Differentiating mechanism from outcome for ancestry-assortative mating in admixed human populations.

Population genetic theory, and the empirical methods built upon it, often assume that individuals pair randomly for reproduction. However, natural populations frequently violate this assumption, which may potentially confound genome-wide association studies, selection scans, and demographic inference. Within several recently admixed human populations, empirical genetic studies have reported a correlation in global ancestry proportion between spouses, referred to as ancestry-assortative mating. Here, we use forward genomic simulations to link correlations in ancestry between mates to the underlying mechanistic mate-choice process. We consider the impacts of two types of mate-choice model, using either ancestry-based preferences or social groups as the basis for mate pairing. We find that multiple mate-choice models can produce the same correlations in ancestry proportion between spouses; however, we also highlight alternative analytic approaches and circumstances in which these models may be distinguished. With this work, we seek to highlight potential pitfalls when interpreting correlations in empirical data as evidence for a particular model of human mating practices, as well as to offer suggestions toward development of new best practices for analysis of human ancestry-assortative mating.

Genomic Consequences of Isolation and Inbreeding in an Island Dingo Population.

Dingoes come from an ancient canid lineage that originated in East Asia around 8,000 to 11,000 years BP. As Australia's largest terrestrial predator, dingoes play an important ecological role. A small, protected population exists on a world heritage listed offshore island, K'gari (formerly Fraser Island). Concern regarding the persistence of dingoes on K'gari has risen due to their low genetic diversity and elevated inbreeding levels. However, whole-genome sequence data is lacking from this population. Here, we include five new whole-genome sequences of K'gari dingoes. We analyze a total of 18 whole-genome sequences of dingoes sampled from mainland Australia and K'gari to assess the genomic consequences of their demographic histories. Long (>1 Mb) runs of homozygosity (ROHs)-indicators of inbreeding-are elevated in all sampled dingoes. However, K'gari dingoes showed significantly higher levels of very long ROH (>5 Mb), providing genomic evidence for small population size, isolation, inbreeding, and a strong founder effect. Our results suggest that, despite current levels of inbreeding, the K'gari population is purging strongly deleterious mutations, which, in the absence of further reductions in population size, may facilitate the persistence of small populations despite low genetic diversity and isolation. However, there may be little to no purging of mildly deleterious alleles, which may have important long-term consequences, and should be considered by conservation and management programs.

Genotypic and phenotypic consequences of domestication in dogs.

Runs of homozygosity (ROH) are genomic regions that arise when two copies of an identical ancestral haplotype are inherited from parents with a recent common ancestor. In this study, we performed a novel comprehensive analysis to infer genetic diversity among dogs and quantified the association between ROH and non-disease phenotypes. We found distinct patterns of genetic diversity across clades of breed dogs and elevated levels of long ROH, compared to non- domesticated dogs. These high levels of F ROH (inbreeding coefficient) are a consequence of recent inbreeding among domesticated dogs during breed establishment. We identified statistically significant associations between F ROH and height, weight, lifespan, muscled, white head, white chest, furnish, and length of fur. After correcting for population structure, we identified more than 45 genes across the three examined quantitative traits that exceeded the threshold for suggestive significance, indicating significant polygenic inheritance for the complex quantitative phenotypes in dogs.

The Maintenance of Deleterious Variation in Wild Chinese Rhesus Macaques.

Understanding how deleterious variation is shaped and maintained in natural populations is important in conservation and evolutionary biology, as decreased fitness caused by these deleterious mutations can potentially lead to an increase in extinction risk. It is known that demographic processes can influence these patterns. For example, population bottlenecks and inbreeding increase the probability of inheriting identical-by-descent haplotypes from a recent common ancestor, creating long tracts of homozygous genotypes called runs of homozygosity (ROH), which have been associated with an accumulation of mildly deleterious homozygotes. Counter intuitively, positive selection can also maintain deleterious variants in a population through genetic hitchhiking. Here we analyze the whole genomes of 79 wild Chinese rhesus macaques across five subspecies and characterize patterns of deleterious variation with respect to ROH and signals of recent positive selection. We show that the fraction of homozygotes occurring in long ROH is significantly higher for deleterious homozygotes than tolerated ones, whereas this trend is not observed for short and medium ROH. This confirms that inbreeding, by generating these long tracts of homozygosity, is the main driver of the high burden of homozygous deleterious alleles in wild macaque populations. Furthermore, we show evidence that homozygous LOF variants are being purged. Next, we identify 7 deleterious variants at high frequency in regions putatively under selection near genes involved with olfaction and other processes. Our results shed light on how evolutionary processes can shape the distribution of deleterious variation in wild non-human primates.

