During meiosis, the recombination-initiating DNA double-strand breaks (DSBs) are repaired by crossovers or noncrossovers (gene conversions). While crossovers are easily detectable, noncrossover identification is hampered by the small size of their converted tracts and the necessity of sequence polymorphism. We report identification and characterization of a mouse chromosome-wide set of noncrossovers by next-generation sequencing of 10 mouse intersubspecific chromosome substitution strains. Based on 94 identified noncrossovers, we determined the mean length of a conversion tract to be 32 bp. The spatial chromosome-wide distribution of noncrossovers and crossovers significantly differed, although both sets overlapped the known hotspots of PRDM9-directed histone methylation and DNA DSBs, thus supporting their origin in the standard DSB repair pathway. A significant deficit of noncrossovers descending from asymmetric DSBs proved their proposed adverse effect on meiotic recombination and pointed to sister chromatids as an alternative template for their repair. The finding has implications for the molecular mechanism of hybrid sterility in mice from crosses between closely related Mus musculus musculus and Mus musculus domesticus subspecies.

Department of Cell Biology Faculty of Science Charles University CZ 12000 Prague Czech Republic

Laboratory of Mouse Molecular Genetics Division BIOCEV Institute of Molecular Genetics Czech Academy of Sciences CZ 25250 Vestec Czech Republic

Zobrazit více v PubMed

Arbeithuber B, Betancourt AJ, Ebner T, Tiemann-Boege I.. 2015. Crossovers are associated with mutation and biased gene conversion at recombination hotspots. Proc Natl Acad Sci USA. 112:2109–2114. PubMed PMC

Baker CL, Kajita S, Walker M, Saxl RL, Raghupathy N, et al.2015. PRDM9 drives evolutionary erosion of hotspots in Mus musculus through haplotype-specific initiation of meiotic recombination. PLoS Genet. 11:e1004916. PubMed PMC

Baker CL, Walker M, Kajita S, Petkov PM, Paigen K.. 2014. PRDM9 binding organizes hotspot nucleosomes and limits Holliday junction migration. Genome Res. 24:724–732. PubMed PMC

Balcova M, Faltusova B, Gergelits V, Bhattacharyya T, Mihola O, et al.2016. Hybrid sterility locus on chromosome X controls meiotic recombination rate in mouse. PLoS Genet. e1005906. 12: PubMed PMC

Baudat F, Buard J, Grey C, Fledel-Alon A, Ober C, et al.2010. PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science. 327:836–840. PubMed PMC

Baudat F, de Massy B.. 2007. Regulating double-stranded DNA break repair towards crossover or non-crossover during mammalian meiosis. Chromosome Res. 15:565–577. PubMed

Baudat F, Manova K, Yuen JP, Jasin M, Keeney S.. 2000. Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Mol Cell. 6:989–998. PubMed

Bhattacharyya T, Gregorova S, Mihola O, Anger M, Sebestova J, et al.2013. Mechanistic basis of infertility of mouse intersubspecific hybrids. Proc Natl Acad Sci USA. 110:E468–E477. PubMed PMC

Bhattacharyya T, Reifova R, Gregorova S, Simecek P, Gergelits V, et al.2014. X chromosome control of meiotic chromosome synapsis in mouse inter-subspecific hybrids. PLoS Genet. 10:e1004088. PubMed PMC

Boulton A, Myers RS, Redfield RJ.. 1997. The hotspot conversion paradox and the evolution of meiotic recombination. Proc Natl Acad Sci USA. 94:8058–8063. PubMed PMC

Brick K, Thibault-Sennett S, Smagulova F, Lam K-WG, Pu Y, et al.2018. Extensive sex differences at the initiation of genetic recombination. Nature. 561:338–342. PubMed PMC

Broman KW, Murray JC, Sheffield VC, White RL, Weber JL.. 1998. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet. 63:861–869. PubMed PMC

Carofiglio F, Sleddens-Linkels E, Wassenaar E, Inagaki A, van Cappellen WA, et al.2018. Repair of exogenous DNA double-strand breaks promotes chromosome synapsis in SPO11-mutant mouse meiocytes, and is altered in the absence of HORMAD1. DNA Repair (Amst). 63:25–38. PubMed

