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Evidence of reduced recombination rate in human regulatory domains.

ABSTRACT: Recombination rate is non-uniformly distributed across the human genome. The variation of recombination rate at both fine and large scales cannot be fully explained by DNA sequences alone. Epigenetic factors, particularly DNA methylation, have recently been proposed to influence the variation in recombination rate.We study the relationship between recombination rate and gene regulatory domains, defined by a gene and its linked control elements. We define these links using expression quantitative trait loci (eQTLs), methylation quantitative trait loci (meQTLs), chromatin conformation from publicly available datasets (Hi-C and ChIA-PET), and correlated activity links that we infer across cell types. Each link type shows a "recombination rate valley" of significantly reduced recombination rate compared to matched control regions. This recombination rate valley is most pronounced for gene regulatory domains of early embryonic development genes, housekeeping genes, and constitutive regulatory elements, which are known to show increased evolutionary constraint across species. Recombination rate valleys show increased DNA methylation, reduced doublestranded break initiation, and increased repair efficiency, specifically in the lineage leading to the germ line. Moreover, by using only the overlap of functional links and DNA methylation in germ cells, we are able to predict the recombination rate with high accuracy.Our results suggest the existence of a recombination rate valley at regulatory domains and provide a potential molecular mechanism to interpret the interplay between genetic and epigenetic variations.

SUBMITTER: Liu Y

PROVIDER: S-EPMC5651596 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Evidence of reduced recombination rate in human regulatory domains.

Liu Yaping Y Sarkar Abhishek A Kheradpour Pouya P Ernst Jason J Kellis Manolis M

Genome biology 20171020 1

<h4>Background</h4>Recombination rate is non-uniformly distributed across the human genome. The variation of recombination rate at both fine and large scales cannot be fully explained by DNA sequences alone. Epigenetic factors, particularly DNA methylation, have recently been proposed to influence the variation in recombination rate.<h4>Results</h4>We study the relationship between recombination rate and gene regulatory domains, defined by a gene and its linked control elements. We define these ...[more]

PMID: 29058599

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Project description:BackgroundHuman papillomavirus (HPV) has a causal role in cervical cancer with almost half a million new cases occurring each year. Presence of the carcinogenic HPV is necessary for the development of the invasive carcinoma of the genital tract. Therefore, persistent infection with carcinogenic HPV causes virtually all cervical cancers. Some aspects of the molecular evolution of this virus, as the putative importance of recombination in its evolutionary history, are an opened current question. In addition, recombination could also be a significant issue nowadays since the frequency of co-infection with more than one HPV type is not a rare event and, thus, new recombinant types could be currently being generated.ResultsWe have used human alpha-PV sequences from the public database at Los Alamos National Laboratory to report evidence that recombination may exist in this virus. A model-based population genetic approach was used to infer the recombination signal from the HPV DNA sequences grouped attending to phylogenetic and epidemiological information, as well as to clinical manifestations. Our results agree with recently published ones that use a different methodology to detect recombination associated to the gene L2. In addition, we have detected significant recombination signal in the genes E6, E7, L2 and L1 at different groups, and importantly within the high-risk type HPV16. The method used has recently been shown to be one of the most powerful and reliable procedures to detect the recombination signal.ConclusionWe provide new support to the recent evidence of recombination in HPV. Additionally, we performed the recombination estimation assuming the best-fit model of nucleotide substitution and rate variation among sites, of the HPV DNA sequence sets. We found that the gene with recombination in most of the groups is L2 but the highest values were detected in L1 and E6. Gene E7 was recombinant only within the HPV16 type. The topic deserves further study because recombination is an important evolutionary mechanism that could have high impact both in pharmacogenomics (i.e. on the influence of genetic variation on the response to drugs) and for vaccine development.

Project description:The data set submitted here contains the raw SNP genotyping data obtained from the analysis of 24 biparental segregating maize (Zea mays L.) populations and their respective parents. The processed and filtered data were used to construct genetic linkage maps which we used in our study of variation of recombination rate in maize. In sexually reproducing organisms, meiotic crossovers ensure the proper segregation of chromosomes and contribute to genetic diversity by shuffling allelic combinations. Such genetic reassortment is exploited in breeding to combine favorable alleles, and in genetic research to identify genetic factors underlying traits of interest via linkage or association-based approaches. Crossover numbers and distributions along chromosomes vary between species, but little is known about their intraspecies variation. In our study, we report on the variation of recombination rates between 22 European maize inbred lines that belong to the Dent and Flint gene pools. We genotyped 23 doubled-haploid populations derived from crosses between these lines with a 50k-SNP array and constructed high-density genetic maps, showing good correspondence with the maize B73 genome sequence assembly. By aligning each genetic map to the B73 sequence, we obtained the recombination rates along chromosomes specific to each population. We identified significant differences in recombination rates at the genome-wide, chromosome, and intrachromosomal levels between populations, as well as significant variation for genome-wide recombination rates among maize lines. Crossover interference analysis using a two-pathway modeling framework revealed a negative association between recombination rate and interference strength. To our knowledge, the present work provides the most comprehensive study on intraspecific variation of recombination rates and crossover interference strength in eukaryotes. Differences found in recombination rates will allow for selection of high or low recombining lines in crossing programs. Our methodology should pave the way for precise identification of genes controlling recombination rates in maize and other organisms. Related publication: Bauer E, Falque M, Walter H, Bauland C, Camisan C, Campo L, Meyer N, Ranc N, Rincent R, Schipprack W, Altmann T, Flament P, Melchinger AE, Menz M, Moreno-González J, Ouzunova M, Revilla P, Charcosset A, Martin OC, Schön C-C (2013) Intraspecific variation of recombination rate in maize. Genome Biology (submitted) We genotyped 2233 maize DH lines from 24 biparental populations, and the 23 parents of these populations using the Illumina MaizeSNP50 BeadChip. We created two large half-sib panels, one each for the Dent and the Flint germplasm. The Dent populations have the prefix CFD, the Flint populations have the prefix CFF. In each panel, a common central parent was crossed to diverse founder lines, and doubled haploids were generated from the respective F1 plants. For a detailed description of the material, see Bauer et al. (2013) Genome Biology (submitted). We submit here three datasets: 1) Dataset Parents comprises all 23 parental lines. 2) Dataset CFD comprises all 1005 DH lines from Dent crosses, 3) Dataset CFF comprises all 1262 DH lines from Flint crosses.

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Evidence of reduced recombination rate in human regulatory domains.

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Evidence of reduced recombination rate in human regulatory domains.

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