Data science for cattle health: innovative method reveals 33 previously invisible genetic anomalies

Cattle breeding is a key sector of French agriculture, supported by a solid network of breeders, field operators (breeding advice, selection), veterinarians and researchers. Genetic improvement is one of the levers of economic and environmental efficiency in breeding. It aims to identify and then distribute the most promising breeding stock for each breed, particularly in terms of animal health.

Mutations are a natural phenomenon in all living beings, and can generate genetic anomalies. These usually go unnoticed, as they are carried by only one of the two homologous chromosomes. However, when an individual is homozygous (i.e. carries two abnormal copies of the same gene), they can express themselves and affect health. This phenomenon, which occurs following mating between individuals distantly related to the same ancestor, can be encouraged by the widespread distribution of certain breeding stock carrying the mutation.

Faced with this challenge, France was one of the first countries to set up a surveillance network called the Observatoire National des Anomalies Bovines in 2002 (www.onab.fr), whose role is to collect reports and biological samples of abnormal calves, encourage research and inform professionals. However, this strategy relies on the observation of distinctive clinical signs, and cannot identify mutations responsible for immune or metabolic disorders whose manifestations may be confused with diseases of environmental origin (caused by pathogens or inadequate feeding, for example).

The HHED (Homozygous Haplotype Enrichment/Depletion) method applied to the 3 main French dairy breeds (Holstein, Montbéliarde and Normande) has made it possible to detect 33 new regions of the genome linked to excess juvenile mortality and/or reduced productive life in female cattle carrying two abnormal copies of the same gene.

Candidate mutations have been identified for 8 of these genomic regions, and 3 have been subjected to detailed analysis to understand the underlying biological causes. One of the major discoveries is the description of BLIRD (Bovine Leucocyte Intestine Retention Defect) syndrome in Holsteins, caused by a mutation in the gene synthesizing integrin beta 7 (ITGB7), a cell adhesion protein essential for intestinal immunity.

The fact that this genetic anomaly had previously gone undetected, despite having existed for at least 40 years in this, the world's most numerous and best-studied cattle breed, illustrates the power of this new approach.

Since the French team's preliminary results were presented at WCGALP (World Congress on Genetics Applied to Livestock Production) in 2022, other European, American and Australian research teams have confirmed the deleterious effects of BLIRD syndrome on the survival, growth and dairy performance of affected females.

In France, it is estimated that every year 29,000 calves are born homozygous for at least one of the 33 genomic regions associated with excess juvenile mortality detected thanks to this study, generating costs of several million euros. The characterization and progressive counter-selection of the mutations responsible for these anomalies, by tracing them in populations, should improve the health and sustainability of cattle farms.

The initial study involved the analysis of 50,000 genetic markers tagging the bovine genome, information on which was available for over 500,000 individuals and their ancestors thanks to the genomic evaluations routinely carried out for the improvement of these breeds.

The HHED method identifies regions of the genome where there is an excess of homozygotes in heifers that die naturally before adulthood. At the same time, these same regions are less frequent in adult dairy cows than would be expected based on the genetic heritage of their ancestors. This helps to identify genetic anomalies potentially responsible for excess juvenile mortality.

The effects of these regions have been validated and clarified by analyzing performance for numerous traits of interest and the life history of a validation population comprising 8.8 million cattle. Candidate mutations for these regions were identified by analyzing the genomes of 1,869 animals, including the most influential sires of 70 cattle breeds. Finally, the addition of these candidate mutations to the genetic markers taken into account for the genomic evaluations of these breeds facilitated the recruitment of homozygous carrier calves and non-carrier calves, which made it possible to finely describe the pathological consequences of the genetic anomalies detected, after comparing their phenotypic characteristics.

Reference

Besnard F. et al. (2024). Massive detection of cryptic recessive genetic defects in dairy cattle mining millions of life histories. Genome Biology, DOI : https://doi.org/10.1186/s13059-024-03384-7