Fine mapping highlights ITGAL and MUS81 loss-of-function mutations modulating recessive impacts in dairy cattle

We recently described several major-effect recessive loci impacting
anatomical and lactation traits in dairy cattle. Two of these loci in
particular presented multiple candidate causative variants, comprising
tightly linked coding variants that could not be easily differentiated on
a statistical or functional basis. Here, we re-examine the candidacy of
these variants by leveraging a dataset of 1 million genotyped animals.
Assessing lactation and bodyweight effects in conjunction with rare,
recombined genotypes for the IL4R, KIAA0556, ITGAL, DPF2, and MUS81
candidates, we highlight ITGAL and MUS81 as the most likely causative
genes for the two QTL. Recombinant homozygotes for these genes present
larger, more significant effects than other candidates at the same loci,
with both representing premature stop mutations anticipated to inactivate
ITGAL and MUS81. We further examined homozygotes for the ITGAL mutation to
better understand the range of phenotypes impacted. While outwardly
normal, ITGAL mutants showed significant differences in the number and
composition of circulating leukocytes, consistent with the role of ITGAL
as a key mediator of leukocyte signalling, adhesion, and migration. These
results demonstrate how near-perfectly linked candidate mutations can be
differentiated given population-scale data, and highlight the ITGAL and
MUS81 mutations as diagnostic targets to help manage the frequency of
these variants.