Population genetic studies have found evidence for dramatic population growth in recent human history. It is unclear how this recent population growth, combined with the effects of negative natural ...selection, has affected patterns of deleterious variation, as well as the number, frequency, and effect sizes of mutations that contribute risk to complex traits. Because researchers are performing exome sequencing studies aimed at uncovering the role of low-frequency variants in the risk of complex traits, this topic is of critical importance. Here I use simulations under population genetic models where a proportion of the heritability of the trait is accounted for by mutations in a subset of the exome. I show that recent population growth increases the proportion of nonsynonymous variants segregating in the population, but does not affect the genetic load relative to a population that did not expand. Under a model where a mutation's effect on a trait is correlated with its effect on fitness, rare variants explain a greater portion of the additive genetic variance of the trait in a population that has recently expanded than in a population that did not recently expand. Further, when using a single-marker test, for a given false-positive rate and sample size, recent population growth decreases the expected number of significant associations with the trait relative to the number detected in a population that did not expand. However, in a model where there is no correlation between a mutation's effect on fitness and the effect on the trait, common variants account for much of the additive genetic variance, regardless of demography. Moreover, here demography does not affect the number of significant associations detected. These findings suggest recent population history may be an important factor influencing the power of association tests and in accounting for the missing heritability of certain complex traits.
Population genetic studies suggest that most amino-acid changing mutations are deleterious. Such mutations are of tremendous interest in human population genetics as they are important for the ...evolutionary process and may contribute risk to common disease. Genomic studies over the past 5 years have documented differences across populations in the number of heterozygous deleterious genotypes, number of homozygous derived deleterious genotypes, number of deleterious segregating sites and proportion of sites that are potentially deleterious. These differences have been attributed to population history affecting the ability of natural selection to remove deleterious variants from the population. However, recent studies have suggested that the genetic load is the same across populations and that the efficacy of natural selection has not differed across human populations. Here I show that these observations are not incompatible with each other and that the apparent differences are due to examining different features of the genetic data and differing definitions of terms.
While much effort has focused on detecting positive and negative directional selection in the human genome, relatively little work has been devoted to balancing selection. This lack of attention is ...likely due to the paucity of sophisticated methods for identifying sites under balancing selection. Here we develop two composite likelihood ratio tests for detecting balancing selection. Using simulations, we show that these methods outperform competing methods under a variety of assumptions and demographic models. We apply the new methods to whole-genome human data, and find a number of previously-identified loci with strong evidence of balancing selection, including several HLA genes. Additionally, we find evidence for many novel candidates, the strongest of which is FANK1, an imprinted gene that suppresses apoptosis, is expressed during meiosis in males, and displays marginal signs of segregation distortion. We hypothesize that balancing selection acts on this locus to stabilize the segregation distortion and negative fitness effects of the distorter allele. Thus, our methods are able to reproduce many previously-hypothesized signals of balancing selection, as well as discover novel interesting candidates.
Phenotype prediction is a key goal for medical genetics. Unfortunately, most genome-wide association studies are done in European populations, which reduces the accuracy of predictions via polygenic ...scores in non-European populations. Here, we use population genetic models to show that human demographic history and negative selection on complex traits can result in population-specific genetic architectures. For traits where alleles with the largest effect on the trait are under the strongest negative selection, approximately half of the heritability can be accounted for by variants in Europe that are absent from Africa, leading to poor performance in phenotype prediction across these populations. Further, under such a model, individuals in the tails of the genetic risk distribution may not be identified via polygenic scores generated in another population. We empirically test these predictions by building a model to stratify heritability between European-specific and shared variants and applied it to 37 traits and diseases in the UK Biobank. Across these phenotypes, ∼30% of the heritability comes from European-specific variants. We conclude that genetic association studies need to include more diverse populations to enable the utility of phenotype prediction in all populations.