Churchill GA, Airey DC, Allayee H, Angel JM, Attie AD, et al.; Complex Trait Consortium. 2004. The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat Genet. 36:1133–1137. PubMed

Clement Y, Arndt PF.. 2013. Meiotic recombination strongly influences GC-content evolution in short regions in the mouse genome. Mol Biol Evol. 30:2612–2618. PubMed

Cole F, Baudat F, Grey C, Keeney S, de Massy B, et al.2014. Mouse tetrad analysis provides insights into recombination mechanisms and hotspot evolutionary dynamics. Nat Genet. 46:1072–1080. PubMed PMC

Cole F, Kauppi L, Lange J, Roig I, Wang R, et al.2012. Homeostatic control of recombination is implemented progressively in mouse meiosis. Nat Cell Biol. 14:424–430. PubMed PMC

Cole F, Keeney S, Jasin M.. 2010. Comprehensive, fine-scale dissection of homologous recombination outcomes at a hot spot in mouse meiosis. Mol Cell. 39:700–710. PubMed PMC

Cox A, Ackert-Bicknell CL, Dumont BL, Ding Y, Bell JT, et al.2009. A new standard genetic map for the laboratory mouse. Genetics. 182:1335–1344. PubMed PMC

Davies B, Hatton E, Altemose N, Hussin JG, Pratto F, et al.2016. Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice. Nature. 530:171–176. PubMed PMC

de Boer E, Jasin M, Keeney S.. 2015. Local and sex-specific biases in crossover vs. noncrossover outcomes at meiotic recombination hot spots in mice. Genes Dev. 29:1721–1733. PubMed PMC

Din W, Anand R, Boursot P, Darviche D, Dod B, et al.1996. Origin and radiation of the house mouse: clues from nuclear genes. J Evol Biol. 9:519–539.

Duret L, Galtier N.. 2009. Biased gene conversion and the evolution of mammalian genomic landscapes. Annu Rev Genom Hum Genet. 10:285–311. PubMed

Forejt J. 1996. Hybrid sterility in the mouse. Trends Genet. 12:412–417. PubMed

Forejt J, Pialek J, Trachtulec Z.. 2012. Hybrid male sterility genes in the mouse subspecific crosses. In: Macholan M, Baird SJE, Muclinger P, Pialek J, editors. Evolution of the House Mouse. Cambridge, UK: Cambridge University Press. p. 482–503.

Geraldes A, Basset P, Gibson B, Smith KL, Harr B, et al.2008. Inferring the history of speciation in house mice from autosomal, X-linked, Y-linked and mitochondrial genes. Mol Ecol. 17:5349–5363. PubMed PMC

Goldfarb T, Lichten M.. 2010. Frequent and efficient use of the sister chromatid for DNA double-strand break repair during budding yeast meiosis. PLoS Biol. 8:e1000520. PubMed PMC

Gray S, Cohen PE.. 2016. Control of meiotic crossovers: from double-strand break formation to designation. Annu Rev Genet. 50:175–210. PubMed PMC

Gregorova S, Divina P, Storchova R, Trachtulec Z, Fotopulosova V, et al.2008. Mouse consomic strains: exploiting genetic divergence between Mus m. musculus and Mus m. domesticus subspecies. Genome Res. 18:509–515. PubMed PMC

Gregorova S, Forejt J.. 2000. PWD/Ph and PWK/Ph inbred mouse strains of Mus m. musculus subspecies—a valuable resource of phenotypic variations and genomic polymorphisms. Folia Biol (Praha). 46:31–41. PubMed

Gregorova S, Gergelits V, Chvatalova I, Bhattacharyya T, Valiskova B, et al.2018. Modulation of Prdm9-controlled meiotic chromosome asynapsis overrides hybrid sterility in mice. Elife. 7:e34282. doi:34210.37554/eLife.34282. PubMed PMC

Grey C, Clement JA, Buard J, Leblanc B, Gut I, et al.2017. In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites. Genome Res. 27:580–590. PubMed PMC

