Male homosexuality has been a long-standing mystery from an evolutionary perspective, one that has spurred many hypotheses.  Ray Blanchard and colleagues have extensively documented previously that the likelihood of homosexuality increases with a man's number of older brothers, and they have suggested that this might be explained by an immune response, but there was no evidence…until now. In an open access PNAS article published online December 11th, he and his group report that mothers of homosexual sons are more likely than other mothers to have  substantially increased levels of antibodies to NLGN4Y, a  Y- chromosome linked protein involved in brain differentiation. If confirmed, this will be a major advance in understanding a factor that can influence sexual orientation. 

The article is open access: Bogaert, A. F., Skorska, M. N., Wang, C., Gabrie, J., MacNeil, A. J., Hoffarth, M. R., … Blanchard, R. (2017). Male homosexuality and maternal immune responsivity to the Y-linked protein NLGN4Y. Proceedings of the National Academy of Sciences, 201705895.

Abstract: We conducted a direct test of an immunological explanation of the finding that gay men have a greater number of older brothers than do heterosexual men. This explanation posits that some mothers develop antibodies against a Y-linked protein important in male brain development, and that this effect becomes increasingly likely with each male gestation, altering brain structures underlying sexual orientation in their later-born sons. Immune assays targeting two Y-linked proteins important in brain development—protocadherin 11 Y-linked (PCDH11Y) and neuroligin 4 Y-linked (NLGN4Y; isoforms 1 and 2)—were developed. Plasma from mothers of sons, about half of whom had a gay son, along with additional controls (women with no sons, men) was analyzed for male protein-specific antibodies. Results indicated women had significantly higher anti-NLGN4Y levels than men. In addition, after statistically controlling for number of pregnancies, mothers of gay sons, particularly those with older brothers, had significantly higher anti-NLGN4Y levels than did the control samples of women, including mothers of heterosexual sons. The results suggest an association between a maternal immune response to NLGN4Y and subsequent sexual orientation in male offspring.