Loss of MHC and neutral variation in Peary caribou: genetic drift is not mitigated by balancing selection or exacerbated by MHC allele distributions

Theory and empirical results suggest that the rate of loss of variation at Mhc and neutral microsatellite loci may differ because selection influences Mhc genes, and because a high proportion of rare alleles at Mhc loci may result in high rates of loss via drift. Most published studies compare Mhc and microsatellite variation in various contemporary populations to infer the effects of population size on genetic variation, even though different populations are likely to have different demographic histories that may also affect contemporary genetic variation. We directly compared loss of variation at Mhc and microsatellite loci in Peary caribou by comparing historical and contemporary samples. We observed that similar proportions of genetic variation were lost over time at each type of marker despite strong evidence for selection at Mhc genes. These results suggest that microsatellites can be used to estimate genome-wide levels of variation, but also that adaptive potential is likely to be lost following population bottlenecks. However, gene conversion and recombination at Mhc loci may act to increase variation following bottlenecks.     

MHC diversity in bottlenecked populations: a simulation model

The depletion of variation at MHC loci, which play a crucial role in pathogen recognition, has been postulated to be one of important extinction risk factors for endangered populations. Thus, it is important to understand how selection affects the level of polymorphism in these genes when populations undergo a reduction in size. We followed MHC diversity in computer simulations of population bottlenecks. The fates of MHC alleles in the simulations were determined either by drift, or by balancing selection resulting from host–parasite coevolution. We found that the impact of selection on MHC polymorphism in bottlenecked populations was dependent upon the timescales involved. Initially, selection maintained lower number of alleles than drift, but after ~40 generations of hosts selection maintained higher MHC diversity, as compared to drift. The adverse effects of decreased MHC polymorphism on population viability may be, to some extent, compensated for if selection helps to retain MHC alleles which show high functional diversity, which should allow protection against a broader range of pathogens. Our simulation shows, however, that the mean divergence of alleles retained under selection in bottlenecked populations is not, on average, significantly higher than the divergence due to drift.     

Use of a multivariate model using allele frequency distributions to analyse patterns of genetic differentiation among populations

Very few studies have attempted to relate the properties of some ordination techniques to classical tools of population genetics as F -statistics. A multivariate model to analyse population genetics data based on the properties of 'joint scaling' of populations and loci is developed. The design of population genetics data means that this model deals with a modified version of the classical Multiple Correspondence Analysis which is called Constant Row Total-Multiple Correspondence Analysis (CRT-MCA) and is an original tool in population genetics. Such a model allows estimates of the degree of population differentiation by studying the variability of the distribution of allele frequencies in different samples. Some clear relationships exist between some model parameters and the classical F_st statistics. The CRT-MCA also allows all the studied loci to be considered simultaneously and the role of each locus in patterns of population differentiation to be expressed. Such a multivariate approach prevents the use of any pooling strategy as is classically used in studies of hierarchical F -statistics. The relevance of the CRT-MCA model is illustrated by the analysis of population structure of 15 dogwhelk ( Nucella lapillus ) populations in south-west England. The advantages and limitations of CRT-MCA are presented.     

Natural selection on cork oak: allele frequency reveals divergent selection in cork oak populations along a temperature cline

A recent study of population divergence at neutral markers and adaptive traits in cork oak has observed an association between genetic distances at locus QpZAG46 and genetic distances for leaf size and growth. In that study it was proposed that certain loci could be linked to genes encoding for adaptive traits in cork oak and, thus, could be used in adaptation studies. In order to investigate this hypothesis, here we (1) looked for associations between molecular markers and a set of adaptive traits in cork oak, and (2) explored the effects of the climate on among-population patterns in adaptive traits and molecular markers. For this purpose, we chose 9-year-old plants originating from thirteen populations spanning a broad range of climatic conditions. Plants established in a common garden site were genotyped at six nuclear microsatellites and phenotypically characterized for six functional traits potentially related to plant performance. Our results supported the proposed linkage between locus QpZAG46 and genes encoding for leaf size and growth. Temperature caused adaptive population divergence in leaf size and growth, which was expressed as differences in the frequencies of the alleles at locus QpZAG46.     

