Major histocompatibility complex (MHC)-linked genes affecting development

Abstract

Genes affecting growth and development which are linked to the major histocompatibility complex have been found in the mouse (t-complex) and in the rat (growth and reproduction complex, grc), and there is some evidence that they also exist in humans. The genes of the t-complex have different effects depending upon the specific combinations involved: skeletal and fertility abnormalities, complete or partial embryonic mortality, high transmission ratios (segregation distortion) in males, high level of linkage disequilibrium with H-2, and suppression of recombination over the adjacent portion of the chromosome. The grc in the homozygous state causes small body size, sterility in the male and reduced fertility in the female, partial embryonic mortality, and a high level of linkage disequilibrium with RT1. It also interacts epistatically with the heterozygous Tal (tail anomaly lethal) gene to cause complete embryonic death. Mice carrying t-haplotypes and rats carrying the grc have an antigen in the male germ cells which cross-reacts very strongly (t-antigen). Suggestive evidence for such genes in humans comes from (1) studies on the relationship between skeletal defects and HLA haplotypes; (2) the association of specific HLA and complement haplotypes with a high transmission ratio in males, linkage disequilibrium among certain HLA and complement specificities and suppression of recombination in some MHC haplotypes; and (3) the lack of homozygotes in an isolated inbreeding population of desert nomads (Kel Kummer Tuaregs). In addition, immunogenetic studies on couples having chronic spontaneous abortions suggest that there is an unusually high incidence of homozygosity for the HLA-D/DR and HLA-A loci in these couples, and this finding is consistent with the presence of linked loci which behave like t or grc.