Current perspectives on the intensity of natural selection of MHC loci

Polymorphism of genes in the major histocompatibility complex (MHC) is believed to be maintained by balancing selection. However, direct evidence of selection has proven difficult to demonstrate. In 1994, Satta and colleagues estimated the selection intensity of the human MHC (human leukocyte antigen (HLA)) loci; however, at that time the number of HLA sequences was limited. By comparing five different methods, this study demonstrated the best way to calculate the selection coefficient, through a computer simulation study. Since the study, many HLA nucleotide sequences have been made available. Our new analysis takes advantage of these newly available sequences and compares new estimates with those of the previous study. Generally, our new results are consistent with those of the 1994 study. Our results show that, even after 20 years of exhaustive sequencing of human HLA, the number of dominant HLA alleles, on which our original estimate of selection intensity depended, appears to be conserved. Indeed, according to the frequency distribution for each HLA allele, most sequences in the database were minor or private alleles; therefore, we conclude that the selection intensities of HLA loci are at most 4.4 % even though the HLA is the prominent example on which the natural selection has been operating.