MRLR: unraveling high-resolution meiotic recombination by linked reads

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Abstract

Motivation

Meiotic recombination facilitates the transmission of exchanged genetic material between homologous chromosomes and plays a crucial role in increasing the genetic variations in eukaryotic organisms. In humans, thousands of crossover events have been identified by genotyping related family members. However, most of these crossover regions span tens to hundreds of kb, which is not sufficient resolution to accurately identify the crossover breakpoints in a typical trio family.

Results

We have developed MRLR, a software using 10X linked reads to identify crossover events at a high resolution. By reconstructing the gamete genome, MRLR only requires a trio family dataset and can efficiently discover the crossover events. Using MRLR, we revealed a fine-scale pattern of crossover regions in six human families. From the two closest heterozygous alleles around the crossovers, we determined that MRLR achieved a median resolution 4.5 kb. This method can delineate a genome-wide landscape of crossover events at a precise scale, which is important for both functional and genomic features analysis of meiotic recombination.

Availability and implementation

MRLR is freely available at https://github.com/ChongLab/MRLR, implemented in Perl.

Supplementary information

Supplementary data are available at Bioinformatics online.

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Most cited references 20

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A high-resolution recombination map of the human genome.

Augustine Kong, Daniel Gudbjartsson, Jesús Sainz … (2002)

Determination of recombination rates across the human genome has been constrained by the limited resolution and accuracy of existing genetic maps and the draft genome sequence. We have genotyped 5,136 microsatellite markers for 146 families, with a total of 1,257 meiotic events, to build a high-resolution genetic map meant to: (i) improve the genetic order of polymorphic markers; (ii) improve the precision of estimates of genetic distances; (iii) correct portions of the sequence assembly and SNP map of the human genome; and (iv) build a map of recombination rates. Recombination rates are significantly correlated with both cytogenetic structures (staining intensity of G bands) and sequence (GC content, CpG motifs and poly(A)/poly(T) stretches). Maternal and paternal chromosomes show many differences in locations of recombination maxima. We detected systematic differences in recombination rates between mothers and between gametes from the same mother, suggesting that there is some underlying component determined by both genetic and environmental factors that affects maternal recombination rates.

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Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex.

A Jeffreys, L Kauppi, R. Neumann (2001)

There is considerable interest in understanding patterns of linkage disequilibrium (LD) in the human genome, to aid investigations of human evolution and facilitate association studies in complex disease. The relative influences of meiotic crossover distribution and population history on LD remain unclear, however. In particular, it is uncertain to what extent crossovers are clustered into 'hot spots, that might influence LD patterns. As a first step to investigating the relationship between LD and recombination, we have analyzed a 216-kb segment of the class II region of the major histocompatibility complex (MHC) already characterized for familial crossovers. High-resolution LD analysis shows the existence of extended domains of strong association interrupted by patchwork areas of LD breakdown. Sperm typing shows that these areas correspond precisely to meiotic crossover hot spots. All six hot spots defined share a remarkably similar symmetrical morphology but vary considerably in intensity, and are not obviously associated with any primary DNA sequence determinants of hot-spot activity. These hot spots occur in clusters and together account for almost all crossovers in this region of the MHC. These data show that, within the MHC at least, crossovers are far from randomly distributed at the molecular level and that recombination hot spots can profoundly affect LD patterns.

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A common sequence motif associated with recombination hot spots and genome instability in humans.

Simon Myers, Colin Freeman, Adam Auton … (2008)

In humans, most meiotic crossover events are clustered into short regions of the genome known as recombination hot spots. We have previously identified DNA motifs that are enriched in hot spots, particularly the 7-mer CCTCCCT. Here we use the increased hot-spot resolution afforded by the Phase 2 HapMap and novel search methods to identify an extended family of motifs based around the degenerate 13-mer CCNCCNTNNCCNC, which is critical in recruiting crossover events to at least 40% of all human hot spots and which operates on diverse genetic backgrounds in both sexes. Furthermore, these motifs are found in hypervariable minisatellites and are clustered in the breakpoint regions of both disease-causing nonallelic homologous recombination hot spots and common mitochondrial deletion hot spots, implicating the motif as a driver of genome instability.

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Author and article information

Journal

Title: Bioinformatics

Publisher: Oxford University Press (OUP)

ISSN (Print): 1367-4803

ISSN (Electronic): 1460-2059

Publication date Created: January 01 2020

Publication date Created: June 19 2019

Publication date Other: January 01 2020

Publication date (Print): January 01 2020

Publication date (Electronic): June 19 2019

Volume: 36

Issue: 1

Pages: 10-16

Affiliations

[1 ]Department of Genetics, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA

[2 ]Informatics Institute, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA

[3 ]Department of Medicine, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA

Article

DOI: 10.1093/bioinformatics/btz503

SO-VID: 09451b3c-4664-450c-b71b-3da901615319

License:

https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

MRLR: unraveling high-resolution meiotic recombination by linked reads

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Abstract

Motivation

Results

Availability and implementation

Supplementary information

Related collections

HR-EBSD (High Resolution - Electron Back Scatter Diffraction)

Most cited references 20

A high-resolution recombination map of the human genome.

Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex.

A common sequence motif associated with recombination hot spots and genome instability in humans.

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