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The FUT2 is rich in polymorphisms that show population-specific patterns in its coding sequence. In this study, we found four novel substitutions in 121 Ghanaian samples. In addition, statistical tests considering population expansion scenarios suggested that balancing selection might be responsible for the genetic diversity of FUT2 in this population.
The evolution of metabolic control is examined with models that unify approaches of classical quantitative genetics and metabolic control theory. The quantitative traits considered are the activities of enzymes embedded within metabolic pathways. In the models, polygenic mutation alters the enzyme activities (Vmax/Km) according to prescribed distributions, and the population evolves following classical haploid viability selection. Stabilizing selection operates on global properties of the metabolic pathway, including either flux or metabolite pool concentration. Analytical results and numerical simulations demonstrate several important properties of these characters, including skewed, non-Gaussian equilibrium distributions, and an expected positive correlation between activities of enzymes flanking a substrate pool undergoing stabilizing selection. The house-of-cards approximation proved to be accurate in predicting the equilibrium distribution of allelic effects for a biologically reasonable segment of the parameter space. Further experimental and theoretical work is needed before a clear assessment can be made whether the observed variance in enzyme activities is explicable by a mutation-selection balance, and this system provides an excellent opportunity for such a test.
In models of maintenance of genetic variance (V (G)) it has often been assumed that mutant alleles act additively. However, experimental data show that the dominance coefficient varies among mutant alleles and those of large effect tend to be recessive. On the basis of empirical knowledge of mutations, a joint-effect model of pleiotropic and real stabilizing selection that includes dominance is constructed and analyzed. It is shown that dominance can dramatically alter the prediction of equilibrium V (G). Analysis indicates that for the situations where mutations are more recessive for fitness than for a quantitative trait, as supported by the available data, the joint-effect model predicts a significantly higher V (G) than does an additive model. Importantly, for what seem to be realistic distributions of mutational effects (i.e., many mutants may not affect the quantitative trait substantially but are likely to affect fitness), the observed high levels of genetic variation in the quantitative trait under strong apparent stabilizing selection can be generated. This investigation supports the hypothesis that most V (G) comes from the alleles nearly neutral for fitness in heterozygotes while apparent stabilizing selection is contributed mainly by the alleles of large effect on the quantitative trait. Thus considerations of dominance coefficients of mutations lend further support to our previous conclusion that mutation-selection balance is a plausible mechanism of the maintenance of the genetic variance in natural populations.
HLA data from the A and B loci for 22 populations were compared with the neutrality expectations from Ewens' sampling theory. In 25 of 44 cases, there was significantly less homozygosity than expected. Although a number of factors can affect homozygosity in this manner, upon close examination only symmetrical balancing selection appears to be consistent with these data.
Natural populations are structured spatially into local populations and genetically into diverse 'genetic backgrounds' defined by different combinations of selected alleles. If selection maintains genetic backgrounds at constant frequency then neutral diversity is enhanced. By contrast, if background frequencies fluctuate then diversity is reduced. Provided that the population size of each background is large enough, these effects can be described by the structured coalescent process. Almost all the extant results based on the coalescent deal with a single selected locus. Yet we know that very large numbers of genes are under selection and that any substantial effects are likely to be due to the cumulative effects of many loci. Here, we set up a general framework for the extension of the coalescent to multilocus scenarios and we use it to study the simplest model, where strong balancing selection acting on a set of n loci maintains 2n backgrounds at constant frequencies and at linkage equilibrium. Analytical results show that the expected linked neutral diversity increases exponentially with the number of selected loci and can become extremely large. However, simulation results reveal that the structured coalescent approach breaks down when the number of backgrounds approaches the population size, because of stochastic fluctuations in background frequencies. A new method is needed to extend the structured coalescent to cases with large numbers of backgrounds.
High levels of allelic diversity and strong linkage disequilibrium are found in the major histocompatibility (MHC) system in humans and other vertebrates. This article proposes several descriptive statistics that quantify the extent and pattern of strong linkage disequilibrium between pairs of highly polymorphic loci. It also develops an approximate analytic theory incorporating the effects of balancing selection, mutation, recombination, and genetic drift at two closely linked loci and compares the theoretical predictions with published surveys of the MHC class II loci, DQA1 and DQB1, in humans and nonhuman primates. The descriptive statistics proposed include the fraction of complementary haplotypes (haplotypes with D' = 1), the fraction of excess haplotypes, and the numbers of alleles at each locus in complementary haplotypes with one or more alleles at the other locus. The model assumes the infinite alleles model of mutation and the symmetric overdominance model of selection. Analytic approximations in some cases are obtained in the strong selection, weak mutation (SSWM) limit introduced by J. Gillespie. The predictions of the approximate analysis are confirmed by simulation. Both the analytic theory and simulations show that relatively few haplotypes will be found when selection is strong and recombination is weak relative to genetic drift. The model can reproduce many of the observed patterns at DQA1 and DQB1 provided that the recombination rate is assumed to be very small.
