Evidence of gene conversion in the evolutionary process of the codon 41/42 (-CTTT) mutation causing beta-thalassemia in southern China.
The 4-bp deletion (-CTTT) at codon 41/42 (CD41/42) of the human beta-globin gene represents one of the most common beta-thalassemia mutations in East Asia and Southeast Asia, which is historically afflicted with endemic malaria, thus hypothetically evolving under natural selection by malaria infection. To understand the evolutionary process of generating the beta(CD41/42) allele and its maintenance, including the effect of natural selection on the pattern of linkage disequilibrium (LD), we sequenced a 15.933-kb region spanning 20.693 kb of the beta-globin cluster surrounding the 4-bp deletion using a sample from a Chinese population consisting of 24 normal individuals and 16 heterozygotes for the deletion. Forty-nine polymorphic sites were found. Analysis of the data, using a variety of methods including formal population genetics analysis and visual approaches, suggests that the spread of the CD41/42 (-CTTT) deletion is most likely mediated by interallelic gene conversion, although independent deletions in different lineages are also possible. The neutrality test resulted in a significant positive Tajima's D for the beta-globin locus, which is consistent with the existence of balancing selection. This suggests that the 4-bp deletion that occurred at this locus may be an event that is subject to natural selection, due to malaria, which leads to the heterozygote advantage, spread widely with further help by conversion and migration. The evolutionary process of this mutant through gene conversion that could conceivably take place between the 4-bp deletion and the normal sequence in the respective region is discussed in detail.
Zhang
Wen
W
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
Cai
Wang-Wei
WW
Zhou
Wei-Ping
WP
Li
Hai-Peng
HP
Li
Liang
L
Yan
Wei
W
Deng
Qin-Kai
QK
Zhang
Ya-Ping
YP
Fu
Yun-Xin
YX
Xu
Xiang-Min
XM
D001483:Base Sequence; D002681:China; D003062:Codon / Q000235:genetics*; D004252:DNA Mutational Analysis; D019143:Evolution, Molecular; D005785:Gene Conversion / Q000235:genetics*; D014644:Genetic Variation; D005914:Globins / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D011110:Polymorphism, Genetic; D017384:Sequence Deletion; D017086:beta-Thalassemia / Q000235:genetics*
D003062:Codon; D005914:Globins