Sickle Cell Anemia: Whole-genome-sequencing (WGS)-based haplotypes reveal a single origin of the mutation in the HBB gene — 7,300 years ago (259 generations)

There are ten hemoglobin subunit genes in the human genome: HBA1, HBA2, HBB, HBD, HBE1, HBG1, HBG2, HBM, HBQ1 and HBZ. One of the original heritable diseases presented in early genetics textbooks is sickle cell anemia. There are several hereditary variants in the HB genes that are known to afford protection against malaria caused by the mosquito Plasmodium falciparum and recessive lethality. Many such mutants are thought to have evolved in the last 10,000 years. Once the mutation(s) had occurred, a heterozygote (i.e. someone having one mutated allele, and one normal, or consensus, allele) was protected against mosquito-borne malaria –– which is clearly would be a selective advantage for survival to reproduction age in tropical Africa. Unfortunately for the homozygote (i.e. someone having two mutated alleles, and no normal alleles) this autosomal recessive trait leads to a serious anemia and (before modern treatments) was usually fatal during childhood. Hence, this is an excellent “gene-environment interactions” topic to share in these GEITP pages.

In the beta-globin gene (HBB), the sickle bS allele is therefore under a balancing selection because of this “heterozygote advantage.” There are five haplotypes (groups of genes that are inherited together on one chromosome from a single parent) –– Arabian/Indian, Benin, Cameroon, CAR, and Senegal, named after ethno-linguistic groups, or geographic regions –– as well as a sixth category for ‘‘atypical’’ haplotypes. Whether the bS allele has a recent, or an old, origin has been debated since 1978. According to the multi-centric model, the origin of the bS allele is recent, i.e. within the last few thousand years; and each haplotype represents an independent occurrence of the same exact mutation in different corresponding geographic regions. In contrast, according to the unicentric model, the origin of the bS allele is anywhere from tens to hundreds of thousands of years old, and the mutation only occurred once.

In this really REALLY cool study [see attached], authors investigated the origins of the bS allele, by using WGS data from a total of 2,932 individuals from the 1000 Genomes Project, the African Genome Variation Project, and Qatar. They identified a total of 156 bS allele carriers (heterozygotes). Their study yielded a bS allele mutation age of 259 generations –– corresponding to 7,300 years ago during “the Holocene Wet Phase” (also called “Green Sahara”; a good time for increased mosquito infestation)..!! These data clarify the origin of the sickle allele as being consistent with the UNICENTRIC MODEL and should improve and simplify the classification of all sickle haplotypes in the future.

Am J Hum Genet 5 April 2o18; 102: 547–556

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