Haldane (1937) showed that the reduction of equilibrium mean fitness in an infinite population due to recurrent deleterious mutations depends only on the mutation rate but not on the harmfulness of mutants. His analysis, as well as more recent ones (cf. Crow 1970), ignored back mutation. The purpose of the present paper is to extend these results to arbitrary mutation patterns among alleles and to quantitative genetic traits. We derive first-order approximations for the equilibrium mean fitness (and the mutation load) and determine the order of the error term. For a metric trait under mutation-stabilizing-selection balance our result differs qualitatively from that of Crow and Kimura (1964), whose analysis is based on a Gaussian assumption. Our general approach also yields a mathematical proof that the variance under the usual mutation-stabilizing-selection model is, to first order, micro/s (the house-of cards approximation) as micro/s tends to zero. This holds for arbitrary mutant distributions and does not require that the population mean coincide with the optimum. We show how the mutant distribution determines the order of the error term, and thus the accuracy of the house-of-cards approximation. Upper and lower bounds to the equilibrium variance are derived that deviate only to second order as micro/s tends to zero. The multilocus case is treated under the assumption of global linkage equilibrium.
We studied population polymorphism at a major histocompatibility complex (MHC) class II beta gene in the deer mouse (Peromyscus maniculatus). We found that: (i) a single population of P. maniculatus has significantly higher levels of DNA and protein sequence diversity than worldwide samples from homologous genes in other taxa, including humans and mice; and (ii) the genealogy of allelic sequences in P. maniculatus deviates significantly from theoretical expectation under a model of symmetric balancing selection, in that alleles are relatively more divergent than expected. We suggest that the observation of high levels of pairwise allelic sequence divergence and deviation of the genealogy from theoretical expectation in P. maniculatus together provide support for a divergent allele advantage model for the maintenance of MHC polymorphism.
A leading hypothesis for the evolutionary function of sex postulates that sex is an adaptation that purges deleterious mutations from the genome, thereby increasing the equilibrium mean fitness of a sexual population relative to its asexual competitor. This hypothesis requires two necessary conditions: first, the mutation rate per genome must be of order one, and, second, multiple mutations within a genome must act with positive epistasis, that is, two or more mutations of different genes must be more harmful together than if they acted independently. Here, by reconsidering the theory of mutation-selection balance at a single diploid gene locus, we demonstrate a significant advantage of sex due to nearly recessive mutations provided the mutation rate per genome is of order one. The assumption of positive epistasis is unnecessary, and multiple mutations may be assumed to act independently.
Follicle-stimulating hormone (FSH) is essential for human reproduction. The unique functions of this hormone are provided by the FSH receptor-binding beta-subunit encoded by the FSHB gene. Resequencing and genotyping of FSHB in three European, two Asian and one African population, as well as in the great apes (chimpanzee, gorilla, orangutan), revealed low diversity and significant excess of polymorphisms with intermediate frequency alleles. Statistical tests for FSHB showed deviations from neutrality in all populations suggesting a possible effect of balancing selection. Two core haplotypes were identified (carried by 76-96.6% of each population's sample), the sequences of which are clearly separated from each other. As fertility most directly affects an organism's fitness, the carriers of these haplotypes have apparently had more success in human history to contribute to the next generation. There is a preliminary observation suggesting that the second most frequent FSHB haplotype may be associated with rapid conception success in females. Interestingly, the same haplotype is related to an ancestral FSHB variant shared with the ancestor of the great apes. The determination of the functional consequence of the two core FSHB variants may have implications for understanding and regulating human fertility, as well as in assisting infertility treatments.
