De novo rates of a Trypanosoma-resistant mutation in two human populations

• 成果类型: Article
• 署名作者: Melamed, Daniel; Shemer, Revital; Bolotin, Evgeni; Yakass, Michael B.; Fink-Barkai, Dorit; Hiadzi, Edem K.; Skorecki, Karl L.; Livnat, Adi
• 署名单位: University of Haifa; University of Haifa; Technion Israel Institute of Technology; Rappaport Faculty of Medicine; Technion Israel Institute of Technology; University of Ghana; Bar Ilan University; Rambam Health Care Campus
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14251
• DOI: 10.1073/pnas.2424538122
• 发表日期: 2025-09-02
• 关键词: reduction principle; kidney-disease; EVOLUTION; gene; apol1; patterns; variants; genome; origin; dna

摘要

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 (HBB) gene containing the site of the hemoglobin S (HbS) mutation as well as to a paralogous hemoglobin subunit delta (HBD) region, in sperm samples from sub-Saharan African and northern European donors [Melamed etal., Genome Res. 32, 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 HBB gene in Africans compared to the other three test cases combined (the European HBB gene and the European and African HBD gene). Here, we apply this approach to the human apolipoprotein L1 (APOL1) gene containing the site of the G1 1024A-G mutation, which protects against African sleeping sickness caused by Trypanosoma bruceigambiense 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.