Identification of meiotic recombination through gamete genome reconstruction using whole genome linked-reads

Xu, P.; Human Genome Structural Variation Consortium,; Chong, Z.

doi:10.1101/363341

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bioRxiv · 10.1101/363341

Identification of meiotic recombination through gamete genome reconstruction using whole genome linked-reads

Xu, P.·Human Genome Structural Variation Consortium,·Chong, Z.

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Abstract

Meiotic recombination (MR), which transmits exchanged genetic materials between homologous chromosomes to offspring, plays a crucial role in shaping genomic diversity in eukaryotic organisms. In humans, thousands of meiotic recombination hotspots have been mapped by population genetics approaches. However, direct identification of MR events for individuals is still challenging due to the difficulty in resolving the haplotypes of homologous chromosomes and reconstructing the gamete genome. Whole genome linked-read sequencing (lrWGS) can generate haplotype sequences of mega-base pairs (N50 ~2.5Mb) after computational phasing. However, the haplotype information is still isolated in a large number of fragmented genomic regions and limited by switch errors, impeding its further application in the chromosome-scale analysis. In this study, we developed a tool MRLR (Meiotic Recombination identification by Linked-Read sequencing) for the analysis of individual MR events. By leveraging trio pedigree information with lrWGS haplotypes, our pipeline is sufficient to reconstruct the whole human gamete genome with 99.8% haplotyping accuracy. By analyzing the haplotype exchange between homologous chromosomes, MRLR identified 462 high-resolution MR events in 6 human trio samples from the Genome In A Bottle (GIAB) and the Human Genome Structural Variation Consortium (HGSVC). In three datasets of the HGSVC, our results recapitulated 149 (92%) previously identified high-confident MR events and discovered 85 novel events. About half (40) of the new events are supported by single-cell template strand sequencing (Strand-seq) results. We found that 332 (71.9%) MR events co-localize with recombination hotspots (>10 cM/Mb) in human populations, and MR breakpoint regions are enriched in PRDM9 and DMC1 binding sites. In addition, 48% (221) breakpoint regions were detected inside a gene, indicating these MRs can directly affect the haplotype diversity of genic regions. Taken together, our approach provides new opportunities in the haplotype-based genomic analysis of individual meiotic recombination. The MRLR software is implemented in Perl and is freely available at https://github.com/ChongLab/MRLR.

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Xu, P., Human Genome Structural Variation Consortium,, Chong, Z.. 2018-07-06. Identification of meiotic recombination through gamete genome reconstruction using whole genome linked-reads. https://doi.org/10.1101/363341

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