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ABSTRACT: Theories to explain the prevalence of sex and recombination have long been a central theme of evolutionary biology. Yet despite decades of attention dedicated to the evolution of sex and recombination, the widespread pattern of sex differences in the recombination rate is not well understood and has received relatively little theoretical attention. Here, we argue that female meiotic drivers--alleles that increase in frequency by exploiting the asymmetric cell division of oogenesis--present a potent selective pressure favoring the modification of the female recombination rate. Because recombination plays a central role in shaping patterns of variation within and among dyads, modifiers of the female recombination rate can function as potent suppressors or enhancers of female meiotic drive. We show that when female recombination modifiers are unlinked to female drivers, recombination modifiers that suppress harmful female drive can spread. By contrast, a recombination modifier tightly linked to a driver can increase in frequency by enhancing female drive. Our results predict that rapidly evolving female recombination rates, particularly around centromeres, should be a common outcome of meiotic drive. We discuss how selection to modify the efficacy of meiotic drive may contribute to commonly observed patterns of sex differences in recombination.
Genetics 12/2011; 190(2):709-23. · 4.01 Impact Factor
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ABSTRACT: Humans inhabit a remarkably diverse range of environments, and adaptation through natural selection has likely played a central role in the capacity to survive and thrive in extreme climates. Unlike numerous studies that used only population genetic data to search for evidence of selection, here we scan the human genome for selection signals by identifying the SNPs with the strongest correlations between allele frequencies and climate across 61 worldwide populations. We find a striking enrichment of genic and nonsynonymous SNPs relative to non-genic SNPs among those that are strongly correlated with these climate variables. Among the most extreme signals, several overlap with those from GWAS, including SNPs associated with pigmentation and autoimmune diseases. Further, we find an enrichment of strong signals in gene sets related to UV radiation, infection and immunity, and cancer. Our results imply that adaptations to climate shaped the spatial distribution of variation in humans.
PLoS Genetics 04/2011; 7(4):e1001375. · 8.69 Impact Factor
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ABSTRACT: BACKGROUND: Despite the fundamental role of crossing-over in the pairing and segregation of chromosomes during human meiosis, the rates and placements of events vary markedly among individuals. Characterizing this variation and identifying its determinants are essential steps in our understanding of the human recombination process and its evolution. STUDY DESIGN/RESULTS: Using three large sets of European-American pedigrees, we examined variation in five recombination phenotypes that capture distinct aspects of crossing-over patterns. We found that the mean recombination rate in males and females and the historical hotspot usage are significantly heritable and are uncorrelated with one another. We then conducted a genome-wide association study in order to identify loci that influence them. We replicated associations of RNF212 with the mean rate in males and in females as well as the association of Inversion 17q21.31 with the female mean rate. We also replicated the association of PRDM9 with historical hotspot usage, finding that it explains most of the genetic variance in this phenotype. In addition, we identified a set of new candidate regions for further validation. SIGNIFICANCE: These findings suggest that variation at broad and fine scales is largely separable and that, beyond three known loci, there is no evidence for common variation with large effects on recombination phenotypes.
PLoS ONE 01/2011; 6(6):e20321. · 4.09 Impact Factor
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ABSTRACT: Models for detecting the effect of adaptation on population genomic diversity are often predicated on a single newly arisen mutation sweeping rapidly to fixation. However, a population can also adapt to a new environment by multiple mutations of similar phenotypic effect that arise in parallel, at the same locus or different loci. These mutations can each quickly reach intermediate frequency, preventing any single one from rapidly sweeping to fixation globally, leading to a "soft" sweep in the population. Here we study various models of parallel mutation in a continuous, geographically spread population adapting to a global selection pressure. The slow geographic spread of a selected allele due to limited dispersal can allow other selected alleles to arise and start to spread elsewhere in the species range. When these different selected alleles meet, their spread can slow dramatically and so initially form a geographic patchwork, a random tessellation, which could be mistaken for a signal of local adaptation. This spatial tessellation will dissipate over time due to mixing by migration, leaving a set of partial sweeps within the global population. We show that the spatial tessellation initially formed by mutational types is closely connected to Poisson process models of crystallization, which we extend. We find that the probability of parallel mutation and the spatial scale on which parallel mutation occurs are captured by a single compound parameter, a characteristic length, which reflects the expected distance a spreading allele travels before it encounters a different spreading allele. This characteristic length depends on the mutation rate, the dispersal parameter, the effective local density of individuals, and to a much lesser extent the strength of selection. While our knowledge of these parameters is poor, we argue that even in widely dispersing species, such parallel geographic sweeps may be surprisingly common. Thus, we predict that as more data become available, many more examples of intraspecies parallel adaptation will be uncovered.
