Jim Wilson seminar

Place: Genopode Auditorium B

Time: 16h00, 17 May

Title: The Scope and Mechanism of Inbreeding Depression in Humans

Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is rare in many cultures and frequently associated with confounding social factors. Moreover, it is not certain which of the classical rival theories of dominance or overdominance (heterozygote advantage) is the principal mechanism underlying these effects. Here, using genomic inbreeding coefficients (FROH) for >1.3 million individuals, we show that FROH is significantly associated (P < 0.0005) with changes in 31 of 101 complex traits analysed. An increase in FROH is associated with reduced reproductive success (ever having children, age at first birth, age at first sex, number of sexual partners), as well as reduced alcohol intake, likelihood of ever-smoking and self-reported risk taking, and increases in disease risk factors (including heart rate and lymphocyte percentage). The resultant effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% increase [95% CI 44-66%] in the odds of remaining childless. These effects are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants causing inbreeding depression are rare, consistent with the dominance hypothesis. Moreover, for a subset of traits, the effect of FROH differs significantly between men and women. Indeed, increasing FROH significantly decreases total and LDL cholesterol in men, and is thus cardio-protective in this regard. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in genomic inbreeding is independent of environmental confounding. The fact that autozygosity caused by inbreeding influences a broad range of human phenotypes, some positively, others negatively, suggests a complex history of selection.