The Maintenance of Deleterious Variation in Wild Chinese Rhesus Macaques.

Understanding how deleterious variation is shaped and maintained in natural populations is important in conservation and evolutionary biology, as decreased fitness caused by these deleterious mutations can potentially lead to an increase in extinction risk. It is known that demographic processes can influence these patterns. For example, population bottlenecks and inbreeding increase the probability of inheriting identical-by-descent haplotypes from a recent common ancestor, creating long tracts of homozygous genotypes called runs of homozygosity (ROH), which have been associated with an accumulation of mildly deleterious homozygotes. Counterintuitively, positive selection can also maintain deleterious variants in a population through genetic hitchhiking. Here, we analyze the whole genomes of 79 wild Chinese rhesus macaques across five subspecies and characterize patterns of deleterious variation with respect to ROH and signals of recent positive selection. We show that the fraction of homozygotes occurring in long ROH is significantly higher for deleterious homozygotes than tolerated ones, whereas this trend is not observed for short and medium ROH. This confirms that inbreeding, by generating these long tracts of homozygosity, is the main driver of the high burden of homozygous deleterious alleles in wild macaque populations. Furthermore, we show evidence that homozygous LOF variants are being purged. Next, we identify seven deleterious variants at high frequency in regions putatively under selection near genes involved with olfaction and other processes. Our results shed light on how evolutionary processes can shape the distribution of deleterious variation in wild nonhuman primates.

selscan 2.0: scanning for sweeps in unphased data.

SUMMARY: Several popular haplotype-based statistics for identifying recent or ongoing positive selection in genomes require knowledge of haplotype phase. Here, we provide an update to selscan which implements a re-definition of these statistics for use in unphased data. AVAILABILITY AND IMPLEMENTATION: Source code and binaries are freely available at https://github.com/szpiech/selscan, implemented in C/C++, and supported on Linux, Windows, and MacOS.

Genomic consequences of isolation and inbreeding in an island dingo population.

Dingoes come from an ancient canid lineage that originated in East Asia around 8000-11,000 years BP. As Australia's largest terrestrial predator, dingoes play an important ecological role. A small, protected population exists on a world heritage listed offshore island, K'gari (formerly Fraser Island). Concern regarding the persistence of dingoes on K'gari has risen due to their low genetic diversity and elevated inbreeding levels. However, whole-genome sequencing data is lacking from this population. Here, we include five new whole-genome sequences of K'gari dingoes. We analyze a total of 18 whole genome sequences of dingoes sampled from mainland Australia and K'gari to assess the genomic consequences of their demographic histories. Long (>1 Mb) runs of homozygosity (ROH) - indicators of inbreeding - are elevated in all sampled dingoes. However, K'gari dingoes showed significantly higher levels of very long ROH (>5 Mb), providing genomic evidence for small population size, isolation, inbreeding, and a strong founder effect. Our results suggest that, despite current levels of inbreeding, the K'gari population is purging strongly deleterious mutations, which, in the absence of further reductions in population size, may facilitate the persistence of small populations despite low genetic diversity and isolation. However, there may be little to no purging of mildly deleterious alleles, which may have important long-term consequences, and should be considered by conservation and management programs.

Genomes of the extinct Bachman's warbler show high divergence and no evidence of admixture with other extant Vermivora warblers.

Bachman's warbler1 (Vermivora bachmanii)-last sighted in 1988-is one of the only North American passerines to recently go extinct.2,3,4 Given extensive ongoing hybridization of its two extant congeners-the blue-winged warbler (V. cyanoptera) and golden-winged warbler (V. chrysoptera)5,6,7,8-and shared patterns of plumage variation between Bachman's warbler and hybrids between those extant species, it has been suggested that Bachman's warbler might have also had a component of hybrid ancestry. Here, we use historic DNA (hDNA) and whole genomes of Bachman's warblers collected at the turn of the 20th century to address this. We combine these data with the two extant Vermivora species to examine patterns of population differentiation, inbreeding, and gene flow. In contrast to the admixture hypothesis, the genomic evidence is consistent with V. bachmanii having been a highly divergent, reproductively isolated species, with no evidence of introgression. We show that these three species have similar levels of runs of homozygosity (ROH), consistent with effects of a small long-term effective population size or population bottlenecks, with one V. bachmanii outlier showing numerous long ROH and a FROH greater than 5%. We also found-using population branch statistic estimates-previously undocumented evidence of lineage-specific evolution in V. chrysoptera near a pigmentation gene candidate, CORIN, which is a known modifier of ASIP, which is in turn involved in melanic throat and mask coloration in this family of birds. Together, these genomic results also highlight how natural history collections are such invaluable repositories of information about extant and extinct species.