A multivariate quantitative genetic model is analyzed that is based on the assumption that the genetic variation at a locus j primarily influences an underlying physiological variable yj, while influence on the genotypic values is determined by a kind of "developmental function" which is not changed by mutations at this locus. Assuming additivity among loci the developmental function becomes a linear transformation of the underlying variables y onto the genotypic values x, x = By. In this way the pleiotropic effects become constrained by the structure of the B-matrix. The equilibrium variance under mutation-stabilizing selection balance in infinite and finite populations is derived by using the house of cards approximation. The results are compared to the predictions given by M. Turelli in 1985 for pleiotropic two-character models. It is shown that the B-matrix model gives the same results as Turelli's five-allele model, suggesting that the crucial factor determining the equilibrium variance in multivariate models with pleiotropy is the assumption about constraints on the pleiotropic effects, and not the number of alleles as proposed by Turelli. Finally it is shown that under Gaussian stabilizing selection the structure of the B-matrix has effectively no influence on the mean equilibrium fitness of an infinite population. Hence the B-matrix and consequently to some extent also the structure of the genetic correlation matrix is an almost neutral character. The consequences for the evolution of genetic covariance matrices are discussed.
To investigate the evolutionary dynamics at Mhc class II DR genes of mice (genus Mus), we sequenced the peptide binding regions (PBRs) of 41 DRB (= E beta) genes and eight DRA (= E alpha) genes from 15 strains representing eight species. As expected trees of these PBR sequences imply extensive maintenance of ancestral DRB alleles across species. We use a coalescent simulation model to show that the number of interspecific coalescent events (c) observed on these trees was higher than the number expected for neutral genealogies and similar sample sizes and is more consistent with balancing selection that with neutrality. Patterns of ancestral polymorphism in mouse DRB alleles were also used to examine the tempo of synonymous substitution in the PBR of mouse class II genes. Both absolute and relative rate tests on DRA and DRB genes imply increased substitution rates at two- and fourfold degenerate sites of mice and rats relative to primates, and decreased rates for the DRB genes of primates relative to ungulate and carnivore relatives. Thus rates of synonymous substitution at Mhc DR genes in mammals appear to be subject to generation time effects in ways similar to those found at other mammalian genes.
HLA-G is a class Ib HLA gene with unique tissue expression pattern and immunomodulatory properties. Polymorphisms in the HLA-G promoter region have been associated with miscarriage and asthma, whereas expression levels have been associated with a wide range of pathologic conditions as well as survival of embryos after in vitro fertilization and of organs after transplantation. Here, we characterize the sequence variation and haplotype structure of the HLA-G promoter and flanking sequences in 44 African Americans, 47 European Americans and 43 Han Chinese by haplotype-specific PCR and sequencing. In all three populations, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, and a genealogy with two common haplotypes separated by deep branches, features that are suggestive of balancing selection acting in this region. Comparisons to HLA-A and a pseudogene, HLA-J, suggested that the observed pattern of sequence variation in the HLA-G promoter region is not likely due to other selected HLA genes. We suggest that the mechanism for this selection is related to the highly regulated expression pattern of HLA-G and that high- and low-expressing promoters may be favored under temporally and/or spatially varying selective pressures.
The human leukocyte receptor complex (LRC) of Chromosome 19q13.4 encodes polymorphic and highly homologous genes that are expressed by cells of the immune system and regulate their function. There is an enormous diversity at the LRC, most particularly the variable number of killer cell immunoglobulin-like receptor (KIR) genes. KIR have been associated with several disease processes due to their interaction with polymorphic human leukocyte antigen class I molecules. We have assessed haplotype compositions, linkage disequilibrium patterns and allele frequencies in two Caucasoid population samples (n=54, n=100), using a composite of single-nucleotide polymorphism (SNP) markers and high-resolution, allele-specific molecular genotyping. Particular KIR loci segregated with SNP and other markers, forming two blocks that were separated by a region with a greater history of recombination. The KIR haplotype composition and allele frequency distributions were consistent with KIR having been subject to balancing selection (Watterson's F: P=0.001). In contrast, there was a high inter-population heterogeneity measure for the LRC-encoded leukocyte immunoglobulin-like receptor A3 (LILRA3), indicating pathogen-driven disruptive selection (Wright's FST=0.32). An assessment of seven populations representative of African, Asian and Caucasoid ethnic groups (total n=593) provided little evidence for long-range LRC haplotypes. The different natural selection pressures acting on each locus may have contributed to a lack of linkage disequilibrium between them.
