Evidence for hitchhiking of deleterious mutations within the human genome

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.     

The legacy of domestication: accumulation of deleterious mutations in the dog genome

Dogs exhibit more phenotypic variation than any other mammal and are affected by a wide variety of genetic diseases. However, the origin and genetic basis of this variation is still poorly understood. We examined the effect of domestication on the dog genome by comparison with its wild ancestor, the gray wolf. We compared variation in dog and wolf genes using whole-genome single nucleotide polymorphism (SNP) data. The d(N)/d(S) ratio (omega) was around 50% greater for SNPs found in dogs than in wolves, indicating that a higher proportion of nonsynonymous alleles segregate in dogs compared with nonfunctional genetic variation. We suggest that the majority of these alleles are slightly deleterious and that two main factors may have contributed to their increase. The first is a relaxation of selective constraint due to a population bottleneck and altered breeding patterns accompanying domestication. The second is a reduction of effective population size at loci linked to those under positive selection due to Hill-Robertson interference. An increase in slightly deleterious genetic variation could contribute to the prevalence of disease in modern dog breeds.     

The effect of pathogens on selection against deleterious mutations in Drosophila melanogaster

In natural populations, fitness is reduced by both deleterious mutations and parasites. Few studies have examined interactions between these two factors, particularly at the level of individual genes. We examined how the presence of a bacterial pathogen, Pseudomonas aeruginosa, affected the selection against each of eight deleterious mutations in Drosophila melanogaster. We found that mutations tended to become more deleterious in the presence of disease. This increase in the average selection was primarily due to three genes with the remainder showing little evidence of change.     

Accumulation of slightly deleterious mutations in the mitochondrial genome: A hallmark of animal domestication

The hypothesis that domestication leads to a relaxation of purifying selection on mitochondrial (mt) genomes was tested by comparative analysis of mt genes from dog, pig, chicken, and silkworm. The three vertebrate species showed mt genome phylogenies in which domestic and wild isolates were intermingled, whereas the domestic silkworm (Bombyx mori) formed a distinct cluster nested within its closest wild relative (Bombyx mandarina). In spite of these differences in phylogenetic pattern, significantly greater proportions of nonsynonymous SNPs than of synonymous SNPs were unique to the domestic populations of all four species. Likewise, in all four species, significantly greater proportions of RNA-encoding SNPs than of synonymous SNPs were unique to the domestic populations. Thus, domestic populations were characterized by an excess of unique polymorphisms in two categories generally subject to purifying selection: nonsynonymous sites and RNA-encoding sites. Many of these unique polymorphisms thus seem likely to be slightly deleterious; the latter hypothesis was supported by the generally lower gene diversities of polymorphisms unique to domestic populations in comparison to those of polymorphisms shared by domestic and wild populations.     

Nose thyself: individuality in the human olfactory genome

A recent study using cell-based assays together with an olfactory psychophysical survey in humans has established a link between a genetic polymorphism in an odorant receptor and variability in perception of the smell of the steroid androstenone.     

Positive selection, relaxation, and acceleration in the evolution of the human and chimp genome

For years evolutionary biologists have been interested in searching for the genetic bases underlying humanness. Recent efforts at a large or a complete genomic scale have been conducted to search for positively selected genes in human and in chimp. However, recently developed methods allowing for a more sensitive and controlled approach in the detection of positive selection can be employed. Here, using 13,198 genes, we have deduced the sets of genes involved in rate acceleration, positive selection, and relaxation of selective constraints in human, in chimp, and in their ancestral lineage since the divergence from murids. Significant deviations from the strict molecular clock were observed in 469 human and in 651 chimp genes. The more stringent branch-site test of positive selection detected 108 human and 577 chimp positively selected genes. An important proportion of the positively selected genes did not show a significant acceleration in rates, and similarly, many of the accelerated genes did not show significant signals of positive selection. Functional differentiation of genes under rate acceleration, positive selection, and relaxation was not statistically significant between human and chimp with the exception of terms related to G-protein coupled receptors and sensory perception. Both of these were over-represented under relaxation in human in relation to chimp. Comparing differences between derived and ancestral lineages, a more conspicuous change in trends seems to have favored positive selection in the human lineage. Since most of the positively selected genes are different under the same functional categories between these species, we suggest that the individual roles of the alternative positively selected genes may be an important factor underlying biological differences between these species.     

Role of duplicate genes in robustness against deleterious human mutations

It is now widely recognized that robustness is an inherent property of biological systems [1],[2],[3]. The contribution of close sequence homologs to genetic robustness against null mutations has been previously demonstrated in simple organisms [4],[5]. In this paper we investigate in detail the contribution of gene duplicates to back-up against deleterious human mutations. Our analysis demonstrates that the functional compensation by close homologs may play an important role in human genetic disease. Genes with a 90% sequence identity homolog are about 3 times less likely to harbor known disease mutations compared to genes with remote homologs. Moreover, close duplicates affect the phenotypic consequences of deleterious mutations by making a decrease in life expectancy significantly less likely. We also demonstrate that similarity of expression profiles across tissues significantly increases the likelihood of functional compensation by homologs.     