A genetic and linguistic analysis of the admixture histories of the islands of Cabo Verde.

From the 15th to the 19th century, the Trans-Atlantic Slave-Trade (TAST) influenced the genetic and cultural diversity of numerous populations. We explore genomic and linguistic data from the nine islands of Cabo Verde, the earliest European colony of the era in Africa, a major Slave-Trade platform between the 16th and 19th centuries, and a previously uninhabited location ideal for investigating early admixture events between Europeans and Africans. Using local-ancestry inference approaches, we find that genetic admixture in Cabo Verde occurred primarily between Iberian and certain Senegambian populations, although forced and voluntary migrations to the archipelago involved numerous other populations. Inter-individual genetic and linguistic variation recapitulates the geographic distribution of individuals' birth-places across Cabo Verdean islands, following an isolation-by-distance model with reduced genetic and linguistic effective dispersals within the archipelago, and suggesting that Kriolu language variants have developed together with genetic divergences at very reduced geographical scales. Furthermore, based on approximate bayesian computation inferences of highly complex admixture histories, we find that admixture occurred early on each island, long before the 18th-century massive TAST deportations triggered by the expansion of the plantation economy in Africa and the Americas, and after this era mostly during the abolition of the TAST and of slavery in European colonial empires. Our results illustrate how shifting socio-cultural relationships between enslaved and non-enslaved communities during and after the TAST, shaped enslaved-African descendants' genomic diversity and structure on both sides of the Atlantic.

A rarefaction approach for measuring population differences in rare and common variation.

In studying allele-frequency variation across populations, it is often convenient to classify an allelic type as "rare," with nonzero frequency less than or equal to a specified threshold, "common," with a frequency above the threshold, or entirely unobserved in a population. When sample sizes differ across populations, however, especially if the threshold separating "rare" and "common" corresponds to a small number of observed copies of an allelic type, discreteness effects can lead a sample from one population to possess substantially more rare allelic types than a sample from another population, even if the two populations have extremely similar underlying allele-frequency distributions across loci. We introduce a rarefaction-based sample-size correction for use in comparing rare and common variation across multiple populations whose sample sizes potentially differ. We use our approach to examine rare and common variation in worldwide human populations, finding that the sample-size correction introduces subtle differences relative to analyses that use the full available sample sizes. We introduce several ways in which the rarefaction approach can be applied: we explore the dependence of allele classifications on subsample sizes, we permit more than two classes of allelic types of nonzero frequency, and we analyze rare and common variation in sliding windows along the genome. The results can assist in clarifying similarities and differences in allele-frequency patterns across populations.

Evolution of genes involved in the unusual genitals of the bear macaque, Macaca arctoides.

Genital divergence is thought to contribute to reproductive barriers by establishing a "lock-and-key" mechanism for reproductive compatibility. One such example, Macaca arctoides, the bear macaque, has compensatory changes in both male and female genital morphology as compared to close relatives. M. arctoides also has a complex evolutionary history, having extensive introgression between the fascicularis and sinica macaque species groups. Here, phylogenetic relationships were analyzed via whole-genome sequences from five species, including M. arctoides, and two species each from the putative parental species groups. This analysis revealed ~3x more genomic regions supported placement in the sinica species group as compared to the fascicularis species group. Additionally, introgression analysis of the M. arctoides genome revealed it is a mosaic of recent polymorphisms shared with both species groups. To examine the evolution of their unique genital morphology further, the prevalence of candidate genes involved in genital morphology was compared against genome-wide outliers in various population genetic metrics of diversity, divergence, introgression, and selection, while accounting for background variation in recombination rate. This analysis identified 67 outlier genes, including several genes that influence baculum morphology in mice, which were of interest since the bear macaque has the longest primate baculum. The mean of four of the seven population genetic metrics was statistically different in the candidate genes as compared to the rest of the genome, suggesting that genes involved in genital morphology have increased divergence and decreased diversity beyond expectations. These results highlight specific genes that may have played a role in shaping the unique genital morphology in the bear macaque.

A spatially aware likelihood test to detect sweeps from haplotype distributions.

