Genetic analysis of variation in human meiotic recombination

Abstract

The number of recombination events per meiosis varies extensively among individuals. This recombination phenotype differs between female and male, and also among individuals of each gender. In this study, we used high-density SNP genotypes of over 2,300 individuals and their offspring in two datasets to characterize recombination landscape and to map the genetic variants that contribute to variation in recombination phenotypes. We found six genetic loci that are associated with recombination phenotypes. Two of these (RNF212 and an inversion on chromosome 17q21.31) were previously reported in the Icelandic population, and this is the first replication in any other population. Of the four newly identified loci (KIAA1462, PDZK1, UGCG, NUB1), results from expression studies provide support for their roles in meiosis. Each of the variants that we identified explains only a small fraction of the individual variation in recombination. Notably, we found different sequence variants associated with female and male recombination phenotypes, suggesting that they are regulated by different genes. Characterization of genetic variants that influence natural variation in meiotic recombination will lead to a better understanding of normal meiotic events as well as of non-disjunction, the primary cause of pregnancy loss.

Figure 1. Identification of recombination events.

Genotypes at 10 consecutive SNPs for two parents and their four children in this pedigree are provided. Informative makers are marked in red and blue for the mother and father, respectively. Recombination events are shown by color switches (for example from dark to light red), or, if regions are large, they are shown in gray.

Figure 2. Distribution of recombination phenotypes.

Histograms showing the distributions of maternal (red) and paternal (blue) recombinations in the AGRE (A) and FHS (B) samples.

Figure 3. Recombination jungles across the human genome.

The curves in each graph represent the intensity of recombination activity across the chromosome. Regions with the most recombination activity (2 standard deviations above the mean) are shaded in gray and are considered “recombination jungles.” Recombination events for females (top) and males (bottom) are shown for the AGRE (pink and light blue) and FHS (red and dark blue) samples. Chromosome ideograms show centromeres in red and patterns of Giemsa staining in different shades of grey.

Figure 4. Results of genome-wide association studies of female and male recombination phenotypes.

Results of analysis of the AGRE samples for females (A) and males (C) are shown. Combined P-values for the significant loci are plotted in green. Quantile–Quantile plots with observed P-values plotted as a function of expected P-values for female (B) and male (D) recombination phenotypes are shown.

Figure 5. Genomic regions that include the 6 most significant loci associated with recombination phenotypes.

(A–C) Maternal association results for SNPs from analysis of the AGRE samples (red) and combined AGRE and FHS samples (green) plotted for loci on chromosomes 10p.11.23 (A), 17q21.31 (B), and 1q21.1 (C). (D–F) Paternal association results for SNPs from analysis of the AGRE samples (blue) and combined AGRE and FHS samples (green) plotted for loci on chromosomes 4p16.3 (D), 9q31.3 (E), and 7q36.1 (F). The top panel of each figure highlights the most significant SNPs in the region. The center panel of each figure shows genes in each region, and direction of transcription. The bottom panel of each figure shows LD patterns at each locus, where black corresponds to stronger LD and light gray corresponds to weaker LD as shown in (C).

Figure 6. Expression analysis of genes associated with male recombination phenotypes.

(A) Mouse male meiotic cells were purified by FACS from testes. A typical profile is shown with the purified cell fractions circled in red. All meiotic cells were also purified and used as reference sample (circled in blue). (B) Expression patterns for genes associated with male recombination phenotypes. All genes display a strong induction from the onset of meiosis. Relative expression (ΔΔCt) was calculated using mouse β-actin as the endogenous control and the entire meiotic cells as the reference. Error bars indicate ± s.e.m. Sp: Spermatogonia, L/Z: Leptotene/Zygotene, Pa: Pachytene, Di: Diplotene, SS/RS: Secondary spermatocytes and round spermatids.