Effects of population structures and selection strategies on the purging of inbreeding depression due to deleterious mutations

Stochastic simulations were run to compare the effects of nine breeding schemes, using full-sib mating, on the rate of purging of inbreeding depression due to mutations with equal deleterious effect on viability at unlinked loci in an outbred population. A number of full-sib mating lines were initiated from a large outbred population and maintained for 20 generations (if not extinct). Selection against deleterious mutations was allowed to occur within lines only, between lines or equal within and between lines, and surviving lines were either not crossed or crossed following every one or three generations of full-sib mating. The effectiveness of purging was indicated by the decreased number of lethal equivalents and the increased fitness of the purged population formed from crossing surviving lines after 20 generations under a given breeding scheme. The results show that the effectiveness of purging, the survival of the inbred lines and the inbreeding level attained are generally highest with between-line selection and lowest with within-line selection. Compared with no crossing, line crossing could lower the risk of extinction and the inbreeding coefficient of the purged population substantially with little loss of the effectiveness of purging. Compromising between the effectiveness of purging, and the risk of extinction and inbreeding coefficient, the breeding scheme with equal within- and between-line selection and crossing alternatively with full-sib mating is generally the most desirable scheme for purging deleterious mutations. Unless most deleterious mutations have relatively large effects on fitness in species with reproductive ability high enough to cope with the depressed fitness and thus increased risk of extinction with inbreeding, it is not justified to apply a breeding programme aimed at purging inbreeding depression by inbreeding and selection to a population of conservation concern.     

Fixation of deleterious mutations at critical positions in human proteins

Deleterious mutations associated with human diseases are predominantly found in conserved positions and positions that are essential for the structure and/or function of proteins. However, these mutations are purged from the human population over time and prevented from being fixed. Contrary to this belief, here I show that high proportions of deleterious amino acid changing mutations are fixed at positions critical for the structure and/or function of proteins. Similarly, a high rate of fixation of deleterious mutations was observed in slow-evolving amino acid positions of human proteins. The fraction of deleterious substitutions was found to be two times higher in relatively conserved amino acid positions than in highly variable positions. This study also found fixation of a much higher proportion of radical amino acid changes in primates compared with rodents and artiodactyls in slow-evolving positions. Previous studies observed a higher proportion of nonsynonymous substitutions in humans compared with other mammals, which was taken as indirect evidence for the fixation of deleterious mutations in humans. However, the results of this investigation provide direct evidence for this prediction by suggesting that the excess nonsynonymous mutations fixed in humans are indeed deleterious in nature. Furthermore, these results suggest that studies on disease-associated mutations should consider that a significant fraction of such deleterious mutations has already been fixed in the human genome, and thus, the effects of new mutations at those amino acid positions may not necessarily be deleterious and might even result in reversion to benign phenotypes.     

Positive and negative selection on the human genome.

The distinction between deleterious, neutral, and adaptive mutations is a fundamental problem in the study of molecular evolution. Two significant quantities are the fraction of DNA variation in natural populations that is deleterious and destined to be eliminated and the fraction of fixed differences between species driven by positive Darwinian selection. We estimate these quantities using the large number of human genes for which there are polymorphism and divergence data. The fraction of amino acid mutations that is neutral is estimated to be 0.20 from the ratio of common amino acid (A) to synonymous (S) single nucleotide polymorphisms (SNPs) at frequencies of > or =15%. Among the 80% of amino acid mutations that are deleterious at least 20% of them are only slightly deleterious and often attain frequencies of 1-10%. We estimate that these slightly deleterious mutations comprise at least 3% of amino acid SNPs in the average individual or at least 300 per diploid genome. This estimate is not sensitive to human population history. The A/S ratio of fixed differences is greater than that of common SNPs and suggests that a large fraction of protein divergence is adaptive and driven by positive Darwinian selection.     

Recent and ongoing selection in the human genome

The recent availability of genome-scale genotyping data has led to the identification of regions of the human genome that seem to have been targeted by selection. These findings have increased our understanding of the evolutionary forces that affect the human genome, have augmented our knowledge of gene function and promise to increase our understanding of the genetic basis of disease. However, inferences of selection are challenged by several confounding factors, especially the complex demographic history of human populations, and concordance between studies is variable. Although such studies will always be associated with some uncertainty, steps can be taken to minimize the effects of confounding factors and improve our interpretation of their findings.     

Effect of selection against deleterious mutations on the decline in heterozygosity at neutral loci in closely inbreeding populations.

