Inference and analysis of population-specific fine-scale recombination maps across 26 diverse human populations.
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ABSTRACT:
SUBMITTER: Spence JP
PROVIDER: S-EPMC6810367 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Meiotic recombination is an important driver of evolution. Variability in the intensity of recombination across chromosomes can affect sequence composition, nucleotide variation, and rates of adaptation. In many organisms, recombination events are concentrated within short segments termed recombination hotspots. The variation in recombination rate and positions of recombination hotspot can be studied using population genomics data and statistical methods. In this study, we conducted population genomics analyses to address the evolution of recombination in two closely related fungal plant pathogens: the prominent wheat pathogen Zymoseptoria tritici and a sister species infecting wild grasses Z. ardabiliae We specifically addressed whether recombination landscapes, including hotspot positions, are conserved in the two recently diverged species and if recombination contributes to rapid evolution of pathogenicity traits. We conducted a detailed simulation analysis to assess the performance of methods of recombination rate estimation based on patterns of linkage disequilibrium, in particular in the context of high nucleotide diversity. Our analyses reveal overall high recombination rates, a lack of suppressed recombination in centromeres, and significantly lower recombination rates on chromosomes that are known to be accessory. The comparison of the recombination landscapes of the two species reveals a strong correlation of recombination rate at the megabase scale, but little correlation at smaller scales. The recombination landscapes in both pathogen species are dominated by frequent recombination hotspots across the genome including coding regions, suggesting a strong impact of recombination on gene evolution. A significant but small fraction of these hotspots colocalize between the two species, suggesting that hotspot dynamics contribute to the overall pattern of fast evolving recombination in these species.
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Project description:Recombination events are not uniformly distributed and often cluster in narrow regions known as recombination hotspots. Several studies using different approaches have dramatically advanced our understanding of recombination hotspot regulation. Population genetic data have been used to map and quantify hotspots in the human genome. Genetic variation in recombination rates and hotspots usage have been explored in human pedigrees, mouse intercrosses, and by sperm typing. These studies pointed to the central role of the PRDM9 gene in hotspot modulation. In this study, we used single nucleotide polymorphisms (SNPs) from whole-genome resequencing and genotyping studies of mouse inbred strains to estimate recombination rates across the mouse genome and identified 47,068 historical hotspots--an average of over 2477 per chromosome. We show by simulation that inbred mouse strains can be used to identify positions of historical hotspots. Recombination hotspots were found to be enriched for the predicted binding sequences for different alleles of the PRDM9 protein. Recombination rates were on average lower near transcription start sites (TSS). Comparing the inferred historical recombination hotspots with the recent genome-wide mapping of double-strand breaks (DSBs) in mouse sperm revealed a significant overlap, especially toward the telomeres. Our results suggest that inbred strains can be used to characterize and study the dynamics of historical recombination hotspots. They also strengthen previous findings on mouse recombination hotspots, and specifically the impact of sequence variants in Prdm9.
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Project description:Linking variation in quantitative traits to variation in the genome is an important, but challenging task in the study of life-history evolution. Linkage maps provide a valuable tool for the unravelling of such trait-gene associations. Moreover, they give insight into recombination landscapes and between-species karyotype evolution. Here we used genotype data, generated from a 10k single-nucleotide polymorphism (SNP) chip, of over 2000 individuals to produce high-density linkage maps of the great tit (Parus major), a passerine bird that serves as a model species for ecological and evolutionary questions. We created independent maps from two distinct populations: a captive F2-cross from The Netherlands (NL) and a wild population from the United Kingdom (UK). The two maps contained 6554 SNPs in 32 linkage groups, spanning 2010 cM and 1917 cM for the NL and UK populations, respectively, and were similar in size and marker order. Subtle levels of heterochiasmy within and between chromosomes were remarkably consistent between the populations, suggesting that the local departures from sex-equal recombination rates have evolved. This key and surprising result would have been impossible to detect if only one population was mapped. A comparison with zebra finch Taeniopygia guttata, chicken Gallus gallus and the green anole lizard Anolis carolinensis genomes provided further insight into the evolution of avian karyotypes.
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Project description:Recombination rates vary significantly across the genome, and estimates of recombination rates are needed for downstream analyses such as haplotype phasing and genotype imputation. Existing methods for recombination rate estimation are limited by insufficient amounts of informative genetic data or by high computational cost. We present a method and software, called IBDrecomb, for using segments of identity by descent to infer recombination rates. IBDrecomb can be applied to sequenced population cohorts to obtain high-resolution, population-specific recombination maps. In simulated admixed data, IBDrecomb obtains higher accuracy than admixture-based estimation of recombination rates. When applied to 2,500 simulated individuals, IBDrecomb obtains similar accuracy to a linkage-disequilibrium (LD)-based method applied to 96 individuals (the largest number for which computation is tractable). Compared to LD-based maps, our IBD-based maps have the advantage of estimating recombination rates in the recent past rather than the distant past. We used IBDrecomb to generate new recombination maps for European Americans and for African Americans from TOPMed sequence data from the Framingham Heart Study (1,626 unrelated individuals) and the Jackson Heart Study (2,046 unrelated individuals), and we compare them to LD-based, admixture-based, and family-based maps.
