Limits...
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.

Show MeSH

Related in: MedlinePlus

A close up of the association signal at a new candidate region for hotspot usage.The plot was generated using the software LocusZoom [51], as described in the legend of Figure 4.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3117798&req=5

pone-0020321-g006: A close up of the association signal at a new candidate region for hotspot usage.The plot was generated using the software LocusZoom [51], as described in the legend of Figure 4.

Mentions: Given the large role of PRDM9 on historical hotspot usage, we regressed out the genotype of the three most strongly associated SNPs at PRDM9 and reran the test for association. The strongest associations have p-values < 10−5 but do not reach genome-wide significance (Table 1) (the same is true when analyzing sex-specific phenotypes). Among top signals is a region of high linkage disequilibrium in an intron of CCBE1 (p = 5.75×10−6) (Figure 6), a gene expressed in mice oocytes in meiotic prophase I and in ovaries of embryos [40], [41] and more tentatively in human testes and mouse spermatocytes [38]. Moreover, two of the SNPs in high LD with the top SNP are reported to be trans eQTLs for PHF5A, a splicing factor subunit that is expressed in mouse spermatocytes from leptotene through pachytene [42].


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 a new candidate region for hotspot usage.The plot was generated using the software LocusZoom [51], as described in the legend of Figure 4.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020321-g006: A close up of the association signal at a new candidate region for hotspot usage.The plot was generated using the software LocusZoom [51], as described in the legend of Figure 4.
Mentions: Given the large role of PRDM9 on historical hotspot usage, we regressed out the genotype of the three most strongly associated SNPs at PRDM9 and reran the test for association. The strongest associations have p-values < 10−5 but do not reach genome-wide significance (Table 1) (the same is true when analyzing sex-specific phenotypes). Among top signals is a region of high linkage disequilibrium in an intron of CCBE1 (p = 5.75×10−6) (Figure 6), a gene expressed in mice oocytes in meiotic prophase I and in ovaries of embryos [40], [41] and more tentatively in human testes and mouse spermatocytes [38]. Moreover, two of the SNPs in high LD with the top SNP are reported to be trans eQTLs for PHF5A, a splicing factor subunit that is expressed in mouse spermatocytes from leptotene through pachytene [42].

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