Genetic recombination is directed away from functional genomic elements in mice

Brick, Kevin; Smagulova, Fátima; Khil, Pavel P.; Camerini‐Otero, R. Daniel; Petukhova, Galina V.

doi:10.1038/nature11089

Cited by 411 publications

(828 citation statements)

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“…In canids where PRDM9 is absent, recombination occurs in CpG-rich regions around promoters with little association with H3K4me3 marks (Auton et al 2013). In mouse prdm9 mutants, recombination hotspots are reverted to gene promoters as it is observed in yeast, plants, and in our analysis, suggesting a functional gain to specify location of recombination (Brick et al 2012).…”

Section: Te-related Motifs Are Thus Present In Recombinogenic Windowssupporting

confidence: 48%

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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Section: Te-related Motifs Are Thus Present In Recombinogenic Windowssupporting

confidence: 48%

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

et al. 2017

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“…Recent efforts have focused on understanding the patterns of recombination in species lacking PRDM9(54, 55) as well as mouse Prdm9 knockouts (27). These results suggest that in the absence of PRDM9 to localize breakpoints, most recombination is initiated at promoters and at other sites of PRDM9 independent H3K4 trimethylation.…”

Section: Sm S15 Analysis Of a Subject With A Predicted Prdm9 Knockoutmentioning

confidence: 94%

“…Our figures for the NA12878 / NA12882 duo are consistent with previously published estimates of 60% (confidence interval: 58% 61%) from multiple individuals (22). Prdm9 knockout mice demonstrate abnormal location of recombination hotspots with enrichment at gene promoters and enhancers, and also fail to properly repair double stranded breaks and are infertile (both sexes sterile) (26,27). Dogs, the only known mammalian lineage lacking Prdm9, lost early in canid evolution, retain recombination hotspots which unlike humans or knockout mice occur in high GC content regions (28).…”

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confidence: 99%

Health and population effects of rare gene knockouts in adult humans with related parents

Narasimhan

Hunt

Mason

et al. 2015

Preprint

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Abstract:Complete gene knockouts are highly informative about gene function. We exome sequenced 3,222 British Pakistani heritage adults with high parental relatedness, discovering 1,111 rare variant homozygous likely loss of function (rhLOF) genotypes predicted to disrupt (knockout) 781 genes. Based on depletion of rhLOF genotypes, we estimate that 13.6% of knockouts are incompatible with adult life, finding on average 1.6 heterozygous recessive lethal LOF variants per adult. Linking to lifelong health records, we observed no association of rhLOF genotypes with prescription or doctor consultation rate, and no disease related phenotypes in 33 of 42 individuals with rhLOF genotypes in recessive Mendelian disease genes. Phased genome sequencing of a healthy PRDM9 knockout mother, her child and controls, showed meiotic recombination sites localised away from PRDM9 dependent hotspots, demonstrating PRDM9 redundancy in humans. Main Text:The study of gene function by correlating genotype with phenotype has provided profound biological insights for several decades. In particular, complete gene knockouts, typically caused by homozygous loss of function (LOF) genotypes, have been used to identify the function of many genes, predominantly through studies in model organisms and of severe Mendelian inherited diseases in humans. However, information on the consequences of knocking out most genes in humans is still missing. Naturally occurring complete gene knockouts, whilst exceptional in outbred populations, offer the opportunity to study directly the lifelong effects of systemic gene inactivation in a living human. They provide a key entry point into human biology that can then be tested in other systems, and can lead to direct validation of specific biological hypotheses. The first large survey of LOF variants in adult humans demonstrated ~100 predicted LOF genotypes per individual, describing around ~20 genes carrying homozygous predicted LOF alleles and hence likely completely inactivated(1). As expected almost all these homozygous genotypes were common (allele frequency) variants, and were concentrated in genes likely to have weak or neutral effects on fitness and health, for instance olfactory receptors. In contrast, rare predicted LOF genotypes in these outbred . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/031641 doi: bioRxiv preprint first posted online Nov. 14, 2015; samples were usually heterozygous and thus of uncertain overall impact on gene function. Several approaches have been described recently to identify naturally occurring human knockouts. A large exome sequencing aggregation study (ExAC), of predominantly outbred individuals, identified 1,775 genes with homozygous predicted LOF genotypes in 60,706 individuals(2). In population isolates, 1,171 genes with complete predicted LOF were identified in 104,220 Icelandic individuals(3), and modest enrichment for homozygou...

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“…The current model posits that PRDM9 binds to hotspot recognition sites in DNA and trimethylates nearby histones, thereby activating chromatin and attracting the topoisomerase SPO11, which then catalyzes the initial DNA double-strand break (DSB) that physically begins the exchange of DNA sequences between recombining chromatids. Now, the laboratories of Petukhova and Camerini-Otero have jointly provided a series of papers that introduce a dramatically new capability in studying hotspot functions, one that has already provided intriguing new results and promises to open up new possibilities in the study of genetic recombination mechanisms [9][10][11]. Their methodology exploits the single-stranded (ss) DNA tails that arise on either side of the newly formed DSBs.…”

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confidence: 99%