Biology subjects

Hiadzi, E. K.

Publications and source records attributed to Hiadzi, E. K..

2 recordsLinked to original sources

bioRxiv2024

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

Until recently, mutation rates have only been measured as averages across many genomic positions. Recently, a method to measure mutation rates at the single-mutation resolution 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. 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 apolipopro-tein L1 (APOL1) gene containing the site of the G1 1024A[->]G mutation, which protects against African sleeping sickness caused by Trypanosoma brucei gambiense while causing a substantially increased risk of chronic kidney disease (CKD) 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 inconsistent with 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 single-mutation resolution.

evolutionary biology↗

bioRxiv2021

De novo mutation rates at the single-mutation resolution in a human HBB gene-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 human {beta}-globin (HBB) gene and to the identical, homologous{delta} -globin (HBD) region in sperm cells from both African and European donors. The HBB region 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 between de novo mutation 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 the HBB region studied. Finally, the rate of the 20A[->]T mutation, called the "HbS mutation" when it appears in HBB, is significantly higher than expected from the genome-wide average for this mutation type. Nine instances were observed in the African HBB ROI, where it is of adaptive significance, representing at least three independent originations, and no instances were observed in the European HBB ROI or in the European or African HBD ROI. Further studies will be needed to examine de novo mutation rates at the single-mutation resolution across these and other loci and organisms and to uncover the molecular mechanisms responsible.

evolutionary biology↗