Genetics 10/2010; 186(2):647-68. · 4.01 Impact Factor
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ABSTRACT: Loci involved in local adaptation can potentially be identified by an unusual correlation between allele frequencies and important ecological variables or by extreme allele frequency differences between geographic regions. However, such comparisons are complicated by differences in sample sizes and the neutral correlation of allele frequencies across populations due to shared history and gene flow. To overcome these difficulties, we have developed a Bayesian method that estimates the empirical pattern of covariance in allele frequencies between populations from a set of markers and then uses this as a null model for a test at individual SNPs. In our model the sample frequencies of an allele across populations are drawn from a set of underlying population frequencies; a transform of these population frequencies is assumed to follow a multivariate normal distribution. We first estimate the covariance matrix of this multivariate normal across loci using a Monte Carlo Markov chain. At each SNP, we then provide a measure of the support, a Bayes factor, for a model where an environmental variable has a linear effect on the transformed allele frequencies compared to a model given by the covariance matrix alone. This test is shown through power simulations to outperform existing correlation tests. We also demonstrate that our method can be used to identify SNPs with unusually large allele frequency differentiation and offers a powerful alternative to tests based on pairwise or global F(ST). Software is available at http://www.eve.ucdavis.edu/gmcoop/.
Genetics 08/2010; 185(4):1411-23. · 4.01 Impact Factor
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Angela M. Hancock,
David B. Witonsky,
Edvard Ehler,
Gorka Alkorta-Aranburu,
Cynthia Beall,
Amha Gebremedhin,
Rem Sukernik,
Gerd Utermann,
Jonathan Pritchard, Graham Coop,
Anna Di Rienzo
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ABSTRACT: Human populations use a variety of subsistence strategies to exploit an exceptionally broad range of ecoregions and dietary
components. These aspects of human environments have changed dramatically during human evolution, giving rise to new selective
pressures. To understand the genetic basis of human adaptations, we combine population genetics data with ecological information
to detect variants that increased in frequency in response to new selective pressures. Our approach detects SNPs that show
concordant differences in allele frequencies across populations with respect to specific aspects of the environment. Genic
and especially nonsynonymous SNPs are overrepresented among those most strongly correlated with environmental variables. This
provides genome-wide evidence for selection due to changes in ecoregion, diet, and subsistence. We find particularly strong
signals associated with polar ecoregions, with foraging, and with a diet rich in roots and tubers. Interestingly, several
of the strongest signals overlap with those implicated in energy metabolism phenotypes from genome-wide association studies,
including SNPs influencing glucose levels and susceptibility to type 2 diabetes. Furthermore, several pathways, including
those of starch and sucrose metabolism, are enriched for strong signals of adaptations to a diet rich in roots and tubers,
whereas signals associated with polar ecoregions are overrepresented in genes associated with energy metabolism pathways.
Proceedings of the National Academy of Sciences 05/2010; 107(Supplement 2):8924-8930. · 9.68 Impact Factor
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Angela M Hancock,
David B Witonsky,
Edvard Ehler,
Gorka Alkorta-Aranburu,
Cynthia Beall,
Amha Gebremedhin,
Rem Sukernik,
Gerd Utermann,
Jonathan Pritchard, Graham Coop,
Anna Di Rienzo
[show abstract]
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ABSTRACT: Human populations use a variety of subsistence strategies to exploit an exceptionally broad range of ecoregions and dietary components. These aspects of human environments have changed dramatically during human evolution, giving rise to new selective pressures. To understand the genetic basis of human adaptations, we combine population genetics data with ecological information to detect variants that increased in frequency in response to new selective pressures. Our approach detects SNPs that show concordant differences in allele frequencies across populations with respect to specific aspects of the environment. Genic and especially nonsynonymous SNPs are overrepresented among those most strongly correlated with environmental variables. This provides genome-wide evidence for selection due to changes in ecoregion, diet, and subsistence. We find particularly strong signals associated with polar ecoregions, with foraging, and with a diet rich in roots and tubers. Interestingly, several of the strongest signals overlap with those implicated in energy metabolism phenotypes from genome-wide association studies, including SNPs influencing glucose levels and susceptibility to type 2 diabetes. Furthermore, several pathways, including those of starch and sucrose metabolism, are enriched for strong signals of adaptations to a diet rich in roots and tubers, whereas signals associated with polar ecoregions are overrepresented in genes associated with energy metabolism pathways.
