De novomutation rates at the single-mutation resolution in a humanHBBgene-region associated with adaptation and genetic disease

While it is known that the mutation rate varies across the genome, previous estimates were based on averaging across various numbers of positions. Here we describe a method to measure the origination rates of target mutations at target base positions and apply it to a 6-bp region in the humanβ-globin (HBB) gene and to the identical, homologousδ-globin (HBD) region in sperm cells from both African and European donors. TheHBBregion of interest (ROI) includes the site of the hemoglobin S (HbS) mutation, which protects against malaria, is common in Africa and has served as a classic example of adaptation by random mutation and natural selection. We found a significant correspondence betweende novomutation rates and past observations of alleles in carriers, showing that mutation rates vary substantially in a mutation-specific manner that contributes to the site frequency spectrum. We also found that the overall point mutation rate is significantly higher in Africans than Europeans in theHBBregion studied. Finally, the rate of the 20A→T mutation, called the “HbS mutation” when it appears inHBB, is significantly higher than expected from the genome-wide average for this mutation type. Nine instances were observed in the AfricanHBBROI, where it is of adaptive significance, representing at least three independent originations, and no instances were observed in the EuropeanHBBROI or in the European or AfricanHBDROI. Further studies will be needed to examinede novomutation rates at the single-mutation resolution across these and other loci and organisms and to uncover the molecular mechanisms responsible.