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Project description:There has been limited success in identifying causal variants underlying association signals observed in genome-wide association studies (GWAS). The use of 1000 Genomes Project (1KGP) allows the imputation to estimate the genetic information at untyped variants. However, long stretches of high linkage disequilibrium within the genome prevent us from differentiating between causal variants and perfect surrogates, thus limiting our ability to identify causal variants. Transethnic strategies have been proposed as a possible solution to mitigate this. However, these studies generally rely on imputing genotypes from multiple ancestries from 1KGP but not against population-specific reference panels. Here, we perform the first transethnic fine-mapping study across three Asian cohorts from diverse ancestries at the loci implicated with eye and blood lipid traits, using population-specific reference panels that have been generated by whole-genome sequencing samples from the same ancestry groups. Our study outlines several challenges faced in a fine-mapping exercise where one simply aims to meta-analyse existing GWAS that have been imputed against reference haplotypes from the 1KGP.
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Project description:Meiotic recombination rates can vary widely across genomes, with hotspots of intense activity interspersed among cold regions. In yeast, hotspots tend to occur in promoter regions of genes, whereas in humans and mice, hotspots are largely defined by binding sites of the positive-regulatory domain zinc finger protein 9. To investigate the detailed recombination pattern in a flowering plant, we use shotgun resequencing of a wild population of the monkeyflower Mimulus guttatus to precisely locate over 400,000 boundaries of historic crossovers or gene conversion tracts. Their distribution defines some 13,000 hotspots of varying strengths, interspersed with cold regions of undetectably low recombination. Average recombination rates peak near starts of genes and fall off sharply, exhibiting polarity. Within genes, recombination tracts are more likely to terminate in exons than in introns. The general pattern is similar to that observed in yeast, as well as in positive-regulatory domain zinc finger protein 9-knockout mice, suggesting that recombination initiation described here in Mimulus may reflect ancient and conserved eukaryotic mechanisms.
| S-EPMC3845195 | biostudies-literature
Project description:Due to its long genetic evolutionary history, Africans exhibit more genetic variation than any other population in the world. Their genetic diversity further lends itself to subdivisions of Africans into groups of individuals with a genetic similarity of varying degrees of granularity. It remains challenging to detect fine-scale structure in a computationally efficient and meaningful way. In this paper, we present a proof-of-concept of a novel fine-scale population structure detection tool with Western African samples. These samples consist of 1396 individuals from 25 ethnic groups (two groups are African American descendants). The strategy is based on a recently developed tool called IPCAPS. IPCAPS, or Iterative Pruning to CApture Population Structure, is a genetic divisive clustering strategy that enhances iterative pruning PCA, is robust to outliers and does not require a priori computation of haplotypes. Our strategy identified in total 12 groups and 6 groups were revealed as fine-scale structure detected in the samples from Cameroon, Gambia, Mali, Southwest USA, and Barbados. Our finding helped to explain evolutionary processes in the analyzed West African samples and raise awareness for fine-scale structure resolution when conducting genome-wide association and interaction studies.
| S-EPMC6942040 | biostudies-literature
Project description:Meiotic recombination is a highly conserved process that has profound effects on genome evolution. At a fine-scale, recombination rates can vary drastically across genomes, often localized into small recombination "hotspots" with highly elevated rates, surrounded by regions with little recombination. In most species studied, the location of hotspots within genomes is highly conserved across broad evolutionary timescales. The main exception to this pattern is in mammals, where hotspot location can evolve rapidly among closely related species and even among populations within a species. Hotspot position in mammals is controlled by the gene, Prdm9, whereas in species with conserved hotspots, a functional Prdm9 is typically absent. Due to a limited number of species where recombination rates have been estimated at a fine-scale, it remains unclear whether hotspot conservation is always associated with the absence of a functional Prdm9. Threespine stickleback fish (Gasterosteus aculeatus) are an excellent model to examine the evolution of recombination over short evolutionary timescales. Using a linkage disequilibrium-based approach, we found recombination rates indeed varied at a fine-scale across the genome, with many regions organized into narrow hotspots. Hotspots had highly divergent landscapes between stickleback populations, where only ∼15% of these hotspots were shared. Our results indicate that fine-scale recombination rates may be diverging between closely related populations of threespine stickleback fish. Interestingly, we found only a weak association of a PRDM9 binding motif within hotspots, which suggests that threespine stickleback fish may possess a novel mechanism for targeting recombination hotspots at a fine-scale.
| S-EPMC6553502 | biostudies-literature
Project description:BACKGROUND: Meiotic recombination causes a shuffling of homologous chromosomes as they are passed from parents to children. Finding the genomic locations where these crossovers occur is important for genetic association studies, understanding population genetic variation, and predicting disease-causing structural rearrangements. There have been several reports that recombination hotspot usage differs between human populations. But while fine-scale genetic maps exist for European and African populations, none have been constructed for Asians. RESULTS: Here we present the first Asian genetic map with resolution high enough to reveal hotspot usage. We constructed this map by applying a hidden Markov model to genotype data for over 500,000 single nucleotide polymorphism markers from Korean and Mongolian pedigrees which include 980 meioses. We identified 32,922 crossovers with a precision rate of 99%, 97% sensitivity, and a median resolution of 105,949 bp. For direct comparison of genetic maps between ethnic groups, we also constructed a map for CEPH families using identical methods. We found high levels of concordance with known hotspots, with approximately 72% of recombination occurring in these regions. We investigated the hypothesized contribution of recombination problems to age-related aneuploidy. Our large sample size allowed us to detect a weak but significant negative effect of maternal age on recombination rate. CONCLUSIONS: We have constructed the first fine-scale Asian genetic map. This fills an important gap in the understanding of recombination pattern variation and will be a valuable resource for future research in population genetics. Our map will improve the accuracy of linkage studies and inform the design of genome-wide association studies in the Asian population.
| S-EPMC3599818 | biostudies-literature