In search of the genetic variants of human sex ratio at birth: Was Fisher wrong about sex ratio evolution?

The human sex ratio (fraction of males) at birth is close to 0.5 at the
population level, an observation commonly explained by Fisher's
principle. However, past human studies yielded conflicting results
regarding the existence of sex ratio-influencing mutations-a prerequisite
to Fisher’s principle, raising the question of whether the nearly even
population sex ratio is instead dictated by the random X/Y chromosome
segregation in male meiosis. Here we show that, because a person’s
offspring sex ratio (OSR) has an enormous measurement error, a gigantic
sample is required to detect OSR-influencing genetic variants. Conducting
a UK Biobank-based genome-wide association study that is more powerful
than previous studies, we detect an OSR-associated genetic variant, which
awaits verification in independent samples. Given the abysmal precision in
measuring OSR, it is unsurprising that the estimated heritability of OSR
is effectively zero. We further show that OSR’s estimated heritability
would remain virtually zero even if OSR is as genetically variable as the
highly heritable human standing height. These analyses, along with
simulations of human sex ratio evolution under selection, demonstrate the
compatibility of the observed genetic architecture of human OSR with
Fisher’s principle and suggest the plausibility of presence of multiple
human OSR-influencing genetic variants.