Many traits of interest are highly heritable and genetically complex, meaning that much of the variation they exhibit arises from differences at numerous loci in the genome. Complex traits and their ...evolution have been studied for more than a century, but only in the last decade have genome-wide association studies (GWASs) in humans begun to reveal their genetic basis. Here, we bring these threads of research together to ask how findings from GWASs can further our understanding of the processes that give rise to heritable variation in complex traits and of the genetic basis of complex trait evolution in response to changing selection pressures (i.e., of polygenic adaptation). Conversely, we ask how evolutionary thinking helps us to interpret findings from GWASs and informs related efforts of practical importance.
One of the foundational results in molecular evolution is that the rate at which neutral substitutions accumulate on a lineage equals the rate at which mutations arise. Traits that affect rates of ...mutation therefore also affect the phylogenetic “molecular clock.” We consider the effects of sex-specific generation times and mutation rates in species with two sexes. In particular, we focus on the effects that the age of onset of male puberty and rates of spermatogenesis have likely had in hominids (great apes), considering a model that approximates features of the mutational process in mammals, birds, and some other vertebrates. As we show, this model can account for a number of seemingly disparate observations: notably, the puzzlingly low X-to-autosome ratios of substitution rates in humans and chimpanzees and differences in rates of autosomal substitutions among hominine lineages (i.e., humans, chimpanzees, and gorillas). The model further suggests how to translate pedigree-based estimates of human mutation rates into split times among extant hominoids (apes), given sex-specific life histories. In so doing, it largely bridges the gap reported between estimates of split times based on fossil and molecular evidence, in particular suggesting that the human–chimpanzee split may have occurred as recently as 6.6 Mya. The model also implies that the “generation time effect” should be stronger in short-lived species, explaining why the generation time has a major influence on yearly substitution rates in mammals but only a subtle one in human pedigrees.
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Polygenic adaptation is thought to be ubiquitous, yet remains poorly understood. Here, we model this process analytically, in the plausible setting of a highly polygenic, quantitative trait that ...experiences a sudden shift in the fitness optimum. We show how the mean phenotype changes over time, depending on the effect sizes of loci that contribute to variance in the trait, and characterize the allele dynamics at these loci. Notably, we describe the two phases of the allele dynamics: The first is a rapid phase, in which directional selection introduces small frequency differences between alleles whose effects are aligned with or opposed to the shift, ultimately leading to small differences in their probability of fixation during a second, longer phase, governed by stabilizing selection. As we discuss, key results should hold in more general settings and have important implications for efforts to identify the genetic basis of adaptation in humans and other species.
Over the past decade, there has been both great interest and confusion about whether recent demographic events — notably the Out-of-Africa-bottleneck and recent population growth — have led to ...differences in mutation load among human populations. The confusion can be traced to the use of different summary statistics to measure load, which lead to apparently conflicting results. We argue, however, that when statistics more directly related to load are used, the results of different studies and data sets consistently reveal little or no difference in the load of non-synonymous mutations among human populations. Theory helps to understand why no such differences are seen, as well as to predict in what settings they are to be expected. In particular, as predicted by modeling, there is evidence for changes in the load of recessive loss of function mutations in founder and inbred human populations. Also as predicted, eastern subspecies of gorilla, Neanderthals and Denisovans, who are thought to have undergone reductions in population sizes that exceed the human Out-of-Africa bottleneck in duration and severity, show evidence for increased load of non-synonymous mutations (relative to western subspecies of gorillas and modern humans, respectively). A coherent picture is thus starting to emerge about the effects of demographic history on the mutation load in populations of humans and close evolutionary relatives.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Human genome-wide association studies (GWASs) are revealing the genetic architecture of anthropomorphic and biomedical traits, i.e., the frequencies and effect sizes of variants that contribute to ...heritable variation in a trait. To interpret these findings, we need to understand how genetic architecture is shaped by basic population genetics processes-notably, by mutation, natural selection, and genetic drift. Because many quantitative traits are subject to stabilizing selection and because genetic variation that affects one trait often affects many others, we model the genetic architecture of a focal trait that arises under stabilizing selection in a multidimensional trait space. We solve the model for the phenotypic distribution and allelic dynamics at steady state and derive robust, closed-form solutions for summary statistics of the genetic architecture. Our results provide a simple interpretation for missing heritability and why it varies among traits. They predict that the distribution of variances contributed by loci identified in GWASs is well approximated by a simple functional form that depends on a single parameter: the expected contribution to genetic variance of a strongly selected site affecting the trait. We test this prediction against the results of GWASs for height and body mass index (BMI) and find that it fits the data well, allowing us to make inferences about the degree of pleiotropy and mutational target size for these traits. Our findings help to explain why the GWAS for height explains more of the heritable variance than the similarly sized GWAS for BMI and to predict the increase in explained heritability with study sample size. Considering the demographic history of European populations, in which these GWASs were performed, we further find that most of the associations they identified likely involve mutations that arose shortly before or during the Out-of-Africa bottleneck at sites with selection coefficients around s = 10-3.