Comparative genomic approaches have been used to identify sites where mutations are under purifying selection and of functional consequence by searching for sequences that are conserved across ...distantly related species. However, the performance of these approaches has not been rigorously evaluated under population genetic models. Further, short-lived functional elements may not leave a footprint of sequence conservation across many species. We use simulations to study how one measure of conservation, the Genomic Evolutionary Rate Profiling (GERP) score, relates to the strength of selection (Nes). We show that the GERP score is related to the strength of purifying selection. However, changes in selection coefficients or functional elements over time (i.e. functional turnover) can strongly affect the GERP distribution, leading to unexpected relationships between GERP and Nes. Further, we show that for functional elements that have a high turnover rate, adding more species to the analysis does not necessarily increase statistical power. Finally, we use the distribution of GERP scores across the human genome to compare models with and without turnover of sites where mutations under purifying selection. We show that mutations in 4.51% of the noncoding human genome are under purifying selection and that most of this sequence has likely experienced changes in selection coefficients throughout mammalian evolution. Our work reveals limitations to using comparative genomic approaches to identify deleterious mutations. Commonly used GERP score thresholds miss over half of the noncoding sites in the human genome where mutations are under purifying selection.
While it is appreciated that population size changes can impact patterns of deleterious variation in natural populations, less attention has been paid to how gene flow affects and is affected by the ...dynamics of deleterious variation. Here we use population genetic simulations to examine how gene flow impacts deleterious variation under a variety of demographic scenarios, mating systems, dominance coefficients, and recombination rates. Our results show that admixture between populations can temporarily reduce the genetic load of smaller populations and cause increases in the frequency of introgressed ancestry, especially if deleterious mutations are recessive. Additionally, when fitness effects of new mutations are recessive, between-population differences in the sites at which deleterious variants exist creates heterosis in hybrid individuals. Together, these factors lead to an increase in introgressed ancestry, particularly when recombination rates are low. Under certain scenarios, introgressed ancestry can increase from an initial frequency of 5% to 30-75% and fix at many loci, even in the absence of beneficial mutations. Further, deleterious variation and admixture can generate correlations between the frequency of introgressed ancestry and recombination rate or exon density, even in the absence of other types of selection. The direction of these correlations is determined by the specific demography and whether mutations are additive or recessive. Therefore, it is essential that null models of admixture include both demography and deleterious variation before invoking other mechanisms to explain unusual patterns of genetic variation.
The recovery and persistence of rare and endangered species are often threatened by genetic factors, such as the accumulation of deleterious mutations, loss of adaptive potential, and inbreeding ...depression 1. Island foxes (Urocyon littoralis), the dwarfed descendants of mainland gray foxes (Urocyon cinereoargenteus), have inhabited California’s Channel Islands for >9,000 years 2–4. Previous genomic analyses revealed that island foxes have exceptionally low levels of diversity and elevated levels of putatively deleterious variation 5. Nonetheless, all six populations have persisted for thousands of generations, and several populations rebounded rapidly after recent severe bottlenecks 6, 7. Here, we combine morphological and genomic data with population-genetic simulations to determine the mechanism underlying the enigmatic persistence of these foxes. First, through analysis of genomes from 1929 to 2009, we show that island foxes have remained at small population sizes with low diversity for many generations. Second, we present morphological data indicating an absence of inbreeding depression in island foxes, confirming that they are not afflicted with congenital defects common to other small and inbred populations. Lastly, our population-genetic simulations suggest that long-term small population size results in a reduced burden of strongly deleterious recessive alleles, providing a mechanism for the absence of inbreeding depression in island foxes. Importantly, the island fox illustrates a scenario in which genetic restoration through human-assisted gene flow could be a counterproductive or even harmful conservation strategy. Our study sheds light on the puzzle of island fox persistence, a unique success story that provides a model for the preservation of small populations.
