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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

Correlation among the five recombination phenotypes in the AGRE.The strength of the correlation coefficient is color-coded; «s» indicates significance at the 5% level. Other than a negative correlation between telomere and centromere usage (p = 1.97×10−9), the five phenotypes are not significantly correlated with one another.
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pone-0020321-g002: Correlation among the five recombination phenotypes in the AGRE.The strength of the correlation coefficient is color-coded; «s» indicates significance at the 5% level. Other than a negative correlation between telomere and centromere usage (p = 1.97×10−9), the five phenotypes are not significantly correlated with one another.

Mentions: Variation in mean recombination rate and historical hotspot usage in the AGRE sample are shown in Figure 1 (for other phenotypes and samples, see Supplementary Figures 3–7 in Materials S1). Interestingly, historical hotspot usage and mean recombination rate are not significantly correlated (Figure 2), confirming the finding for a smaller set of Hutterites [10]. In fact, the only association among our five recombination phenotypes that is consistently significant across population samples is a negative relationship between telomere and centromere usage (see Supplementary Figure 8 in Materials S1 for FHS and HUTT results). Thus, the five phenotypes capture distinct aspects of recombination.


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)

Correlation among the five recombination phenotypes in the AGRE.The strength of the correlation coefficient is color-coded; «s» indicates significance at the 5% level. Other than a negative correlation between telomere and centromere usage (p = 1.97×10−9), the five phenotypes are not significantly correlated with one another.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020321-g002: Correlation among the five recombination phenotypes in the AGRE.The strength of the correlation coefficient is color-coded; «s» indicates significance at the 5% level. Other than a negative correlation between telomere and centromere usage (p = 1.97×10−9), the five phenotypes are not significantly correlated with one another.
Mentions: Variation in mean recombination rate and historical hotspot usage in the AGRE sample are shown in Figure 1 (for other phenotypes and samples, see Supplementary Figures 3–7 in Materials S1). Interestingly, historical hotspot usage and mean recombination rate are not significantly correlated (Figure 2), confirming the finding for a smaller set of Hutterites [10]. In fact, the only association among our five recombination phenotypes that is consistently significant across population samples is a negative relationship between telomere and centromere usage (see Supplementary Figure 8 in Materials S1 for FHS and HUTT results). Thus, the five phenotypes capture distinct aspects of recombination.

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