De novo rates of a <i>Trypanosoma</i>-resistant mutation in two human populations.

Abstract

Mutation rates have long been measured as averages across many genomic positions. Recently, a method to measure the rates of individual mutations was applied to a narrow region in the human hemoglobin subunit beta (<i>HBB</i>) gene containing the site of the hemoglobin S (HbS) mutation as well as to a paralogous hemoglobin subunit delta (<i>HBD</i>) region, in sperm samples from sub-Saharan African and northern European donors [Melamed <i>et al</i>., <i>Genome Res.</i> <b>32</b>, 488-498 (2022)]. The HbS mutation, which protects against malaria while causing sickle-cell anemia in homozygotes, originated de novo significantly more frequently in the <i>HBB</i> gene in Africans compared to the other three test cases combined (the European <i>HBB</i> gene and the European and African <i>HBD</i> gene). Here, we apply this approach to the human apolipoprotein L1 (<i>APOL1</i>) gene containing the site of the G1 1024A→G mutation, which protects against African sleeping sickness caused by <i>Trypanosoma brucei gambiense</i> while causing a substantially increased risk of chronic kidney disease in homozygotes. We find that the 1024A→G mutation is the mutation of highest de novo origination rate and deviates most from the genome-wide average rate for its type (A→G) compared to all other observable mutations in the region and that it originates de novo significantly more frequently in Africans than in Europeans-i.e., in the population where it is of adaptive significance. The results are unexpected given the notion that the probability of a specific mutational event is independent of its value to the organism and underscore the importance of studying mutation rates at the individual-mutation resolution.