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In men, the clinical description of the molecular study of rare diseases is often difficult due to the low number of patients concerned and difficulties in developping animal models for the most severe dominant genetic disorders. Conversely, the structure of bovine populations and the quantities of phenotypic and genomic data available in this species allows the rapid identification of causal mutations and the study of their effects on large cohorts of affected animals.

An international team led by the Inra, in partnership with ALLICE, the CEA and VetAgroSup, by using a few examples, illustrates the numerous opportunities offered by the bovine model. The scientists identified candidate mutations for seven dominant genetic disorders¹ by sequencing the complete genome of an affected animal and by comparing the genomes of over one-thousand tested individuals representing the main ancestors and their breeds. Then, they confirmed that these mutations appeared de novo and that they were the cause of the disorders, by studying the animals related to the affected animals.
    
In addition, the scientists performed clinical examinations and observed perfect genotype-phenotype correlations between the bovine cases and human patients presenting the mutations in the same zone of the same proteins, thus showing that the cow could be a relevant model for the study of human genetic disorders. They provide the proof that a bovine model can, in certain cases, be a better model than mice, which sometimes express attenuated phenotypes.
    
Furthermore, they showed that large families of half-brothers/sisters produced by animal insemination allow the mapping of modifier genes² and that the study of rare mutations in cattle could also be important for fundamental research.  

Finally, scientists find that it is possible to anticipate the emergence of certain recessive genetic disorders, by identifying specific insemination bulls that are carriers of de novo deleterious mutations, and therefore preventing the emergence of the anomaly in the populations.

In conclusion, this study provides a remarkable insight into the potential use of livestock as animal models in the post-genomic era.
   
¹ This article presents cases of type II achondrogenesis (caused by three different mutations of the COL2A1 gene), CHARGE syndrome (CHD7), type II imperfect osteogenesis (COL1A1), Tietz syndrome (MITF), anhidrotic ectodermal dysplasia, along with a pigmentation anomaly with no equivalent in man called dominant red (COPA).

² The modifier genes, by interacting with the mutated gene, may worsen or attenuate the symptoms associated with certain syndromes of genetic origin.