Guillon H, Baudat F, Grey C, Liskay RM, de Massy B.. 2005. Crossover and noncrossover pathways in mouse meiosis. Mol Cell. 20:563–573. PubMed

Guillon H, de Massy B.. 2002. An initiation site for meiotic crossing-over and gene conversion in the mouse. Nat Genet. 32:296–299. PubMed

Halldorsson BV, Hardarson MT, Kehr B, Styrkarsdottir U, Gylfason A, et al.2016. The rate of meiotic gene conversion varies by sex and age. Nat Genet. 48:1377–1384. PubMed PMC

Hinch AG, Zhang G, Becker PW, Moralli D, Hinch R, et al.2019. Factors influencing meiotic recombination revealed by whole-genome sequencing of single sperm. Science. 363:eaau8861. PubMed PMC

Huang T, Yuan S, Gao L, Li M, Yu X, et al.2020. The histone modification reader ZCWPW1 links histone methylation to PRDM9-induced double-strand break repair. Elife. 9:e53459. PubMed PMC

Ideraabdullah FY, de la Casa-Esperon E, Bell TA, Detwiler DA, Magnuson T, et al.2004. Genetic and haplotype diversity among wild-derived mouse inbred strains. Genome Res. 14:1880–1887. PubMed PMC

Jeffreys AJ, May CA.. 2004. Intense and highly localized gene conversion activity in human meiotic crossover hot spots. Nat Genet. 36:151–156. PubMed

Katzman S, Capra JA, Haussler D, Pollard KS.. 2011. Ongoing GC-biased evolution is widespread in the human genome and enriched near recombination hot spots. Genome Biol Evol. 3:614–626. PubMed PMC

Kauppi L, Barchi M, Lange J, Baudat F, Jasin M, et al.2013. Numerical constraints and feedback control of double-strand breaks in mouse meiosis. Genes Dev. 27:873–886. PubMed PMC

Keane TM, Goodstadt L, Danecek P, White MA, Wong K, et al.2011. Mouse genomic variation and its effect on phenotypes and gene regulation. Nature. 477:289–294. PubMed PMC

Keeney S, Baudat F, Angeles M, Zhou ZH, Copeland NG, et al.1999. A mouse homolog of the Saccharomyces cerevisiae meiotic recombination DNA transesterase Spo11p. Genomics. 61:170–182. PubMed

Keeney S, Giroux CN, Kleckner N.. 1997. Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family. Cell. 88:375–384. PubMed

Lam I, Mohibullah N, Keeney S.. 2017. Sequencing Spo11 oligonucleotides for mapping meiotic DNA double-strand breaks in yeast. Methods Mol Biol. 1471:51–98. PubMed

Lange J, Yamada S, Tischfield SE, Pan J, Kim S, et al.2016. The landscape of mouse meiotic double-strand break formation, processing, and repair. Cell. 167:695–708.e6. PubMed PMC

Li R, Bitoun E, Altemose N, Davies RW, Davies B, et al.2019. A high-resolution map of non-crossover events reveals impacts of genetic diversity on mammalian meiotic recombination. Nat Commun. 10:3900. PubMed PMC

Littrell J, Tsaih SW, Baud A, Rastas P, Solberg-Woods L, et al.2018. A high-resolution genetic map for the laboratory rat. G3 (Bethesda). 3:2241–2248. PubMed PMC

Liu EY, Morgan AP, Chesler EJ, Wang W, Churchill GA, et al.2014. High-resolution sex-specific linkage maps of the mouse reveal polarized distribution of crossovers in male germline. Genetics. 197:91–106. PubMed PMC

Lustyk D, Kinsky S, Ullrich KK, Yancoskie M, Kasikova L, et al.2019. Genomic structure of Hstx2 modifier of Prdm9-dependent hybrid male sterility in mice. Genetics. 213:1047–1063. PubMed PMC

Mihola O, Trachtulec Z, Vlcek C, Schimenti JC, Forejt J.. 2009. A mouse speciation gene encodes a meiotic histone H3 methyltransferase. Science. 323:373–375. PubMed

