A frameshift mutation in GON4L is associated with proportionate dwarfism in Fleckvieh cattle

Abstract

BackgroundLow birth weight and postnatal growth restriction are the most evident symptoms of dwarfism. Accompanying skeletal aberrations may compromise the general condition and locomotion of affected individuals. Several paternal half sibs with low birth weight and size were born in 2013 in the Fleckvieh cattle population.\n\nResultsAffected calves were strikingly underweight at birth despite a normal gestation length and had craniofacial abnormalities such as elongated narrow heads and brachygnathia inferior. Despite a normal general condition, their growth remained restricted during rearing. We genotyped 27 affected and 10,454 unaffected animals at 44,672 SNPs and performed association testing followed by homozygosity mapping to map the growth failure to a 1.85 Mb segment on bovine chromosome 3. Analysis of whole-genome re-sequencing data from one affected and 289 unaffected animals revealed a 1bp deletion (g.15079217delC, rs723240647) in the coding region of the GON4L gene that segregated with the dwarfism-associated haplotype. We show that the deletion introduces intron retention and premature termination of translation, putatively resulting in a severely truncated protein that lacks domains that are likely essential to normal protein function. The widespread use of an unnoticed carrier bull for artificial insemination has resulted in a tenfold increase in the frequency of the deleterious allele in the female population.\n\nConclusionsA frameshift mutation in GON4L is associated with autosomal recessive proportionate dwarfism in Fleckvieh cattle. The mutation has segregated in the population for more than fifty years without being recognized as a genetic disorder. However, the widespread use of an unnoticed carrier bull for artificial insemination caused a sudden accumulation of homozygous calves with dwarfism. Our findings provide the basis for genome-based mating strategies to avoid the inadvertent mating of carrier animals and thereby prevent the birth of homozygous calves with impaired growth.