HLA-H: A pseudogene with increased variation due to balancing selection atneighboring loci

The HLA complex includes the most polymorphic genes in the human genome. Ho wever, the HLA class Ib loci have little, if any, nucleotide variation, pre sumably due to their specialized functions or perhaps due to a lack of func tion. This population genetic study of HLA-H, a class I pseudogene, was ini tiated to determine the pattern of variation at neutral sites within the HL A complex. We found that the pattern of variation for HLA-H is consistent w ith the neutral model. However, the amount of variation in HLA-H is signifi cantly greater than estimates for other silent sites within the human genom e outside of the MHC (theta = 0.0144, P < 0.000001). Our study further indi cates that other possible causes of increased variation such as a high muta tion rate for HLA-H, interlocus gene conversion, increased diversity in the sample population in general, and selection acting directly on HLA-H are u nlikely. Instead, these data suggest that HLA-H has increased variation as a result of balancing selection acting on nearby loci such as HLA-A.