Proceedings of the National Academy of Sciences 05/2010; 107 Suppl 2:8924-30. · 9.68 Impact Factor
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ABSTRACT: There has long been interest in understanding the genetic basis of human adaptation. To what extent are phenotypic differences among human populations driven by natural selection? With the recent arrival of large genome-wide data sets on human variation, there is now unprecedented opportunity for progress on this type of question. Several lines of evidence argue for an important role of positive selection in shaping human variation and differences among populations. These include studies of comparative morphology and physiology, as well as population genetic studies of candidate loci and genome-wide data. However, the data also suggest that it is unusual for strong selection to drive new mutations rapidly to fixation in particular populations (the 'hard sweep' model). We argue, instead, for alternatives to the hard sweep model: in particular, polygenic adaptation could allow rapid adaptation while not producing classical signatures of selective sweeps. We close by discussing some of the likely opportunities for progress in the field.
Current biology: CB 02/2010; 20(4):R208-15. · 10.99 Impact Factor
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ABSTRACT: Expression quantitative trait loci (eQTL) mapping is a powerful tool for identifying genetic regulatory variation. However, at present, most eQTLs in humans were identified using gene expression data from cell lines, and it remains unknown whether these eQTLs also have a regulatory function in other expression contexts, such as human primary tissues. Here we investigate this question using a targeted strategy. Specifically, we selected a subset of large-effect eQTLs identified in the HapMap lymphoblastoid cell lines, and examined the association of these eQTLs with gene expression levels across individuals in five human primary tissues (heart, kidney, liver, lung and testes). We show that genotypes at the eQTLs we selected are often predictive of variation in gene expression levels in one or more of the five primary tissues. The genotype effects in the primary tissues are consistently in the same direction as the effects inferred in the cell lines. Additionally, a number of the eQTLs we tested are found in more than one of the tissues. Our results indicate that functional studies in cell lines may uncover a substantial amount of genetic variation that affects gene expression levels in human primary tissues.
Human Molecular Genetics 09/2009; 18(22):4296-303. · 7.64 Impact Factor
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ABSTRACT: Although recombination is essential to the successful completion of human meiosis, it remains unclear how tightly the process is regulated and over what scale. To assess the nature and stringency of constraints on human recombination, we examined crossover patterns in transmissions to viable, non-trisomic offspring, using dense genotyping data collected in a large set of pedigrees. Our analysis supports a requirement for one chiasma per chromosome rather than per arm to ensure proper disjunction, with additional chiasmata occurring in proportion to physical length. The requirement is not absolute, however, as chromosome 21 seems to be frequently transmitted properly in the absence of a chiasma in females, a finding that raises the possibility of a back-up mechanism aiding in its correct segregation. We also found a set of double crossovers in surprisingly close proximity, as expected from a second pathway that is not subject to crossover interference. These findings point to multiple mechanisms that shape the distribution of crossovers, influencing proper disjunction in humans.
PLoS Genetics 09/2009; 5(9):e1000658. · 8.69 Impact Factor
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ABSTRACT: Various observations argue for a role of adaptation in recent human evolution, including results from genome-wide studies and analyses of selection signals at candidate genes. Here, we use genome-wide SNP data from the HapMap and CEPH-Human Genome Diversity Panel samples to study the geographic distributions of putatively selected alleles at a range of geographic scales. We find that the average allele frequency divergence is highly predictive of the most extreme F(ST) values across the whole genome. On a broad scale, the geographic distribution of putatively selected alleles almost invariably conforms to population clusters identified using randomly chosen genetic markers. Given this structure, there are surprisingly few fixed or nearly fixed differences between human populations. Among the nearly fixed differences that do exist, nearly all are due to fixation events that occurred outside of Africa, and most appear in East Asia. These patterns suggest that selection is often weak enough that neutral processes -- especially population history, migration, and drift -- exert powerful influences over the fate and geographic distribution of selected alleles.
