Prospects of studying animal life histories to identify undetected genetic defects: the example of BLIRD
Résumé
Due to their limited effective size and intense selection, cattle breeds are experiencing a gradual increase in inbreeding, which favors the emergence of recessive defects. While a few of these are highly visible, many remain overlooked due to the lack of specific signs. With the tremendous development of genomic selection and genotyping, new methods have been proposed to detect these defects. Here, we performed a screen for homozygous haplotype enrichment or depletion in groups of females with different life histories. After validation of the results in at-risk versus control mating, 33 new deleterious haplotypes were identified with frequencies ranging from 1.5 to 7.6% in Holstein, Montbeliarde and Normande dairy cows. Profiles of survival curves and causes of mortality varied between loci. Candidate causal variants were identified for ten haplotypes after analysis of large datasets of whole genome sequences. In particular, we highlighted a deleterious point mutation of ITGB7 (p.G375S) which occurred in 1983, and since then reached a frequency of 4.8% in the French Holstein population. After performing a series of validations based on large-scale genotyping, clinical examination, and functional studies, we demonstrated that this variant affects the contact site between the two integrins ITGA4 and ITGB7. We observed an expression default of the α4β7 intestinal homing receptor on the surface of T lymphocytes, causing a newly described disease we named BLIRD for Bovine Lymphocyte Intestinal Retention Defect. With a 25-30% reduction in daily gain, high juvenile mortality rates, and premature culling of surviving homozygotes during the first lactation, BLIRD has a dramatic impact on the dairy industry. In conclusion, we propose an innovative strategy to detect deleterious recessive loci that remained overlooked by previous approaches. Taken as a whole, the dozen of loci validated within each breed is responsible for the death of 0.5 to 1% of the dairy females born each year in France. The management of all these new defects in selection will contribute to improve both animal welfare and the income of breeders.