Evolutionary history of sickle-cell mutation: implications for global genetic medicine

Abstract

Resistance afforded by the sickle-cell trait against severe malaria has led to high frequencies of the sickle-cell mutation [HBB; c.20 T > A, p.Glu6Val; OMIM: 141900 (HBB-βS)] in most parts of Africa. High-coverage sequencing and genotype data have now confirmed the single African origin of the sickle-cell gene variant [HBB; c.20 T > A, p.Glu6Val; OMIM: 141900 (HBB-βS)]. Nevertheless, the classical HBB-like genes cluster haplotypes remain a rich source of HBB-βS evolutionary information. The overlapping distribution of HBB-βS and other disease-associated variants means that their evolutionary genetics must be investigated concurrently. In this review: 1) we explore the evolutionary history of HBB-βS and its implications in understanding human migration within and out of Africa: e.g. HBB haplotypes and recent migration paths of the Bantu expansion, occurrence of ~ 7% of the Senegal haplotype in Angola reflecting changes in population/SCD dynamics, and existence of all five classical HBB haplotype in Cameroon and Egypt suggesting a much longer presence of HBB-βS in these regions; 2) we discuss the time estimates of the emergence of HBB-βS in Africa; and finally, 3) we discuss implications for genetic medicine in understanding complex epistatic interactions between HBB-βS and other gene variants selected under environmental pressure in Africa e.g. variants in HBB, HBA, G6PD, APOL, APOE, OSBPL10, RXRA.

Child mortality from sickle cell disease in Nigeria: a model-estimated, population-level analysis of data from the 2018 Demographic and Health Survey

“…Additionally, the DHS did not test for other conditions related to sickle cell disease such as beta thalassaemia, important modifiers of disease such as the proportion of fetal haemoglobin, or the presence of other gene variants. 2 , 25 Our assumption of Hardy-Weinberg equilibrium ignores the possibility of high consanguinity, which could increase the prevalence of sickle cell disease. 18 The potential survival advantage of children with sickle trait ( HbAS ) where the malaria burden is high 2 could elevate the observed prevalence of the S allele and lead to an overestimation of the expected prevalence of HbSS .…”

Confronting Racism in All Forms of Pain Research: Reframing Study Designs

“…A Eurocentric biomedical metanarrative often occurs, which conflates the heredity of SCD that is based on genetic ancestry with racialized identity to explain SCD as a condition that "affects Black people" and has been used by some to argue the existence of biological races. An antiracism reframe using a biopsychosocial metanarrative separates racialized identity from ancestry to understand that sickle cell trait served as a protective function in areas where malaria is endemic (e.g., sub-Saharan Africa, India) 25,35 and that people from these regions are racialized in WEIRD countries or experience colorism in the Global South. In WEIRD countries, individuals with SCD who are racialized as Black face the burden of a history of colonization, enslavement, and/or segregation with ongoing social practices that limit access to healthcare, impact psychological wellbeing, and maintain disparities 36,44,106 .…”

Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program

“…Both variants are maintained at relatively high frequencies among populations such as those in sub-Saharan Africa, where malaria is endemic, but the geographic and population distributions and evolutionary histories of the rs334 hemoglobin S and rs33930165 hemoglobin C variant alleles are distinct. 46,47 To further address the mechanism of the associations at HBB, we first assessed the relationship between rs334 and other potential immune-response-related genes in the genomic region. Although there are several type 1 interferon-inducible viral-related genes located about 400 kb centromeric to HBB on chromosome 11, we found no evidence of physical interaction between HBB and these neighboring genes when we used available promoter capture datasets in relevant blood cell types (with the HUGIN tool) nor any evidence of influence of rs334 on gene expression (eQTL) in whole blood when we used GTEx v8.…”