PLoS Genetics 07/2009; 5(6):e1000500. · 8.69 Impact Factor
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Joseph K Pickrell, Graham Coop,
John Novembre,
Sridhar Kudaravalli,
Jun Z Li,
Devin Absher,
Balaji S Srinivasan,
Gregory S Barsh,
Richard M Myers,
Marcus W Feldman,
Jonathan K Pritchard
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ABSTRACT: Genome-wide scans for recent positive selection in humans have yielded insight into the mechanisms underlying the extensive phenotypic diversity in our species, but have focused on a limited number of populations. Here, we present an analysis of recent selection in a global sample of 53 populations, using genotype data from the Human Genome Diversity-CEPH Panel. We refine the geographic distributions of known selective sweeps, and find extensive overlap between these distributions for populations in the same continental region but limited overlap between populations outside these groupings. We present several examples of previously unrecognized candidate targets of selection, including signals at a number of genes in the NRG-ERBB4 developmental pathway in non-African populations. Analysis of recently identified genes involved in complex diseases suggests that there has been selection on loci involved in susceptibility to type II diabetes. Finally, we search for local adaptation between geographically close populations, and highlight several examples.
Genome Research 04/2009; 19(5):826-37. · 13.61 Impact Factor
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ABSTRACT: Krause J, Lalueza-Fox C, Orlando L, et al. recently examined patterns of genetic variation at FOXP2 in 2 Neanderthals. This gene is of particular interest because it is involved in speech and language and was previously shown to harbor the signature of recent positive selection. The authors found the same 2 amino acid substitutions in Neanderthals as in modern humans. Assuming that these sites were the targets of selection and no interbreeding between the 2 groups, they concluded that selection at FOXP2 occurred before the populations split, over 300 thousand years ago. Here, we show that the data are unlikely under this scenario but may instead be consistent with low rates of gene flow between modern humans and Neanderthals. We also collect additional data and introduce a modeling framework to estimate levels of modern human contamination of the Neanderthal samples. We find that, depending on the assumptions, additional control experiments may be needed to rule out contamination at FOXP2.
Molecular Biology and Evolution 08/2008; 25(7):1257-9. · 5.55 Impact Factor
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ABSTRACT: Population genetic theory suggests that natural selection should be less effective in regions of low recombination, potentially leading to differences in rates of adaptation among recombination environments. To date, this prediction has mainly been tested in Drosophila, with somewhat conflicting results. We investigated the association between human recombination rates and adaptation in primates, by considering rates of protein evolution (measured by d(N)/d(S)) between human, chimpanzee, and rhesus macaque. We found no correlation between either broad- or fine-scale rates of recombination and rates of protein evolution, once GC content is taken into account. Moreover, genes in regions of very low recombination, which are expected to show the most pronounced reduction in the efficacy of selection, do not evolve at a different rate than other genes. Thus, there is no evidence for differences in the efficacy of selection across recombinational environments. An interesting implication is that indirect selection for recombination modifiers has probably been a weak force in primate evolution.
Genome Research 05/2008; 18(4):544-54. · 13.61 Impact Factor
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ABSTRACT: Recombination plays a crucial role in meiosis, ensuring the proper segregation of chromosomes. Recent linkage disequilibrium (LD) and sperm-typing studies suggest that recombination rates vary tremendously across the human genome, with most events occurring in narrow "hotspots." To examine variation in fine-scale recombination patterns among individuals, we used dense, genome-wide single-nucleotide polymorphism data collected in nuclear families to localize crossovers with high spatial resolution. This analysis revealed that overall recombination hotspot usage is similar in males and females, with individual hotspots often active in both sexes. Across the genome, roughly 60% of crossovers occurred in hotspots inferred from LD studies. Notably, however, we found extensive and heritable variation among both males and females in the proportion of crossovers occurring in these hotspots.