The sixth complement component (C6) has a common charge polymorphism, C6A and C6B, with similar gene frequencies in all major populations. In addition, C6B2 is also found in Japanese populations at a frequency of about 6%. Sequence analyses of the coding region of three human and ape C6 alleles indicated four nonsynonymous and three synonymous changes in C6*B2 relative to C6*A, suggesting that a recombination event occurred between C6*B2 and C6*A to give rise to C6*B. Sequence variation in a 3.86 kb region encompassing exon 3, where the causal base change of the common C6 polymorphism is found, indicated that several single nucleotide polymorphisms (SNPs) were in extensive linkage disequilibrium (LD), with little differentiation among populations. Sliding window estimates of two test statistics for neutrality revealed significant values in a subregion where the replacement coding polymorphism resides, in all three human populations. These results raise the possibility that the two common C6 alleles in human populations are maintained by balancing selection.
We examined variation at a class II major histocompatibility complex (MHC) gene (DRB1) in the captive red wolf population and samples of coyotes from Texas and North Carolina. We found 4 alleles in the 48 red wolves, 8 alleles in the 10 coyotes from Texas and 15 alleles in the 29 coyotes from North Carolina. Two of the four alleles found in red wolves, Caru-2 and Caru-4, were found in both the Texas and North Carolina coyote samples. Allele Caru-1, previously found in gray wolves, was also found in the North Carolina sample. The most frequent red wolf allele, Caru-3, was not found in any of the coyote samples. However, an allele found in both the Texas and North Carolina coyote samples is only one nucleotide (one amino acid) different from this red wolf allele. Overall, it appears from examination of this MHC gene that red wolves are more closely related to coyotes than to gray wolves. There were a number of different types of evidence supporting the action of balancing selection in red wolves. Namely, there was: (i) an excess of heterozygotes compared with expectations; (ii) a higher rate of nonsynonymous than synonymous substitution for the functionally important antigen-binding site positions; (iii) an eight times higher average heterozygosity of individual amino acids at the positions identified as part of the antigen-binding site than those not associated with it; (iv) the amino acid divergence of four red wolf alleles was greater than that expected from a simulation of genetic drift; and (v) the distribution of alleles, and the distributions of amino acids at many positions were more even than expected from neutrality. Examination of the level and pattern of linkage disequilibria between pairs of sites suggest that the heterozygosity, substitution and frequencies at individual amino acids are not highly dependent upon each other.
The leukocyte immunoglobulin-like receptor (LILR) family consists of 13 loci, and a number of variations have been identified in these genes. Some polymorphisms of the LILR genes are reported to be associated with susceptibility to diseases such as rheumatoid arthritis and multiple sclerosis. LILRA3, one of the LILR genes, exhibits a presence or absence variation due to a 6.7-kb deletion in various populations. In this study, variation screening of the LILRA3 gene revealed high allele frequency of the 6.7-kb LILRA3 deletion (71%) in Japanese, in contrast to the frequency reported for the other populations. In addition, we identified a splice acceptor mutation in intron 1 with allele frequency of 19%, resulting in three alternatively spliced isoforms. Surprisingly, all of these isoforms were found to contain premature termination codons (PTCs) in the exon 3. Taken together, approximately 80% of Japanese lack functional LILRA3 alleles. The maximum likelihood coalescent analysis suggested that two major lineages, functional alleles and PTC-containing alleles, have been maintained for 2.75 million years in humans. These results prompted us to hypothesize that balancing selection had maintained both the functional and non-functional alleles at the LILRA3 locus. This hypothesis is consistent with the observation that the 6.7-kb LILRA3 deletion is detected worldwide in the presence of functional LILRA3 alleles.
Glucose-6-phosphate dehydrogenase (G6PD) mutations that result in reduced enzyme activity have been implicated in malarial resistance and constitute one of the best examples of selection in the human genome. In the present study, we characterize the nucleotide diversity across a 5.2-kb region of G6PD in a sample of 160 Africans and 56 non-Africans, to determine how selection has shaped patterns of DNA variation at this gene. Our global sample of enzymatically normal B alleles and A, A-, and Med alleles with reduced enzyme activities reveals many previously uncharacterized silent-site polymorphisms. In comparison with the absence of amino acid divergence between human and chimpanzee G6PD sequences, we find that the number of G6PD amino acid polymorphisms in human populations is significantly high. Unlike many other G6PD-activity alleles with reduced activity, we find that the age of the A variant, which is common in Africa, may not be consistent with the recent emergence of severe malaria and therefore may have originally had a historically different adaptive function. Overall, our observations strongly support previous genotype-phenotype association studies that proposed that balancing selection maintains G6PD deficiencies within human populations. The present study demonstrates that nucleotide sequence analyses can reveal signatures of both historical and recent selection in the genome and may elucidate the impact that infectious disease has had during human evolution.