Non-additive association analysis using proxy phenotypes identifies novel cattle sydromes

Mammalian species carry ~100 loss-of-function variants per individual, where ~1-5 of these impact essential genes and cause embryonic lethality or severe disease when homozygous. The functions of the remainder are more difficult to resolve, though are assumed to impact fitness in less manifest ways.  Here, we present data behind one of the largest sequence-resolution screens of cattle to date, targeting discovery and validation of non-additive effects in 130,725 animals. We highlight six novel recessive loci with impacts generally exceeding the largest effect variants identified from additive GWAS, presenting analogues of human diseases and hitherto unrecognised disorders. These loci present compelling missense (PLCD4, MTRF1, DPF2), premature stop (MUS81), and splice-disrupting mutations (GALNT2, FGD4), together explaining substantial proportions of inbreeding depression. These results demonstrate that the frequency distribution of deleterious alleles segregating in selected species c...