Science 04/2008; 319(5868):1395-8. · 31.20 Impact Factor
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ABSTRACT: Evolutionary pressures due to variation in climate play an important role in shaping phenotypic variation among and within species and have been shown to influence variation in phenotypes such as body shape and size among humans. Genes involved in energy metabolism are likely to be central to heat and cold tolerance. To test the hypothesis that climate shaped variation in metabolism genes in humans, we used a bioinformatics approach based on network theory to select 82 candidate genes for common metabolic disorders. We genotyped 873 tag SNPs in these genes in 54 worldwide populations (including the 52 in the Human Genome Diversity Project panel) and found correlations with climate variables using rank correlation analysis and a newly developed method termed Bayesian geographic analysis. In addition, we genotyped 210 carefully matched control SNPs to provide an empirical null distribution for spatial patterns of allele frequency due to population history alone. For nearly all climate variables, we found an excess of genic SNPs in the tail of the distributions of the test statistics compared to the control SNPs, implying that metabolic genes as a group show signals of spatially varying selection. Among our strongest signals were several SNPs (e.g., LEPR R109K, FABP2 A54T) that had previously been associated with phenotypes directly related to cold tolerance. Since variation in climate may be correlated with other aspects of environmental variation, it is possible that some of the signals that we detected reflect selective pressures other than climate. Nevertheless, our results are consistent with the idea that climate has been an important selective pressure acting on candidate genes for common metabolic disorders.
PLoS Genetics 03/2008; 4(2):e32. · 8.69 Impact Factor
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Nature Genetics 11/2007; 39(10):1188-90. · 35.53 Impact Factor
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ABSTRACT: There is strong evidence that hotspots of meiotic recombination in humans are transient features of the genome. For example, hotspot locations are not shared between human and chimpanzee. Biased gene conversion in favor of alleles that locally disrupt hotspots is a possible explanation of the short lifespan of hotspots. We investigate the implications of such a bias on human hotspots and their evolution. Our results demonstrate that gene conversion bias is a sufficiently strong force to produce the observed lack of sharing of intense hotspots between species, although sharing may be much more common for weaker hotspots. We investigate models of how hotspots arise, and find that only models in which hotspot alleles do not initially experience drive are consistent with observations of rather hot hotspots in the human genome. Mutations acting against drive cannot successfully introduce such hotspots into the population, even if there is direct selection for higher recombination rates, such as to ensure correct segregation during meiosis. We explore the impact of hotspot alleles on patterns of haplotype variation, and show that such alleles mask their presence in population genetic data, making them difficult to detect.
PLoS Genetics 04/2007; 3(3):e35. · 8.69 Impact Factor
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ABSTRACT: A previous polymorphism survey of the type 2 diabetes gene CAPN10 identified a segment showing an excess of polymorphism levels in all population samples, coinciding with localized breakdown of linkage disequilibrium (LD) in a sample of Hausa from Cameroon, but not in non-African samples. This raised the possibility that a recombination hotspot is present in all populations and we had insufficient power to detect it in the non-African data. To test this possibility, we estimated the crossover rate by sperm typing in five non-African men; these estimates were consistent with the LD decay in the non-African, but not in the Hausa data. Moreover, resequencing the orthologous region in a sample of Western chimpanzees did not show either an excess of polymorphism level or rapid LD decay, suggesting that the processes underlying the patterns observed in humans operated only on the human lineage. These results suggest that a hotspot of recombination has recently arisen in humans and has reached higher frequency in the Hausa than in non-Africans, or that there is no elevation in crossover rate in any human population, and the observed variation results from long-standing balancing selection.
Genetics 03/2007; 175(2):795-804. · 4.01 Impact Factor
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ABSTRACT: Recombination has essential functions in mammalian meiosis, which impose several constraints on the recombination process. However, recent studies have shown that, in spite of these roles, recombination rates vary tremendously among humans, and show marked differences between humans and closely related species. These findings provide important insights into the determinants of recombination rates and raise new questions about the selective pressures that affect recombination over different genomic scales, with implications for human genetics and evolutionary biology.
Nature Reviews Genetics 02/2007; 8(1):23-34. · 38.08 Impact Factor
