PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans

Berg, Ingrid; Neumann, Rita; Lam, Gabriel K. Y.; Sarbajna, Shriparna; Odenthal-Hesse, Linda; May, Celia A.; Jeffreys, Alec J.

doi:10.1038/ng.658

Cited by 308 publications

(496 citation statements)

References 30 publications

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“…For instance, variation in the PR domain-containing 9 (PRDM9) was recently reported to strongly influence recombination hot-spot activity and meiotic instability in humans. 12 Variation in this gene could therefore promote recombination errors such as needed in NAHR.…”

Section: Discussionmentioning

confidence: 99%

Two families with sibling recurrence of the 17q21.31 microdeletion syndrome due to low-grade mosaicism

et al. 2012

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The 17q21.31 microdeletion syndrome is characterised by intellectual disability, epilepsy, distinctive facial dysmorphism, and congenital anomalies. To date, all individuals reported with this syndrome have been simplex patients, resulting from de novo deletions. Here, we report sibling recurrence of the 17q21.31 microdeletion syndrome in two independent families. In both families, the mother was confirmed to be the parent-of-origin for the 17q21.31 deletion. Fluorescence in situ hybridisation analyses in buccal mucosa cells, of the mother of family 1, identified monosomy 17q21.31 in 4/50 nuclei (8%). In mother of family 2, the deletion was identified in 2/60 (3%) metaphase and in 3/100 (3%) interphase nuclei in peripheral lymphocytes, and in 7/100 (7%) interphase nuclei in buccal cells. A common 17q21.31 inversion polymorphism predisposes to non-allelic homologous recombination and hereby to the 17q21.31 microdeletion syndrome. On the basis of the 17q21.31 inversion status of the parents, we calculated that the probability of the second deletion occurring by chance alone was 1/14 438 and 1/4812, respectively. If the inversion status of the parents of a child with the 17q21.31 microdeletion syndrome is unknown, the overall risk of a second child with the 17q21.31 microdeletion is 1/9461. We conclude that the presence of low-level maternal somatic-gonadal mosaicism is associated with the microdeletion recurrence in these families. This suggests that the recurrence risk for parents with a child with a 17q21.31 microdeletion for future pregnancies is higher than by chance alone and testing for mosaicism in the parents might be considered as a helpful tool in the genetic counselling.

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Section: Discussionmentioning

confidence: 99%

Two families with sibling recurrence of the 17q21.31 microdeletion syndrome due to low-grade mosaicism

et al. 2012

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“…This particular structure may confer a strong potential to generate variability by recombination or replication slippage within the array. Indeed, studies documented variability in the contact residues predicting DNA binding between human populations (Baudat et al, 2010;Berg et al, 2010;Parvanov et al, 2010), and the number of zinc fingers and their contact residues vary significantly across rodents, primates and other Metazoans (Oliver et al, 2009). The changing of contact residues could create a new family of hotspots by the binding of the protein to new sequence motifs, thereby counteracting the loss of hotspots due to biased gene conversion.…”

Section: How Does the Methodology By Which Recombination Is Measured mentioning

confidence: 99%

“…In particular, it appears that a 13-mer degenerate motif may be responsible for recruiting recombination events in at least 40% of human hotspots (Myers et al, 2008). This motif binds to the zinc-finger protein PRDM9 in humans, and allelic variation controls hotspot activity in both humans and mice (Baudat et al, 2010;Berg et al, 2010). Relatedly, the Drosophila zincfinger protein, Trade Embargo (trem), initiates doublestrand breaks (DSBs) and is necessary for localization of the protein Mei-P22 to discrete foci on meiotic chromosomes, some or all of which are thought to mark sites for future DSBs (Lake et al, 2011).…”

Section: Determinants and Correlatesmentioning

confidence: 99%

Recombination rate variation in closely related species

2011

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Despite their importance to successful meiosis and various evolutionary processes, meiotic recombination rates sometimes vary within species or between closely related species. For example, humans and chimpanzees share virtually no recombination hotspot locations in the surveyed portion of the genomes. However, conservation of recombination rates between closely related species has also been documented, raising an apparent contradiction. Here, we evaluate how and why conflicting patterns of recombination rate conservation and divergence may be observed, with particular emphasis on features that affect recombination, and the scale and method with which recombination is surveyed. Additionally, we review recent studies identifying features influencing fine-scale and broad-scale recombination patterns and informing how quickly recombination rates evolve, how changes in recombination impact selection and evolution in natural populations, and more broadly, which forces influence genome evolution.

