The landscape of recombination in African Americans

Abstract

Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P value < 10(-245)). We identify a 17-base-pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of PRDM9 alleles common in West Africans and rare in Europeans. Sites of this motif are predicted to be risk loci for disease-causing genomic rearrangements in individuals carrying these alleles. More generally, this map provides a resource for research in human genetic variation and evolution.

Figure 1

Building an African American genetic map. (A) HAPMIX detection of crossovers between segments of inferred ancestry is illustrated in a father-mother-child trio. Black segments show inferred crossovers; arrows showtransmission of ancestral crossovers from parent to child, Purple/green segments show de novo events (paternal/maternal origin respectively), corresponding to events identified directly using two additional children (bottom,“Pedigree inferred”).(B) The AA Map localizes five hotspots in a region of the MHC whose positions (blue) were previously mapped by sperm typing. (C) Comparison of maps shows a hotspot at 33.1Mb in the African-derived AA and YRI maps, but not the deCODE and CEU maps (all maps smoothed to 10kb).

Figure 2

Association of PRDM9 genetic variation with hotspot activity. (A) A GWAS measuring association of the “African-enrichment” (AE) phenotype shows a single genome-wide significant peak at PRDM9, with rs6889665 the best associated SNP. (B) Relationship between alleles at the rs6889665 and predicted binding target of the PRDM9 zinc finger array for West African and European samples. The alleles are grouped into 8 clusters according to their best-matching region to the 13-bp motif, and annotated by the number of bases matching the motif. The African-enriched rs6889665 “C” allele always co-occurs with motifs with a poor (5/8) match to the 13-mer. (C) Gene tree³² of the LD block containing the PRDM9 ZF array (Methods); numbered circles show SNPs and significant P-values for association, after conditioning on rs6889665.

Figure 3

A sequence motif specifying the positions of African-enriched hotspots. (A) Logo plot showing a degenerate 17-bp hotspot motif, with stack height proportional to -log P-value, and relative letter height proportional to the mean crossover rate increase given each base. Below is the bioinformatic PRDM9 binding prediction for the rs6889665 AE associated alleles (from Figure 2B), matching the motif at 10/11 bases (lines). (B) Average crossover rate (in 2 kb sliding windows) in the AA (red line) and deCODE (black line) maps surrounding the 500 strongest motif matches. (C) In seven rs6889665 “CC” individuals from the pedigree study, we localized 82 crossovers to within 10 kb, and plot average AA, YRI, deCODE and CEU map rates. There is no strong peak above local background in the deCODE or CEU maps.