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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 are 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., Author summary One of the most significant and challenging tasks in modern genomics is to assess the functional consequences of a particular nucleotide change in a genome. A common approach to address this challenge prioritizes sequences that share similar nucleotides across distantly related species, with the rationale that mutations at such positions were deleterious and removed from the population by purifying natural selection. Our manuscript shows that one popular measure of sequence conservation, the GERP score, performs well at identifying selected mutations if mutations at a site were under selection across all of mammalian evolution. Changes in selection at a given site dramatically reduces the power of GERP to detect selected mutations in humans. We also combine population genetic models with the distribution of GERP scores at noncoding sites across the human genome to show that the degree of selection at individual sites has changed throughout mammalian evolution. Importantly, we demonstrate that at least 80 Mb of noncoding sequence under purifying selection in humans will not have extreme GERP scores and will likely be missed by modern comparative genomic approaches. Our work argues that new approaches, potentially based on genetic variation within species, will be required to identify deleterious mutations.

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., Author summary Individuals from distinct populations sometimes will produce fertile offspring and will exchange genetic material in a process called hybridization. Genomes of hybrid individuals often show non-random patterns of hybrid ancestry across the genome, where some regions have a high frequency of ancestry from the second population and other regions have less. Typically, this pattern has been attributed to adaptive introgression, where beneficial genetic variants are passed from one population to the other, or to genomic incompatibilities between these distinct species. However, other mechanisms could lead to these heterogeneous patterns of ancestry in hybrids. Here we use simulations to investigate whether deleterious mutations affect the patterns of introgressed ancestry across genomes. We show that when ancestry from a larger population is added to a smaller population, the ancestry from the larger population dramatically increases in frequency because it carries fewer deleterious mutations. This occurs even in the absence of beneficial mutations in either population. Additionally, we show that differences in sex chromosome evolution relative to autosomes, or differences in mating system, can affect patterns of introgression in similar ways. Our study argues that deleterious mutations should be included in population genetic models used to identify unusual regions of the genome that appear to be under selection in hybrids.