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“…Open chromatin structure is known to play an important role in CO formation in both yeast (Wu and Lichten 1994;Berchowitz et al 2009;Borde et al 2009;Pan et al 2011) and mammals (Buard et al 2009;Berg et al 2010;Grey et al 2011), especially through the trimethylation of lysine 4 of histone H3 (H3K4me3 landmark). DNA methylation also represses CO formation (Maloisel and Rossignol 1998) and is sufficient to silence CO hotspots in Arabidopsis (Yelina et al 2015).…”

Section: Retrotransposons Associate With Reduced Recombination Ratementioning

confidence: 99%

High-Resolution Mapping of Crossover Events in the Hexaploid Wheat Genome Suggests a Universal Recombination Mechanism

et al. 2017

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During meiosis, crossovers (COs) create new allele associations by reciprocal exchange of DNA. In bread wheat (Triticum aestivum L.), COs are mostly limited to subtelomeric regions of chromosomes, resulting in a substantial loss of breeding efficiency in the proximal regions, though these regions carry 60-70% of the genes. Identifying sequence and/or chromosome features affecting recombination occurrence is thus relevant to improve and drive recombination. Using the recent release of a reference sequence of chromosome 3B and of the draft assemblies of the 20 other wheat chromosomes, we performed fine-scale mapping of COs and revealed that 82% of COs located in the distal ends of chromosome 3B representing 19% of the chromosome length. We used 774 SNPs to genotype 180 varieties representative of the Asian and European genetic pools and a segregating population of 1270 F 6 lines. We observed a common location for ancestral COs (predicted through linkage disequilibrium) and the COs derived from the segregating population. We delineated 73 small intervals (,26 kb) on chromosome 3B that contained 252 COs. We observed a significant association of COs with genic features (73 and 54% in recombinant and nonrecombinant intervals, respectively) and with those expressed during meiosis (67% in recombinant intervals and 48% in nonrecombinant intervals). Moreover, while the recombinant intervals contained similar amounts of retrotransposons and DNA transposons (42 and 53%), nonrecombinant intervals had a higher level of retrotransposons (63%) and lower levels of DNA transposons (28%). Consistent with this, we observed a higher frequency of a DNA motif specific to the TIR-Mariner DNA transposon in recombinant intervals. KEYWORDS recombination; meiosis; bread wheat; linkage disequilibrium; transposon; hotspot; sequence motif M EIOTIC recombination is a process that allows reshuffling of diversity by the reciprocal exchange of DNA called a crossover (CO). This phenomenon is conserved in most eukaryotes (for a review see Mercier et al. 2015) and follows the formation of a double-strand break (DSB) of DNA generated by the topoisomerase SPO11 complex. However, the number of DSBs is at least 10-to 50-fold greater than the number of COs which rarely exceeds three per bivalent chromosome per meiosis (Mercier et al. 2015). This paucity of COs per meiosis with regards to the number of DSBs suggests the existence of a tight control and regulation of recombination in plants that promote DSB repair in a manner that does not lead to COs. For example, the study of the two helicases AtFANCM and RECQ4 (AtRECQ4A and AtRECQ4B) (Crismani et al. 2012;Knoll et al. 2012;Girard et al. 2014;Séguéla-Arnaud et al. 2015) revealed three-and sixfold CO frequency increases in the Atfancm single mutant and the Atrecq4a/Atrecq4b double mutant, respectively, compared to the wild type. These increases result from additional COs from the class-II pathway which suggests that FANCM and RECQ4 prevent CO formation and direct recombination intermediates towar...

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PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans

Cited by 308 publications

References 30 publications

Two families with sibling recurrence of the 17q21.31 microdeletion syndrome due to low-grade mosaicism

Two families with sibling recurrence of the 17q21.31 microdeletion syndrome due to low-grade mosaicism

Recombination rate variation in closely related species

High-Resolution Mapping of Crossover Events in the Hexaploid Wheat Genome Suggests a Universal Recombination Mechanism

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