The brachyspina syndrome under the spotlight

Carole Charlier and her colleagues are working on a set of recessive diseases in cattle. The object of their research is to identify the genes and mutations that cause these diseases in order to develop genetic tests which make it possible to identify individuals that carry these mutations and therefore avoid risky crossings (see: Domestic animals, the new Eldorado for geneticists). She continues, “We were engaged in a standard study of a recessive disease and that work led us to the discovery of an effect on the fertility of Holstein-Friesian cattle. We were trying to identify the gene and mutation responsible for the brachyspina syndrome, an extremely rare syndrome which is observed, almost anecdotally, in the calves of this breed. The few recorded cases of this congenital disease, described in 2006 by our Danish collaborators, involve stillborn calves which present a series of defects. The principal defect and the one that gives its name to this syndrome, is a deformed and shortened spine. Other defects involve the internal organs, limbs, ribs etc. The symptoms observed in the Holstein-Friesian calves are very similar to those observed in the Fanconi Anemia condition in humans which is the human equivalent of this disease”.

By taking advantage of next-generation high-throughput DNA sequencing technologies which are  accessible through the GIGA-Genotranscriptomics platform (directed by Wouter Coppieters), the research by the team from Liege led them to the  FANCI gene which is a well-studied gene that is well-known for its key role in the repair mechanisms of DNA. “It is part of an entire complex which is essential for correcting errors that occur in the genome and develops in the same way as an entire series of genes that are involved in human cancers”, continues the researcher. More precisely, her team has succeeded in showing that the mutation causing the brachyspina syndrome in the Holstein-Friesian breed is a 3.3 kb deletion in this gene.

A rare recessive disease that is not so rare in fact

Once the causal mutation was identified, the researchers, principally Wanbo Li, conducted a population study based on their discovery. There was great surprise when the results of this study showed that more than 7% of the animals were carriers of this mutation in the Hosltein-Friesian breed! “As it is one of the most popular dairy cows in the world, we should have observed many more cases of sick animals at birth”, the researcher points out. To reconcile these two seemingly contradictory observations, the scientists postulated that individuals that carried two copies of the mutation would die during gestation. Carole Charlier continues, “thanks to quantitative data on the fertility of deletion carrier and non-carrier bulls in the FANCI gene, we have been able to confirm this hypothesis”. Thus a large majority of homozygous mutant calves (both of whose parents were carriers) die at the embryonic stage which results in a significant reduction in crossings involving two carrier parents.