Cataloging Human Allelic Variation Using Long-Read Sequencing Reveals Population Specificity and Two Distinct Groupings of Related Alleles.

The PRDM9 protein determines sites of meiotic recombination in humans by directing meiotic DNA double-strand breaks to specific loci. Targeting specificity is encoded by a long array of CH zinc fingers that bind to DNA. This zinc finger array is hypervariable, and the resulting alleles each have a potentially different DNA binding preference. The assessment of diversity is important for understanding the complexity of human population genetics, inheritance linkage patterns, and predisposition to genetic disease. Due to the repetitive nature of the zinc finger array, the large-scale sequencing of human is challenging. We, therefore, developed a long-read sequencing strategy to infer the diploid zinc finger array genotype in a high-throughput manner. From an unbiased study of allelic diversity in 720 individuals from seven human populations, we detected 69 alleles. Several alleles differ in frequency among human populations, and 32 alleles had not been identified by previous studies, which were heavily biased to European populations. alleles are distinguished by their DNA binding site preferences and fall into two major categories related to the most common and alleles. We also found that it is likely that inter-conversion between allele types is rare. By mapping meiotic double-strand breaks (DSBs) in the testis, we found that small variations in can substantially alter the meiotic recombination landscape, demonstrating that minor variants may play an under-appreciated role in shaping patterns of human recombination. In summary, our data greatly expands knowledge of diversity in humans.