Mukaj A, Pialek J, Fotopulosova V, Morgan AP, Odenthal-Hesse L, et al.2020. Prdm9 inter-subspecific interactions in hybrid male sterility of house mouse. Mol Biol Evol.37:3423–3438. PubMed PMC

Myers S, Bowden R, Tumian A, Bontrop RE, Freeman C, et al.2010. Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination. Science. 327:876–879. PubMed PMC

Ng SH, Parvanov E, Petkov PM, Paigen K.. 2008. A quantitative assay for crossover and noncrossover molecular events at individual recombination hotspots in both male and female gametes. Genomics. 92:204–209. PubMed PMC

Odenthal-Hesse L, Berg IL, Veselis A, Jeffreys AJ, May CA.. 2014. Transmission distortion affecting human noncrossover but not crossover recombination: a hidden source of meiotic drive. PLoS Genet. 10:e1004106. PubMed PMC

Paigen K, Petkov PM.. 2018. PRDM9 and its role in genetic recombination. Trends Genet. 34:291–300. PubMed PMC

Parvanov ED, Petkov PM, Paigen K.. 2010. Prdm9 controls activation of mammalian recombination hotspots. Science. 327:835–835. PubMed PMC

Powers NR, Parvanov ED, Baker CL, Walker M, Petkov PM, et al.2016. The meiotic recombination activator PRDM9 trimethylates both H3K36 and H3K4 at recombination hotspots in vivo. PLoS Genet. 12:e1006146. PubMed PMC

Pratto F, Brick K, Khil P, Smagulova F, Petukhova GV, et al.2014. DNA recombination. Recombination initiation maps of individual human genomes. Science. 346:1256442. PubMed PMC

Romanienko PJ, Camerini-Otero RD.. 2000. The mouse Spo11 gene is required for meiotic chromosome synapsis. Mol Cell. 6:975–987. PubMed

Shen B, Jiang J, Seroussi E, Liu GE, Ma L.. 2018. Characterization of recombination features and the genetic basis in multiple cattle breeds. BMC Genomics. 19:304. PubMed PMC

Smagulova F, Brick K, Pu YM, Camerini-Otero RD, Petukhova GV.. 2016. The evolutionary turnover of recombination hot spots contributes to speciation in mice. Genes Dev. 30:266–280. PubMed PMC

Smagulova F, Gregoretti IV, Brick K, Khil P, Camerini-Otero RD, et al.2011. Genome-wide analysis reveals novel molecular features of mouse recombination hotspots. Nature. 472:375–378. PubMed PMC

Tiemann-Boege I, Schwarz T, Striedner Y, Heissl A.. 2017. The consequences of sequence erosion in the evolution of recombination hotspots. Philos Trans R Soc Lond B Biol Sci. 372: 20160462. PubMed PMC

Wang L, Valiskova B, Forejt J.. 2018. Cisplatin-induced DNA double-strand breaks promote meiotic chromosome synapsis in PRDM9-controlled mouse hybrid sterility. Elife. 7:e42511. PubMed PMC

Webb AJ, Berg IL, Jeffreys A.. 2008. Sperm cross-over activity in regions of the human genome showing extreme breakdown of marker association. Proc Natl Acad Sci USA. 105:10471–10476. PubMed PMC

Wells D, Bitoun E, Moralli D, Zhang G, Hinch A, et al.2020. ZCWPW1 is recruited to recombination hotspots by PRDM9 and is essential for meiotic double strand break repair. Elife. 9:e53392. PubMed PMC

Wickham HAverick MBryan JChang WMcgowan L, et al. 2019. . Welcome to the Tidyverse. JOSS. 4:1686.

Williams AL, Genovese G, Dyer T, Altemose N, Truax K, et al.; on behalf of the T2D-GENES Consortium. 2015. Non-crossover gene conversions show strong GC bias and unexpected clustering in humans. Elife. 4:e04637. PubMed PMC

Meiotic Recognition of Evolutionarily Diverged Homologs: Chromosomal Hybrid Sterility Revisited