Transition matrices for selfing and full-sib mating were derived to investigate the effect of selection against deleterious mutations on the process of inbreeding at a linked neutral locus. Selection was allowed to act within lines only (selection type I) or equally within and between lines (type II). For selfing lines under selection type I, inbreeding is always retarded, the retardation being determined by the recombination fraction between the neutral and selected loci and the inbreeding depression from the selected locus, irrespective of the selection coefficient (s) and dominance coefficient (h) of the mutant allele. For selfing under selection type II or full-sib mating under both selection types, inbreeding is delayed by weak selection (small s and sh), due to the associative overdominance created at the neutral locus, and accelerated by strong selection, due to the elevated differential contributions between alternative alleles at the neutral locus within individuals and between lines (for selection type II). For multiple fitness loci under selection, stochastic simulations were run for populations with selfing, full-sib mating, and random mating, using empirical estimates of mutation parameters and inbreeding load in Drosophila. The simulations results are in general compatible with empirical observations.     

The strength of selection on ultraconserved elements in the human genome

Ultraconserved elements are stretches of consecutive nucleotides that are perfectly conserved in multiple mammalian genomes. Although these sequences are identical in the reference human, mouse, and rat genomes, we identified numerous polymorphisms within these regions in the human population. To determine whether polymorphisms in ultraconserved elements affect fitness, we genotyped unrelated human DNA samples at loci within these sequences. For all single-nucleotide polymorphisms tested in ultraconserved regions, individuals homozygous for derived alleles (alleles that differ from the rodent reference genomes) were present, viable, and healthy. The distribution of allele frequencies in these samples argues against strong, ongoing selection as the force maintaining the conservation of these sequences. We then used two methods to determine the minimum level of selection required to generate these sequences. Despite the lack of fixed differences in these sequences between humans and rodents, the average level of selection on ultraconserved elements is less than that on essential genes. The strength of selection associated with ultraconserved elements suggests that mutations in these regions may have subtle phenotypic consequences that are not easily detected in the laboratory.     

Evidence for inefficient selection against deleterious mutations in cytochrome oxidase I of asexual bdelloid rotifers

Evolutionary theory predicts that natural selection should be less efficient in asexually than in sexually reproducing organisms. Obligate asexuals are expected to adapt slowly to changing environments and to accumulate mildly deleterious mutations to their genomes, potentially explaining their typically short evolutionary lifespans. One group of animals that appear to challenge these ideas is the bdelloid rotifers, a large and ancient clade of obligate asexuals. Previous work has found no evidence for inefficient selection against deleterious mutations in protein-coding genes of bdelloids. However, these studies relied mostly on between-species comparisons and were therefore unable to detect mildly deleterious mutations that persist within populations but are removed by selection over longer time periods. Here, we test for inefficient purifying selection acting on the cytochrome oxidase I (cox1) mitochondrial gene in 3 clades of bdelloids. Patterns of variation are compared to those of two facultatively sexual clades: a monogonont rotifer (Brachionus) and a branchiopod crustacean (Daphnia). As predicted due to the strict linkage between mitochondrial and nuclear genomes, bdelloids exhibit higher frequencies of putatively deleterious amino acid polymorphism within populations than the two facultatively sexual clades. While the monophyly and age of bdelloids makes it hard to rule out other explanations for the observed differences, several possible confounding factors, such as differences in effective population size or patterns of codon usage, are shown not to explain the observed differences. We therefore conclude that bdelloid mitochondrial DNA variation does display the signature of inefficient selection expected of obligate asexuals.     

Reconciling repertoire shift with affinity maturation: the role of deleterious mutations

The shift in Ab repertoire, from Abs dominating certain primary B cell responses to genetically unrelated Abs dominating subsequent "memory" responses, challenges the accepted paradigm of affinity maturation. We used mathematical modeling and computer simulations of the dynamics of B cell responses, hypermutation, selection, and memory cell formation to test hypotheses attempting to explain repertoire shift. We show that repertoire shift can be explained within the framework of the affinity maturation paradigm, only when we recognize the destructive nature of hypermutation: B cells with a high initial affinity for the Ag are less likely to improve through random mutations.     

Parasites and deleterious mutations: interactions influencing the evolutionary maintenance of sex

The restrictive assumptions associated with purely genetic and purely ecological mechanisms suggest that neither of the two forces, in isolation, can offer a general explanation for the evolutionary maintenance of sex. Consequently, attention has turned to pluralistic models (i.e. models that apply both ecological and genetic mechanisms). Existing research has shown that combining mutation accumulation and parasitism allows restrictive assumptions about genetic and parasite parameter values to be relaxed while still predicting the maintenance of sex. However, several empirical studies have shown that deleterious mutations and parasitism can reduce fitness to a greater extent than would be expected if the two acted independently. We show how interactions between these genetic and ecological forces can completely reverse predictions about the evolution of reproductive modes. Moreover, we demonstrate that synergistic interactions between infection and deleterious mutations can render sex evolutionarily stable even when there is antagonistic epistasis among deleterious mutations, thereby widening the conditions for the evolutionary maintenance of sex.