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Variation in human recombination rates and its genetic determinants.

Fledel-Alon A, Leffler EM, Guan Y, Stephens M, Coop G, Przeworski M - PLoS ONE (2011)

Bottom Line: We replicated associations of RNF212 with the mean rate in males and in females as well as the association of Inversion 17q21.31 with the female mean rate.In addition, we identified a set of new candidate regions for further validation.These findings suggest that variation at broad and fine scales is largely separable and that, beyond three known loci, there is no evidence for common variation with large effects on recombination phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.

ABSTRACT

Background: Despite the fundamental role of crossing-over in the pairing and segregation of chromosomes during human meiosis, the rates and placements of events vary markedly among individuals. Characterizing this variation and identifying its determinants are essential steps in our understanding of the human recombination process and its evolution.

Study design/results: Using three large sets of European-American pedigrees, we examined variation in five recombination phenotypes that capture distinct aspects of crossing-over patterns. We found that the mean recombination rate in males and females and the historical hotspot usage are significantly heritable and are uncorrelated with one another. We then conducted a genome-wide association study in order to identify loci that influence them. We replicated associations of RNF212 with the mean rate in males and in females as well as the association of Inversion 17q21.31 with the female mean rate. We also replicated the association of PRDM9 with historical hotspot usage, finding that it explains most of the genetic variance in this phenotype. In addition, we identified a set of new candidate regions for further validation.

Significance: These findings suggest that variation at broad and fine scales is largely separable and that, beyond three known loci, there is no evidence for common variation with large effects on recombination phenotypes.

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Related in: MedlinePlus

A close up of the association signal at previously reported and new candidate regions for female mean recombination rate.The figures were generated using the software LocusZoom [51], as described in the legend of Figure 4. A. Replication of association signal for female mean recombination rate near inversion 17q21.13. B. Top associations for female mean recombination rate.
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pone-0020321-g005: A close up of the association signal at previously reported and new candidate regions for female mean recombination rate.The figures were generated using the software LocusZoom [51], as described in the legend of Figure 4. A. Replication of association signal for female mean recombination rate near inversion 17q21.13. B. Top associations for female mean recombination rate.

Mentions: In addition to RNF212, we replicated the effect of SNPs near Inversion 17q21.31 on female mean rate (lowest p-value  =  5.12×10−5, Figure 5A). The top SNP explains 1.45% of the female variance in this trait in FHS, with one allele estimated to add 124 cM on average to the genetic map. Among the strongest associations is SNP rs564636 (p = 1.39×10−6; see Table 1), which lies in an intron in the gene OBSCN, 113 kb from C1orf69 and 98 kb from TRIM11, in a region of high LD that extends as far as the gene HIST3H3 (Figure 5B). In the imputation analysis, several missense SNPs in OBSCN are in high LD and have low p-values. OBSCN, a member of a family of sarcomeric signaling proteins, is expressed in mouse male meiotic cells, suggesting it may be present in female meiotic cells as well [38]; in turn, TRIM11 is expressed in mice oocytes in meiotic prophase I and in ovaries of mice embryos [40], [41]. Another strong association is SNP rs2505115 (p = 1.83×10−6; see Table 1), ∼1 kb downstream of KIAA1462 and 200 kb upstream of MTPAP [19] (Figure 5B). Both KIAA1462 and MTPAP are highly expressed in mice oocytes in meiotic prophase I and in ovaries of mice embryos [40], [41].


Variation in human recombination rates and its genetic determinants.

Fledel-Alon A, Leffler EM, Guan Y, Stephens M, Coop G, Przeworski M - PLoS ONE (2011)

A close up of the association signal at previously reported and new candidate regions for female mean recombination rate.The figures were generated using the software LocusZoom [51], as described in the legend of Figure 4. A. Replication of association signal for female mean recombination rate near inversion 17q21.13. B. Top associations for female mean recombination rate.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3117798&req=5

pone-0020321-g005: A close up of the association signal at previously reported and new candidate regions for female mean recombination rate.The figures were generated using the software LocusZoom [51], as described in the legend of Figure 4. A. Replication of association signal for female mean recombination rate near inversion 17q21.13. B. Top associations for female mean recombination rate.
Mentions: In addition to RNF212, we replicated the effect of SNPs near Inversion 17q21.31 on female mean rate (lowest p-value  =  5.12×10−5, Figure 5A). The top SNP explains 1.45% of the female variance in this trait in FHS, with one allele estimated to add 124 cM on average to the genetic map. Among the strongest associations is SNP rs564636 (p = 1.39×10−6; see Table 1), which lies in an intron in the gene OBSCN, 113 kb from C1orf69 and 98 kb from TRIM11, in a region of high LD that extends as far as the gene HIST3H3 (Figure 5B). In the imputation analysis, several missense SNPs in OBSCN are in high LD and have low p-values. OBSCN, a member of a family of sarcomeric signaling proteins, is expressed in mouse male meiotic cells, suggesting it may be present in female meiotic cells as well [38]; in turn, TRIM11 is expressed in mice oocytes in meiotic prophase I and in ovaries of mice embryos [40], [41]. Another strong association is SNP rs2505115 (p = 1.83×10−6; see Table 1), ∼1 kb downstream of KIAA1462 and 200 kb upstream of MTPAP [19] (Figure 5B). Both KIAA1462 and MTPAP are highly expressed in mice oocytes in meiotic prophase I and in ovaries of mice embryos [40], [41].

Bottom Line: We replicated associations of RNF212 with the mean rate in males and in females as well as the association of Inversion 17q21.31 with the female mean rate.In addition, we identified a set of new candidate regions for further validation.These findings suggest that variation at broad and fine scales is largely separable and that, beyond three known loci, there is no evidence for common variation with large effects on recombination phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.

ABSTRACT

Background: Despite the fundamental role of crossing-over in the pairing and segregation of chromosomes during human meiosis, the rates and placements of events vary markedly among individuals. Characterizing this variation and identifying its determinants are essential steps in our understanding of the human recombination process and its evolution.

Study design/results: Using three large sets of European-American pedigrees, we examined variation in five recombination phenotypes that capture distinct aspects of crossing-over patterns. We found that the mean recombination rate in males and females and the historical hotspot usage are significantly heritable and are uncorrelated with one another. We then conducted a genome-wide association study in order to identify loci that influence them. We replicated associations of RNF212 with the mean rate in males and in females as well as the association of Inversion 17q21.31 with the female mean rate. We also replicated the association of PRDM9 with historical hotspot usage, finding that it explains most of the genetic variance in this phenotype. In addition, we identified a set of new candidate regions for further validation.

Significance: These findings suggest that variation at broad and fine scales is largely separable and that, beyond three known loci, there is no evidence for common variation with large effects on recombination phenotypes.

Show MeSH
Related in: MedlinePlus