•Island fox genomes have low diversity and an elevated load of deleterious mutations•Congenital defects common in inbred carnivores are rare in island fox skeletons•Simulations suggest that island foxes have purged strongly deleterious recessive alleles•Purging may have enabled long-term persistence and rapid recovery from bottlenecks
Robinson et al. analyze genomic, morphological, and simulated data to understand why island foxes do not suffer from inbreeding depression and rapidly rebounded from recent bottlenecks, despite having low genomic diversity and an elevated number of deleterious alleles. They suggest purging of recessive deleterious alleles as a possible mechanism.
Genome sequence data are now being routinely obtained from many nonmodel organisms. These data contain a wealth of information about the demographic history of the populations from which they ...originate. Many sophisticated statistical inference procedures have been developed to infer the demographic history of populations from this type of genomic data. In this review, we discuss the different statistical methods available for inference of demography, providing an overview of the underlying theory and logic behind each approach. We also discuss the types of data required and the pros and cons of each method. We then discuss how these methods have been applied to a variety of nonmodel organisms. We conclude by presenting some recommendations for researchers looking to use genomic data to infer demographic history.
Genetic studies of rare and endangered species often focus on defining and preserving genetically distinct populations, especially those having unique adaptations 1, 2. Much less attention is ...directed at understanding the landscape of deleterious variation, an insidious consequence of geographic isolation and the inefficiency of natural selection to eliminate harmful variants in small populations 3–5. With population sizes of many vertebrates decreasing and isolation increasing through habitat fragmentation and loss, understanding the extent and nature of deleterious variation in small populations is essential for predicting and enhancing population persistence. The Channel Island fox (Urocyon littoralis) is a dwarfed species that inhabits six of California’s Channel Islands and is derived from the mainland gray fox (U. cinereoargenteus). These isolated island populations have persisted for thousands of years at extremely small population sizes 6, 7 and, consequently, are a model for testing ideas about the accumulation of deleterious variation in small populations under natural conditions. Analysis of complete genome sequence data from island foxes shows a dramatic decrease in genome-wide variation and a sharp increase in the homozygosity of deleterious variants. The San Nicolas Island population has a near absence of variation, demonstrating a unique genetic flatlining that is punctuated by heterozygosity hotspots, enriched for olfactory receptor genes and other genes with high levels of ancestral variation. These findings question the generality of the small-population paradigm that maintains substantial genetic variation is necessary for short- and long-term persistence.
•Genomic monomorphism on a scale not seen previously in eukaryotes is shown•Deleterious variation and loss-of-function mutations are not purged•Drift, without balancing selection, accounts for peaks of heterozygosity•Persistence despite the absence of variation questions its role in small populations
Robinson et al. show that the island fox has drastically reduced genetic variation and high levels of deleterious mutations, suggesting that selection has not purged harmful variants. Remarkably, the San Nicolas Island fox has a near absence of variation, questioning the importance of genetic variation in the long-term persistence of small populations.
The human Y chromosome exhibits surprisingly low levels of genetic diversity. This could result from neutral processes if the effective population size of males is reduced relative to females due to ...a higher variance in the number of offspring from males than from females. Alternatively, selection acting on new mutations, and affecting linked neutral sites, could reduce variability on the Y chromosome. Here, using genome-wide analyses of X, Y, autosomal and mitochondrial DNA, in combination with extensive population genetic simulations, we show that low observed Y chromosome variability is not consistent with a purely neutral model. Instead, we show that models of purifying selection are consistent with observed Y diversity. Further, the number of sites estimated to be under purifying selection greatly exceeds the number of Y-linked coding sites, suggesting the importance of the highly repetitive ampliconic regions. While we show that purifying selection removing deleterious mutations can explain the low diversity on the Y chromosome, we cannot exclude the possibility that positive selection acting on beneficial mutations could have also reduced diversity in linked neutral regions, and may have contributed to lowering human Y chromosome diversity. Because the functional significance of the ampliconic regions is poorly understood, our findings should motivate future research in this area.
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