Quantifying selection acting on a complex trait using allele frequency time series data

When selection is acting on a large genetically diverse population, beneficial alleles increase in frequency. This fact can be used to map quantitative trait loci by sequencing the pooled DNA from the population at consecutive time points and observing allele frequency changes. Here, we present a population genetic method to analyze time series data of allele frequencies from such an experiment. Beginning with a range of proposed evolutionary scenarios, the method measures the consistency of each with the observed frequency changes. Evolutionary theory is utilized to formulate equations of motion for the allele frequencies, following which likelihoods for having observed the sequencing data under each scenario are derived. Comparison of these likelihoods gives an insight into the prevailing dynamics of the system under study. We illustrate the method by quantifying selective effects from an experiment, in which two phenotypically different yeast strains were first crossed and then propagated under heat stress (Parts L, Cubillos FA, Warringer J, et al. [14 co-authors]. 2011. Revealing the genetic structure of a trait by sequencing a population under selection. Genome Res). From these data, we discover that about 6% of polymorphic sites evolve nonneutrally under heat stress conditions, either because of their linkage to beneficial (driver) alleles or because they are drivers themselves. We further identify 44 genomic regions containing one or more candidate driver alleles, quantify their apparent selective advantage, obtain estimates of recombination rates within the regions, and show that the dynamics of the drivers display a strong signature of selection going beyond additive models. Our approach is applicable to study adaptation in a range of systems under different evolutionary pressures.     

A model of quantitative traits under frequency-dependent balancing selection

We describe a computer model that stimulates a combination of stabilizing and frequency-dependent selection acting on a quantitative character determined by several loci. The results correspond to many features of natural variations at both the phenotypic and genotypic levels. The model is robust, and its results are not strongly dependent either on the nature and shape of the function describing the stabilizing selection, or on the precise form of frequency dependence, except near the extrema. It suggests a mechanism for the maintenance of large amounts of variability, and shows a relation between population size and heterozygosity roughly corresponding to that found in nature. In this respect it is unlike the purely neutral model.     

Population frequency of the arylsulphatase A pseudo-deficiency allele

Summary The enzymatic diagnosis of metachromatic leukodystrophy is complicated by the frequent occurrence of the pseudo-deficiency of arylsulphatase A (ASA) enzyme activity. An A to G nucleotide transition in the first polyadenylation signal of the ASA gene results in the loss of its major mRNA species and a greatly reduced level of enzyme activity. This nucleotide change (nucleotide 1620 of the ASA cDNA) is the cause of ASA pseudo-deficiency and is closely linked to another A to G transition (nucleotide 1049), within the ASA gene, which changes Asn₃₅₀ to serine but which does not affect ASA activity. The distribution of these 2 nucleotide changes has been investigated in 73 unrelated individuals from the Australian population. The two transitions were found together on 14 (9.6%) out of 146 chromosomes. The transition at nucleotide 1620 was not found alone; however, the other transition was found alone on 7 (4.8%) out of the 146 chromosomes. The carrier frequency of the ASA pseudo-deficiency mutation in Australia is thus estimated to be about 20%.     

