Variations in male sexual orientation: The role of maternal responsivity to male-specific proteins

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The fraternal birth order (FBO) effect—that, on average, gay men have a higher number of older brothers than heterosexual men—is a reliable correlate of men's sexual orientation. This effect is likely to arise before birth, with the most plausible explanation being that during pregnancy a mother develops an immune response to a substance important in male fetal development, an effect that becomes more likely with each male gestation and is thought to cause an alteration in the brain development of some later born males. The target of the response may be protein molecules on the surface of fetal brain cells so that maternal antibodies binding to them alter their role in typical sexual differentiation, leading some later born males to be attracted to men not women. We recently tested this hypothesis by examining whether mothers of gay men, particularly those with previous sons, have an immune reaction (relative to mothers of a heterosexual son) to two proteins, encoded by the Y chromosome, that play a significant role male brain development. We developed immune assays to target these proteins and examined a portion of the blood samples from approximately 130 mothers of sons, about half of whom had a gay son, along with additional control samples (e.g., women without male children). Results showed that mothers of gay sons, particularly those with previous (heterosexual) sons, were significantly more likely to be immune reactive to one of these proteins than mothers of heterosexual sons. Over the next funding period, I will complete a second assay on a part of participants’ blood (Memory B cells) not yet tested. These cells, like antibodies themselves, are a part of the immune system that works in bodily fluids, not within cells. I anticipate that this work will validate our earlier findings. I also plan to examine samples from mothers of boys with other variations in sexual orientation, for example, gender dysphoric boys who, despite being discontent with their biological sex in childhood, will likely grow up gay but not show significant transgenderism as adults. I will also examine these effects in mothers of asexual men, those who do not exhibit attraction to others. That asexual men also have an FBO effect raises the possibility that mechanisms for basic sexual attraction to others are affected by Y-linked proteins and that maternal immunological reactions against the proteins can alter their function in the fetal brain. If our findings prove reliable, they are arguably the most important biological findings in men's sexual orientation in the last 20 years. They not only explain one of the most reliable correlates (FBO) but also provide direct evidence of a specific biological mechanism underlying sexual orientation: a maternal immune response to a Y-linked protein important in male fetal brain development.