The inference of positive selection in genomes is a problem of great interest in evolutionary genomics. By identifying putative regions of the genome that contain adaptive mutations, we are able to learn about the biology of organisms and their evolutionary history. Here we introduce a composite likelihood method that identifies recently completed or ongoing positive selection by searching for extreme distortions in the spatial distribution of the haplotype frequency spectrum along the genome relative to the genome-wide expectation taken as neutrality. Furthermore, the method simultaneously infers two parameters of the sweep: the number of sweeping haplotypes and the "width" of the sweep, which is related to the strength and timing of selection. We demonstrate that this method outperforms the leading haplotype-based selection statistics, though strong signals in low-recombination regions merit extra scrutiny. As a positive control, we apply it to two well-studied human populations from the 1000 Genomes Project and examine haplotype frequency spectrum patterns at the LCT and MHC loci. We also apply it to a data set of brown rats sampled in NYC and identify genes related to olfactory perception. To facilitate use of this method, we have implemented it in user-friendly open source software.

Application of a novel haplotype-based scan for local adaptation to study high-altitude adaptation in rhesus macaques.

When natural populations split and migrate to different environments, they may experience different selection pressures that can lead to local adaptation. To capture the genomic patterns of a local selective sweep, we develop XP-nSL, a genomic scan for local adaptation that compares haplotype patterns between two populations. We show that XP-nSL has power to detect ongoing and recently completed hard and soft sweeps, and we then apply this statistic to search for evidence of adaptation to high altitude in rhesus macaques. We analyze the whole genomes of 23 wild rhesus macaques captured at high altitude (mean altitude > 4000 m above sea level) to 22 wild rhesus macaques captured at low altitude (mean altitude < 500 m above sea level) and find evidence of local adaptation in the high-altitude population at or near 303 known genes and several unannotated regions. We find the strongest signal for adaptation at EGLN1, a classic target for convergent evolution in several species living in low oxygen environments. Furthermore, many of the 303 genes are involved in processes related to hypoxia, regulation of ROS, DNA damage repair, synaptic signaling, and metabolism. These results suggest that, beyond adapting via a beneficial mutation in one single gene, adaptation to high altitude in rhesus macaques is polygenic and spread across numerous important biological systems.

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

Ancestry-Dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity.

Runs of homozygosity (ROH) are important genomic features that manifest when an individual inherits two haplotypes that are identical by descent. Their length distributions are informative about population history, and their genomic locations are useful for mapping recessive loci contributing to both Mendelian and complex disease risk. We have previously shown that ROH, and especially long ROH that are likely the result of recent parental relatedness, are enriched for homozygous deleterious coding variation in a worldwide sample of outbred individuals. However, the distribution of ROH in admixed populations and their relationship to deleterious homozygous genotypes is understudied. Here we analyze whole-genome sequencing data from 1,441 unrelated individuals from self-identified African American, Puerto Rican, and Mexican American populations. These populations are three-way admixed between European, African, and Native American ancestries and provide an opportunity to study the distribution of deleterious alleles partitioned by local ancestry and ROH. We re-capitulate previous findings that long ROH are enriched for deleterious variation genome-wide. We then partition by local ancestry and show that deleterious homozygotes arise at a higher rate when ROH overlap African ancestry segments than when they overlap European or Native American ancestry segments of the genome. These results suggest that, while ROH on any haplotype background are associated with an inflation of deleterious homozygous variation, African haplotype backgrounds may play a particularly important role in the genetic architecture of complex diseases for admixed individuals, highlighting the need for further study of these populations.

Correction: Human demographic history has amplified the effects of background selection across the genome.

[This corrects the article DOI: 10.1371/journal.pgen.1007387.].

Human demographic history has amplified the effects of background selection across the genome.

Natural populations often grow, shrink, and migrate over time. Such demographic processes can affect genome-wide levels of genetic diversity. Additionally, genetic variation in functional regions of the genome can be altered by natural selection, which drives adaptive mutations to higher frequencies or purges deleterious ones. Such selective processes affect not only the sites directly under selection but also nearby neutral variation through genetic linkage via processes referred to as genetic hitchhiking in the context of positive selection and background selection (BGS) in the context of purifying selection. While there is extensive literature examining the consequences of selection at linked sites at demographic equilibrium, less is known about how non-equilibrium demographic processes influence the effects of hitchhiking and BGS. Utilizing a global sample of human whole-genome sequences from the Thousand Genomes Project and extensive simulations, we investigate how non-equilibrium demographic processes magnify and dampen the consequences of selection at linked sites across the human genome. When binning the genome by inferred strength of BGS, we observe that, compared to Africans, non-African populations have experienced larger proportional decreases in neutral genetic diversity in strong BGS regions. We replicate these findings in admixed populations by showing that non-African ancestral components of the genome have also been affected more severely in these regions. We attribute these differences to the strong, sustained/recurrent population bottlenecks that non-Africans experienced as they migrated out of Africa and throughout the globe. Furthermore, we observe a strong correlation between FST and the inferred strength of BGS, suggesting a stronger rate of genetic drift. Forward simulations of human demographic history with a model of BGS support these observations. Our results show that non-equilibrium demography significantly alters the consequences of selection at linked sites and support the need for more work investigating the dynamic process of multiple evolutionary forces operating in concert.