A parasite-driven wedge: infectious diseases may explain language and other biodiversity

Parasite–host coevolutionary races are spatially variable across species' or human cultural ranges. Assortative sociality, biased toward local conspecifics, and limited dispersal (philopatry) in humans and other organisms can be adaptive through reduced contact with dangerous contagions harbored by distant/non-local conspecifics. These factors can generate cultural or population divergence. Thus, parasites are like a wedge driving groups apart through their effective creation of anticontagion behaviors. If this proposition is correct, then biological diversity should positively correlate with parasite diversity. Here we show that the worldwide distribution of indigenous human language diversity, a form of biodiversity, is strongly, positively related to human parasite diversity indicative of a legacy of parasite-mediated diversification. The significant pattern remains when potential confounds are removed. The pattern too is seen in each of the six world regions and is not confounded by regional differences in their history of colonization and conquest. We hypothesize that variation in limited dispersal and assortative sociality with conspecifics in response to the worldwide spatial variation in pathogen diversity provides a fundamental mechanism of population divergence explaining many important aspects of the geographic patterns of biodiversity. This hypothesis has broad implications for a diversity of research topics including language diversity, cultural evolution, speciation, phylogeny and biogeography.     

Discrepancies in dbSNP confirmation rates and allele frequency distributions from varying genotyping error rates and patterns

SUMMARY: Three recent publications have examined the quality and completeness of public database single nucleotide polymorphism (dbSNP) and have come to dramatically different conclusions regarding dbSNPs false positive rate and the proportion of dbSNPs that are expected to be common. These studies employed different genotyping technologies and different protocols in determining minimum acceptable genotyping quality thresholds. Because heterozygous sites typically have lower quality scores than homozygous sites, a higher minimum quality threshold reduces the number of false positive SNPs, but yields fewer heterozygotes and leads to fewer confirmed SNPs. To account for the different confirmation rates and distributions of minor allele frequencies, we propose that the three confirmation studies have different false positive and false negative rates. We developed a mathematical model to predict SNP confirmation rates and the apparent distribution of minor allele frequencies under user-specified false positive and false negative rates. We applied this model to the three published studies and to our own resequencing effort. We conclude that the dbSNP false positive rate is approximately 15-17% and that the reported confirmation studies have vastly different genotyping error rates and patterns.     

Some simulation results for the neutral allele model, with interpretations

Our aim in this paper is to describe a number of results arising from a simulation study of a particular “neutral mutations” model. This simulation was carried out because the stochastic process under consideration does not appear to yield theoretical answers to several questions of biological interest; however, wherever possible, we have attempted to supplement our simulation results with partial theoretical support. Our main concern is to consider the behavior of gene frequencies and of tests of the neutral mutations model based on these gene frequencies in various circumstances, in particular where the population is geographically subdivided and also where full identification of alleles is not possible. We conclude that the effect of geographical subdivision, unless extremely strong, is quite minor, while that of non-identification is moderate.     

Fixation probabilities of random mutants under frequency dependent selection

Evolutionary game dynamics describes frequency dependent selection in asexual, haploid populations. It typically considers predefined strategies and fixed payoff matrices. Mutations occur between these known types only. Here, we consider a situation in which a mutation has produced an entirely new type which is characterized by a random payoff matrix that does not change during the fixation or extinction of the mutant. Based on the probability distribution underlying the payoff values, we address the fixation probability of the new mutant. It turns out that for weak selection, only the first moments of the distribution matter. For strong selection, the probability that a new payoff entry is larger than the wild type's payoff against itself is the crucial quantity.     

Most recent common ancestor probability distributions in gene genealogies under selection

A computational study is made of the conditional probability distribution for the allelic type of the most recent common ancestor in genealogies of samples of n genes drawn from a population under selection, given the initial sample configuration. Comparisons with the corresponding unconditional cases are presented. Such unconditional distributions differ from samples drawn from the unique stationary distribution of population allelic frequencies, known as Wright's formula, and are quantified. Biallelic haploid and diploid models are considered. A simplified structure for the ancestral selection graph of S. M. Krone and C. Neuhauser (1997, Theor. Popul. Biol. 51, 210-237) is enhanced further, reducing the effective branching rate in the graph. This improves efficiency of such a nonneutral analogue of the coalescent for use with computational likelihood-inference techniques.     

