Mechanisms of action of major-histocompatibility-complex-linked genes affecting reproduction

PROBLEM: To provide insight into the mechanisms of action of the major-hist ocompatibility-complex (MHC)-linked genes affecting reproduction. METHOD OF STUDY: The data were obtained using a variety of cellular and mol ecular techniques in experimental animals and from population genetic studi es in humans. RESULTS: In the mouse, the preimplantation embryonic development (Ped) locu s, whose functional gene is Q9, regulates fast and slow cleavage of the ear ly embryo. There is also evidence for a growth and reproduction complex (Gr c)-like region from serologic, molecular; and cytogenetic studies. In the h uman, 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 recu rrent spontaneous abortions, gestational trophoblastic tumors, and unexplai ned infertility. Detailed mapping studies showed that the genes responsible are not the HLA genes themselves, but genes closely linked to the HLA-DR-D Q-B genes. The HLA region genes can interact epistatically with the C3 alle le of transferrin to increase the incidence of fetal loss. In the rat, the Gic region, which is closely linked to the MHC, has been associated with em bryonic loss, growth defects, and susceptibility to chemical carcinogens. T he Grc can interact epistatically with the tail anomaly lethal (Tai) gene o r the hood restriction (H-re) gene to enhance these effects. CONCLUSIONS: There are two basic mechanisms for the effects of MHC-linked g enes on reproduction and development: individual gene effects (Ped [Q9], HL A-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-link ed effects, can also provide some insight into the different theories of hu man origins: These effects are most consistent with the monogenic theory.