Relationship between Deleterious Variation, Genomic Autozygosity, and Disease Risk: Insights from The 1000 Genomes Project.

Genomic regions of autozygosity (ROAs) represent segments of individual genomes that are homozygous for haplotypes inherited identical-by-descent (IBD) from a common ancestor. ROAs are nonuniformly distributed across the genome, and increased ROA levels are a reported risk factor for numerous complex diseases. Previously, we hypothesized that long ROAs are enriched for deleterious homozygotes as a result of young haplotypes with recent deleterious mutations-relatively untouched by purifying selection-being paired IBD as a consequence of recent parental relatedness, a pattern supported by ROA and whole-exome sequence data on 27 individuals. Here, we significantly bolster support for our hypothesis and expand upon our original analyses using ROA and whole-genome sequence data on 2,436 individuals from The 1000 Genomes Project. Considering CADD deleteriousness scores, we reaffirm our previous observation that long ROAs are enriched for damaging homozygotes worldwide. We show that strongly damaging homozygotes experience greater enrichment than weaker damaging homozygotes, while overall enrichment varies appreciably among populations. Mendelian disease genes and those encoding FDA-approved drug targets have significantly increased rates of gain in damaging homozygotes with increasing ROA coverage relative to all other genes. In genes implicated in eight complex phenotypes for which ROA levels have been identified as a risk factor, rates of gain in damaging homozygotes vary across phenotypes and populations but frequently differ significantly from non-disease genes. These findings highlight the potential confounding effects of population background in the assessment of associations between ROA levels and complex disease risk, which might underlie reported inconsistencies in ROA-phenotype associations.

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.

RATIONALE: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response. OBJECTIVES: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children. METHODS: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR. MEASUREMENTS AND MAIN RESULTS: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10-7) and suggestive (P < 7.06 × 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and ß-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings. CONCLUSIONS: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.

Weighted likelihood inference of genomic autozygosity patterns in dense genotype data.

BACKGROUND: Genomic regions of autozygosity (ROA) arise when an individual is homozygous for haplotypes inherited identical-by-descent from ancestors shared by both parents. Over the past decade, they have gained importance for understanding evolutionary history and the genetic basis of complex diseases and traits. However, methods to infer ROA in dense genotype data have not evolved in step with advances in genome technology that now enable us to rapidly create large high-resolution genotype datasets, limiting our ability to investigate their constituent ROA patterns. METHODS: We report a weighted likelihood approach for inferring ROA in dense genotype data that accounts for autocorrelation among genotyped positions and the possibilities of unobserved mutation and recombination events, and variability in the confidence of individual genotype calls in whole genome sequence (WGS) data. RESULTS: Forward-time genetic simulations under two demographic scenarios that reflect situations where inbreeding and its effect on fitness are of interest suggest this approach is better powered than existing state-of-the-art methods to infer ROA at marker densities consistent with WGS and popular microarray genotyping platforms used in human and non-human studies. Moreover, we present evidence that suggests this approach is able to distinguish ROA arising via consanguinity from ROA arising via endogamy. Using subsets of The 1000 Genomes Project Phase 3 data we show that, relative to WGS, intermediate and long ROA are captured robustly with popular microarray platforms, while detection of short ROA is more variable and improves with marker density. Worldwide ROA patterns inferred from WGS data are found to accord well with those previously reported on the basis of microarray genotype data. Finally, we highlight the potential of this approach to detect genomic regions enriched for autozygosity signals in one group relative to another based upon comparisons of per-individual autozygosity likelihoods instead of inferred ROA frequencies. CONCLUSIONS: This weighted likelihood ROA inference approach can assist population- and disease-geneticists working with a wide variety of data types and species to explore ROA patterns and to identify genomic regions with differential ROA signals among groups, thereby advancing our understanding of evolutionary history and the role of recessive variation in phenotypic variation and disease.