genetic variants that affect viability in large cohorts
A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10-6 for fathers and P~2.0 × 10-3 for mothers), consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10-3). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD), body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans.Medical Research Council (Unit Programme number MC_UU_12015/2). This grant supported FRD and JRBP. National Institutes of Health (NIH) (grant number R01GM121372). This grant is to MP and JKP. National Institutes of Health (NIH) (grant number R01MH106842). This grant is to JKP. Columbia University. This research was funded in part by a Research Initiative in Science and Engineering grant to MP and JKP. National Institutes of Health (NIH) (grant number R01GM115889). This grant is to Guy Sella, provided partial support for HM
Inferring Admixture Histories of Human Populations Using Linkage Disequilibrium
Author Manuscript date February 9, 2013Long-range migrations and the resulting admixtures between populations have been important forces shaping human genetic diversity. Most existing methods for detecting and reconstructing historical admixture events are based on allele frequency divergences or patterns of ancestry segments in chromosomes of admixed individuals. An emerging new approach harnesses the exponential decay of admixture-induced linkage disequilibrium (LD) as a function of genetic distance. Here, we comprehensively develop LD-based inference into a versatile tool for investigating admixture. We present a new weighted LD statistic that can be used to infer mixture proportions as well as dates with fewer constraints on reference populations than previous methods. We define an LD-based three-population test for admixture and identify scenarios in which it can detect admixture events that previous formal tests cannot. We further show that we can uncover phylogenetic relationships among populations by comparing weighted LD curves obtained using a suite of references. Finally, we describe several improvements to the computation and fitting of weighted LD curves that greatly increase the robustness and speed of the calculations. We implement all of these advances in a software package, ALDER, which we validate in simulations and apply to test for admixture among all populations from the Human Genome Diversity Project (HGDP), highlighting insights into the admixture history of Central African Pygmies, Sardinians, and Japanese.National Science Foundation (U.S.). Graduate Research Fellowship ProgramNational Institutes of Health (U.S.). (Training Grant 5T32HG004947-04)Simons Foundatio
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The Role of Geography in Human Adaptation
Various observations argue for a role of adaptation in recent human evolution, including results from genome-wide studies and analyses of selection signals at candidate genes. Here, we use genome-wide SNP data from the HapMap and CEPH-Human Genome Diversity Panel samples to study the geographic distributions of putatively selected alleles at a range of geographic scales. We find that the average allele frequency divergence is highly predictive of the most extreme FST values across the whole genome. On a broad scale, the geographic distribution of putatively selected alleles almost invariably conforms to population clusters identified using randomly chosen genetic markers. Given this structure, there are surprisingly few fixed or nearly fixed differences between human populations. Among the nearly fixed differences that do exist, nearly all are due to fixation events that occurred outside of Africa, and most appear in East Asia. These patterns suggest that selection is often weak enough that neutral processes—especially population history, migration, and drift—exert powerful influences over the fate and geographic distribution of selected alleles.</p
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Evolutionary Dynamics of Human Toll-Like Receptors and Their Different Contributions to Host Defense
Infectious diseases have been paramount among the threats to health and survival throughout human evolutionary history. Natural selection is therefore expected to act strongly on host defense genes, particularly on innate immunity genes whose products mediate the direct interaction between the host and the microbial environment. In insects and mammals, the Toll-like receptors (TLRs) appear to play a major role in initiating innate immune responses against microbes. In humans, however, it has been speculated that the set of TLRs could be redundant for protective immunity. We investigated how natural selection has acted upon human TLRs, as an approach to assess their level of biological redundancy. We sequenced the ten human TLRs in a panel of 158 individuals from various populations worldwide and found that the intracellular TLRs—activated by nucleic acids and particularly specialized in viral recognition—have evolved under strong purifying selection, indicating their essential non-redundant role in host survival. Conversely, the selective constraints on the TLRs expressed on the cell surface—activated by compounds other than nucleic acids—have been much more relaxed, with higher rates of damaging nonsynonymous and stop mutations tolerated, suggesting their higher redundancy. Finally, we tested whether TLRs have experienced spatially-varying selection in human populations and found that the region encompassing TLR10-TLR1-TLR6 has been the target of recent positive selection among non-Africans. Our findings indicate that the different TLRs differ in their immunological redundancy, reflecting their distinct contributions to host defense. The insights gained in this study foster new hypotheses to be tested in clinical and epidemiological genetics of infectious disease.</p
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