H-Y antigen

H-Y antigen is a male tissue specific antigen.^[1] Originally thought to trigger the formation of testes (via loci, an autosomal gene that generates the antigen and one that generates the receptor)^[2] it is now known that it does not trigger the formation of testes but may be activated by the formation of testes.^[3]

There are several antigens which qualify as H-Y as defined by rejection of male skin grafts in female hosts or detected by cytotoxic T cells or antibodies. One H-Y, secreted by the testis, defined by antibodies, is identical to Müllerian-inhibiting substance (AMH gene).^[1] Another H-Y, minor histocompatibility antigen, seemed to be encoded in the SMCY gene (acronym for 'selected mouse cDNA on Y'), later identified as an 11-residue peptide from the Lysine-Specific Demethylase 5D protein (KDM5D gene) presented by HLA-B7. A third example is MEA1.

It has been shown that male mice lacking in the H-Y antigen, hence lacking in the gene producing it, have also lost genetic information responsible for spermatogenesis.^[4] This result also identified a gene on the mouse Y chromosome, distinct from the testis-determining gene, that was essential for spermatogenesis, thus raising the possibility that the very product of this "spermatogenesis gene" is the H-Y antigen.^[4]

Among humans, it has been observed that men with more older brothers tend to have a higher chance of being homosexual (see Fraternal birth order and male sexual orientation). For every additional older brother, a man's chance of being homosexual can rise by up to 33%.^[5] One theory to explain this involves H-Y antigens, which suggests that a maternal immune reaction to these antigens has, to an extent, an inhibitory effect on the masculinization of the brain, and therefore, the more male foetuses that the mother of a man has had, the greater the maternal immune response towards him^[6] and thus the greater the inhibitory effect on brain masculinization, which is believed to be a factor in sexual orientation.^[5]

This hypothesis is supported by evidence that older sisters have no discernible influence on the sexual orientation of later-born males, which would be expected since H-Y antigen is male tissue specific, the 'probable involvement of H-Y antigen in the development of sex-typical traits, and the detrimental effects of immunization of female mice to H-Y antigen on the reproductive performance of subsequent male offspring'.^[7] More specifically, recent research (Jan 2018) has found maternal antibodies to the neuroligin NLGN4Y protein, a Y-chromosome protein important in male fetal brain development, to be involved in the fraternal birth order effect.^[8]