Abstract
Deleterious mutations present a significant obstacle to adaptive evolution. Deleterious mutations can inhibit the spread of linked adaptive mutations through a population; conversely, adaptive substitutions can increase the frequency of linked deleterious mutations and even result in their fixation. To assess the impact of adaptive mutations on linked deleterious mutations, we examined the distribution of deleterious and neutral amino acid polymorphism in the human genome. Within genomic regions that show evidence of recent hitchhiking, we find fewer neutral but a similar number of deleterious SNPs compared to other genomic regions. The higher ratio of deleterious to neutral SNPs is consistent with simulated hitchhiking events and implies that positive selection eliminates some deleterious alleles and increases the frequency of others. The distribution of disease-associated alleles is also altered in hitchhiking regions. Disease alleles within hitchhiking regions have been associated with auto-immune disorders, metabolic diseases, cancers, and mental disorders. Our results suggest that positive selection has had a significant impact on deleterious polymorphism and may be partly responsible for the high frequency of certain human disease alleles.
Highlights
The continuous removal of deleterious mutations is essential to maintaining a species’ reproductive output and even its existence
By examining the genome distribution of nonsynonymous single nucleotide polymorphisms (SNPs) classified as either neutral or deleterious, we found a greater reduction in neutral compared to deleterious polymorphism within genomic regions likely to have been influenced by hitchhiking
This observation combined with hitchhiking simulations suggests that while many deleterious SNPs are eliminated due to hitchhiking, a substantial number of rare deleterious mutations must increase to frequencies common enough to be considered polymorphic
Summary
The continuous removal of deleterious mutations is essential to maintaining a species’ reproductive output and even its existence. While deleterious mutations incur a considerable fitness cost [1], they are not always effectively removed from a population. Deleterious mutations are more difficult to remove from small populations and their accumulation can lead to further reductions in population size and eventually to extinction, a process called mutational meltdown [2,3,4]. Many deleterious mutations have reached high population frequencies. Each human is estimated to carry on the order of 1,000 deleterious mutations in their genome [7,8,9]. Most deleterious mutations are rare, a significant fraction is common in the population. 19% of deleterious mutations identified in three human genomes are common enough to be shared among them [9]. The cause and consequence of common deleterious mutations have been difficult to determine
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