The DNA-binding protein PRDM9 has a critical role in specifying meiotic recombination hotspots in mice and apes, but appears to be absent from other vertebrate species, including birds. To study the evolution and determinants of recombination in species lacking PRDM9, we inferred fine-scale genetic maps from population resequencing data for two bird species, the zebra finch Taeniopygia guttata and the long-tailed finch Poephila acuticauda. We find that both species have hotspots, which are enriched near functional genomic elements. Unlike in mice and apes, the two species share most hotspots, with conservation seemingly extending over tens of millions of years. These observations suggest that in the absence of PRDM9, recombination targets functional features that both enable access to the genome and constrain its evolution.
The DNA-binding protein PRDM9 has a critical role in specifying meiotic recombination hotspots in mice and apes, but appears to be absent from other vertebrate species, including birds. To study the evolution and determinants of recombination in species lacking PRDM9, we inferred fine-scale genetic maps from population resequencing data for two bird species, the zebra finch Taeniopygia guttata and the long-tailed finch Poephila acuticauda. We find that both species have hotspots, which are enriched near functional genomic elements. Unlike in mice and apes, the two species share most hotspots, with conservation seemingly extending over tens of millions of years. These observations suggest that in the absence of PRDM9, recombination targets functional features that both enable access to the genome and constrain its evolution.Meiotic recombination is a ubiquitous and fundamental genetic process that shapes variation in populations, yet our understanding of its underlying mechanisms is based on a handful of model organisms, scattered throughout the tree of life. One pattern shared among most sexually reproducing species is that meiotic recombination tends to occur in short segments of 100s to 1000s of base pairs, termed "recombination hotspots" (1). In apes and mice, the location of hotspots is largely determined by PRDM9, a zinc-finger protein that binds to specific motifs in the genome during meiotic prophase and generates H3K4me3 marks, eventually leading to double-strand breaks (DSBs) and both crossover and non-crossover + to whom correspondence should be addressed. * co-first authors [2][3][4][5]. In mammals, the zinc-finger domain of PRDM9 evolves quickly, with evidence of positive selection on residues in contact with DNA (2, 6), and as a result, there is rapid turnover of hotspot locations across species, subspecies, and populations (7-10). Europe PMC Funders GroupAlthough PRDM9 plays a pivotal role in controlling recombination localization in mice and apes, many species lacking PRDM9 nonetheless have hotspots (6). An artificial example is provided by mice knockouts for PRDM9. Despite being sterile, they make similar numbers of DSBs as wild-type mice, and their recombination hotspots appear to default to residual H3K4me3 mark locations, notably at promoters (10). A natural but puzzling example is provided by canids, which carry premature stop codons in PRDM9 yet are able to recombine and remain fertile (11,12). Like in mouse PRDM9 knockouts, in dogs and in other species without PRDM9 such as the yeast Saccharomyces cerevisae and the plant Arabidopsis thaliana, hotspots tend to occur at promoters or other regions with promoter-like features (11, 13,14). In yet other taxa without PRDM9, including Drosophila species (15), honeybees (16), and Caenorhabditis elegans (17), short, intense recombination hotspots appear to be absent altogether.To further explore how the absence of PRDM9 shapes the fine-scale recombination landscape and impacts its evolution, we turn to birds, because an analysis of the chick...
Background: Predisposition to complex diseases is explained in part by genetic variation, and complex diseases are frequently comorbid, consistent with pleiotropic genetic variation influencing comorbidity. Genome Wide Association (GWA) studies typically assess association between SNPs and a single-disease phenotype. Fisher metaanalysis combines evidence of association from single-disease GWA studies, assuming that each study is an independent test of the same hypothesis. The Rank Product (RP) method overcomes limitations posed by Fisher assumptions, though RP was not designed for GWA data.
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