High frequencies of alleles MICA*020 and MICA*027 in Amerindians and evidence of positive selection on exon 3.

MICA is a nonclassical polymorphic MHC molecule. We investigated MICA allelic frequencies and MICA-HLA-B-HLA-C haplotypes in Brazilian Amerindians to describe the polymorphism and to extract information about the evolution of MICA gene. Kaingang is the first population described to have a high frequency of MICA*020, found associated with HLA-B*3505-HLA-Cw*0401. Allele MICA*020 probably originated de novo in South America. The Guarani population had high frequencies of MICA*027. Allele MICA*00801 is common worldwide but rare among Amerindians, occurring only because of gene flow. The analysis of the 64 described MICA alleles revealed that in exons 2 and 4, synonymous substitutions are in excess, a result compatible with purifying selection. The opposite was observed for exons 3 and 6 and the excess of nonsynonymous substitutions was significant for exon 3, indicating positive selection. Few of the alleles described so far had exon 6 sequenced, impeding conclusions for the corresponding portion of the molecule. The analysis of the entire gene is required for a better understanding of the evolution of MICA's polymorphism and its functional consequences. This knowledge is of prime importance in view of the increasing awareness of the functional and medical implications of MICA gene variability.