Science1 publisher3 min readPublished
Explaining the older-sister effect on male sexual orientation would need 37 to 58% of eggs miscarried
Michel Raymond's team modelled whether unrecorded losses of male embryos could produce the pattern seen in eight populations, and the share of fertilised eggs the model demands sits well above the rate clinics record.
The Scientist · Science desk

What happened
- A modelling study proposes that a man's older sisters stand in for his mother's earlier pregnancies, some of which may have ended in miscarriages of male embryos that were never recorded.
- The team calculated that between 37 and 58 per cent of fertilised eggs would have to be miscarried for that route to fully account for the older-sister association.
- The proposed biology has repeat male pregnancies strengthening a maternal antibody response to male proteins involved in fetal brain development, with those antibodies possibly reaching a male fetus's brain.
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Why it matters
- constraint No antibody was measured here, so landing inside the range of the possible leaves the maternal immune hypothesis where it was; Raymond said it is not currently possible to decide whether it is correct.
- contradiction Kabatek's suggestion that the antibody target need not be sex specific would take the explanation off the Y chromosome, and with it the NLGN4Y antibody evidence that the male-protein version rests on.
- decision Anyone wanting to test the idea now has to fund measurement of losses that happen before a pregnancy is known, because sibling counts alone cannot reach the denominator the model uses.
The two numbers this study puts next to each other are not measured the same way. The model's requirement, 37 to 58 per cent, is a share of fertilised eggs [12]. The figure usually quoted for the United States, 10 to 20 per cent, is a share of known pregnancies [14]. Set the bounds against each other and the model asks for between about 1.9 and 5.8 times the clinical rate [1]. Eggs that fertilise and never implant fall inside the study's denominator and outside the clinic's. Raymond said there is "huge variation, depending on what you consider a miscarriage" [15], and some losses happen before a woman knows she is pregnant [16].
The model asks only whether miscarriage on its own could generate an older-sister effect of the size eight populations show [3][9]. No antibody was measured. "However, it is also possible that the maternal immune hypothesis is not correct, and at this stage, it is not possible to decide," Raymond said [19]. He also said the work "shows that miscarriage is potentially an important phenomenon to take into account" [18]. The eight datasets did not routinely record whether the participating mothers included trans men and non-binary people [13].
The model gives every woman the same probability of miscarriage at every pregnancy [7], and Raymond said real risk probably varies between women even once age is accounted for [8]. If some women miscarry rarely, a run of older daughters may indicate a mother whose pregnancies mostly survived, which is the reverse of what the proxy needs.
Ray Blanchard at the University of Toronto, who had also proposed that older sisters stand in for miscarried male pregnancies, told New Scientist the study supports his idea [20]. "It could have come up with results saying that my hypothesis was basically very unlikely, but it came up with results indicating that, while my hypothesis may not 100 per cent account for the effect of older sisters, we're within the realm of what is possible," he said [21].
A 2017 study found that mothers of gay sons with older brothers had higher levels of antibodies against NLGN4Y, a Y-chromosome-linked protein involved in brain development, than mothers of heterosexual sons [23]. Elena Jazin at Uppsala University has documented NLGN4Y expression in human embryos of 8 to 11 weeks and says expression probably begins earlier [24]. How far a pregnancy has to progress before it can sensitise the mother is unresolved [22].
Jan Kabátek at the University of Melbourne has found that older siblings raise a woman's odds of entering a same-sex union, which a response to male-specific proteins does not readily explain [25]. Kabátek says the target could be proteins that are not sex specific [26]. That version would move the hypothesis off the Y chromosome and away from NLGN4Y. Identical twins share a sexual orientation more often than fraternal twins, which points to a genetic contribution as well [27].
Each additional older sister is linked to about a 20 per cent rise in the odds of a man being gay, roughly two-thirds the size of the 30 per cent associated with each older brother [2]. Raymond said of the miscarriage explanation: "It's nothing more than a possibility right now" [6].
What to watch
- Whether anyone measures pre-implantation and very early pregnancy loss in the same cohorts that collect sibling data, putting both numbers on one denominator.
- A version of the model that lets miscarriage risk vary between women, which Raymond says reflects reality better than the equal-risk assumption.
- Whether the NLGN4Y antibody result replicates in mothers whose gay sons have older sisters but no older brothers.