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In numerous applications, from working with animal models to mapping the genetic basis of human disease susceptibility, knowing whether a single disrupting mutation in a gene is likely to be ...deleterious is useful. With this goal in mind, a number of measures have been developed to identify genes in which protein-truncating variants (PTVs), or other types of mutations, are absent or kept at very low frequency in large population samples-genes that appear 'intolerant' to mutation. One measure in particular, the probability of being loss-of-function intolerant (pLI), has been widely adopted. This measure was designed to classify genes into three categories, null, recessive and haploinsufficient, on the basis of the contrast between observed and expected numbers of PTVs. Such population-genetic approaches can be useful in many applications. As we clarify, however, they reflect the strength of selection acting on heterozygotes and not dominance or haploinsufficiency.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Human populations have undergone major changes in population size in the past 100,000 years, including recent rapid growth. How these demographic events have affected the burden of deleterious ...mutations in individuals and the frequencies of disease mutations in populations remains unclear. We use population genetic models to show that recent human demography has probably had little impact on the average burden of deleterious mutations. This prediction is supported by two exome sequence data sets showing that individuals of west African and European ancestry carry very similar burdens of damaging mutations. We further show that for many diseases, rare alleles are unlikely to contribute a large fraction of the heritable variation, and therefore the impact of recent growth is likely to be modest. However, for those diseases that have a direct impact on fitness, strongly deleterious rare mutations probably do have an important role, and recent growth will have increased their impact.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In many species, meiotic recombination events tend to occur in narrow intervals of the genome, known as hotspots. In humans and mice, double strand break (DSB) hotspot locations are determined by the ...DNA-binding specificity of the zinc finger array of the PRDM9 protein, which is rapidly evolving at residues in contact with DNA. Previous models explained this rapid evolution in terms of the need to restore PRDM9 binding sites lost to gene conversion over time, under the assumption that more PRDM9 binding always leads to more DSBs. This assumption, however, does not align with current evidence. Recent experimental work indicates that PRDM9 binding on both homologs facilitates DSB repair, and that the absence of sufficient symmetric binding disrupts meiosis. We therefore consider an alternative hypothesis: that rapid PRDM9 evolution is driven by the need to restore symmetric binding because of its role in coupling DSB formation and efficient repair. To this end, we model the evolution of PRDM9 from first principles: from its binding dynamics to the population genetic processes that govern the evolution of the zinc finger array and its binding sites. We show that the loss of a small number of strong binding sites leads to the use of a greater number of weaker ones, resulting in a sharp reduction in symmetric binding and favoring new PRDM9 alleles that restore the use of a smaller set of strong binding sites. This decrease, in turn, drives rapid PRDM9 evolutionary turnover. Our results therefore suggest that the advantage of new PRDM9 alleles is in
the number of binding sites used effectively, rather than in increasing net PRDM9 binding. By extension, our model suggests that the evolutionary advantage of hotspots may have been to increase the efficiency of DSB repair and/or homolog pairing.
Mutations can originate from the chance misincorporation of nucleotides during DNA replication or from DNA lesions that arise between replication cycles and are not repaired correctly. We introduce a ...model that relates the source of mutations to their accumulation with cell divisions, providing a framework for understanding how mutation rates depend on sex, age, and cell division rate. We show that the accrual of mutations should track cell divisions not only when mutations are replicative in origin but also when they are non-replicative and repaired efficiently. One implication is that observations from diverse fields that to date have been interpreted as pointing to a replicative origin of most mutations could instead reflect the accumulation of mutations arising from endogenous reactions or exogenous mutagens. We further find that only mutations that arise from inefficiently repaired lesions will accrue according to absolute time; thus, unless life history traits co-vary, the phylogenetic "molecular clock" should not be expected to run steadily across species.
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Natural selection at one site shapes patterns of genetic variation at linked sites. Quantifying the effects of "linked selection" on levels of genetic diversity is key to making reliable inference ...about demography, building a null model in scans for targets of adaptation, and learning about the dynamics of natural selection. Here, we introduce the first method that jointly infers parameters of distinct modes of linked selection, notably background selection and selective sweeps, from genome-wide diversity data, functional annotations and genetic maps. The central idea is to calculate the probability that a neutral site is polymorphic given local annotations, substitution patterns, and recombination rates. Information is then combined across sites and samples using composite likelihood in order to estimate genome-wide parameters of distinct modes of selection. In addition to parameter estimation, this approach yields a map of the expected neutral diversity levels along the genome. To illustrate the utility of our approach, we apply it to genome-wide resequencing data from 125 lines in Drosophila melanogaster and reliably predict diversity levels at the 1Mb scale. Our results corroborate estimates of a high fraction of beneficial substitutions in proteins and untranslated regions (UTR). They allow us to distinguish between the contribution of sweeps and other modes of selection around amino acid substitutions and to uncover evidence for pervasive sweeps in untranslated regions (UTRs). Our inference further suggests a substantial effect of other modes of linked selection and of adaptation in particular. More generally, we demonstrate that linked selection has had a larger effect in reducing diversity levels and increasing their variance in D. melanogaster than previously appreciated.
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