Allelic histories: positive selection on a HIV-resistance allele

The CCR5-Delta32 allele crucially determines the course of HIV infection and appears to be highly protective against the disease. Population genetic studies suggest that the allele has been under positive selection in Europe in the past. In a recent paper, Alison Galvani and Montgomery Slatkin collate the available evidence and use a mathematical model to strongly suggest that smallpox could have exerted sufficient selection pressure to explain the distribution of the allele across Europe. This is a beautiful example of the power of mathematical models in evolutionary genetics.     

A new theory of MHC evolution: beyond selection on the immune genes

The major histocompatibility complex (MHC) is a dense region of immune genes with high levels of polymorphism, which are arranged in haplotype blocks. Traditional models of balancing selection (i.e. overdominance and negative frequency dependence) were developed to study the population genetics of single genes. However, the MHC is a multigene family surrounded by linked (non-neutral) polymorphisms, and not all of its features are well explained by these models. For example, (i) the high levels of polymorphism in small populations, (ii) the unexpectedly large genetic differentiation between populations, (iii) the shape of the allelic genealogy associated with trans-species evolution, and (iv) the close associations between particular MHC (human leucocyte antigen, HLA) haplotypes and the approximately 100 pathologies in humans. Here, I propose a new model of MHC evolution named Associative Balancing Complex evolution that can explain these phenomena. The model proposes that recessive deleterious mutations accumulate as a 'sheltered load' nearby MHC genes. These mutations can accumulate because (i) they are rarely expressed as homozygotes given the high MHC gene diversity and (ii) purifying selection is inefficient with low recombination rates (cf. Muller's ratchet). Once fixed, these mutations add to balancing selection and further reinforce linkage through epistatic selection against recombinants.     

A correction for allele frequency estimates derived from isofemale lines

Isofemale lines are commonly used inDrosophila and other genera for the purpose of assaying genetic variation. Isofemale lines can be kept in the laboratory for many generations before genetic work is carried out, and permit the confirmation of newly discovered alleles. A problem not realized by many workers is that the commonly used estimate of allele frequency from these lines is biased. This estimation bias occurs at all times after the first laboratory generation, regardless of whether single individuals or pooled samples are used in each well of an electrophoretic gel. This bias can potentially affect the estimation of population genetic parameters, and in the case of rare allele analysis it can cause gross overestimates of gene flow. This paper provides a correction for allele frequency estimates derived from isofemale lines for any time after the lines are established in the laboratory. When pooled samples are used, this estimator performs better than the standard estimator at all times after the first generation. The estimator is also insensitive to multiple inseminations. After the lines have drifted oneN _e generations, multiple inseminations actually make the new estimator perform better than it does in singly inseminated females. Simulations show that estimates made using either estimator after the lines have drifted to fixation have a much greater error associated with their use than do those estimates made earlier in time using the correction. In general it is better to use corrected estimates of gene frequency soon after lines are established than to use uncorrected estimates made after the first laboratory generation. This work was supported by an NSERC fellowship to A.D.L.     

The polymorphism frequency spectrum of finitely many sites under selection

The distribution of genetic polymorphisms in a population contains information about evolutionary processes. The Poisson random field (PRF) model uses the polymorphism frequency spectrum to infer the mutation rate and the strength of directional selection. The PRF model relies on an infinite-sites approximation that is reasonable for most eukaryotic populations, but that becomes problematic when is large ( greater, similar 0.05). Here, we show that at large mutation rates characteristic of microbes and viruses the infinite-sites approximation of the PRF model induces systematic biases that lead it to underestimate negative selection pressures and mutation rates and erroneously infer positive selection. We introduce two new methods that extend our ability to infer selection pressures and mutation rates at large : a finite-site modification of the PRF model and a new technique based on diffusion theory. Our methods can be used to infer not only a "weighted average" of selection pressures acting on a gene sequence, but also the distribution of selection pressures across sites. We evaluate the accuracy of our methods, as well that of the original PRF approach, by comparison with Wright-Fisher simulations.