Problem: To provide insight into the mechanisms of action of the major-histocompatibility-complex (MHC)-linked genes affecting reproduction.
Method of study: The data were obtained using a variety of cellular and molecular techniques in experimental animals and from population genetic studies in humans.
Results: In the mouse, the preimplantation embryonic development (Ped) locus, whose functional gene is Q9, regulates fast and slow cleavage of the early embryo. There is also evidence for a growth and reproduction complex (Grc)-like region from serologic, molecular, and cytogenetic studies. In the human, the human leukocyte antigen (HLA)-G gene has been associated with an increased rate of embryonic cleavage in those embryos that express the HLA-G antigen. Sharing of HLA antigens in couples has been associated with recurrent spontaneous abortions, gestational trophoblastic tumors, and unexplained infertility. Detailed mapping studies showed that the genes responsible are not the HLA genes themselves, but genes closely linked to the HLA-DR-DQ-B genes. The HLA region genes can interact epistatically with the C3 allele of transferrin to increase the incidence of fetal loss. In the rat, the Grc region, which is closely linked to the MHC, has been associated with embryonic loss, growth defects, and susceptibility to chemical carcinogens. The Grc can interact epistatically with the tail anomaly lethal (Tal) gene or the hood restriction (Hre) gene to enhance these effects.
Conclusions: There are two basic mechanisms for the effects of MHC-linked genes on reproduction and development: individual gene effects (Ped [Q9], HLA-G) and extended genetic effects (MHC-linked genes in the rat [Grc] and in the human). The nature of these genetic effects, particularly the MHC-linked effects, can also provide some insight into the different theories of human origins: These effects are most consistent with the monogenic theory.