RT Journal Article SR Electronic T1 A frameshift mutation in GON4L is associated with dwarfism in Fleckvieh cattle JF bioRxiv FD Cold Spring Harbor Laboratory SP 036889 DO 10.1101/036889 A1 Hermann Schwarzenbacher A1 Christine Wurmser A1 Krzysztof Flisikowski A1 Lubica Misurova A1 Simone Jung A1 Martin C. Langenmayer A1 Angelika Schnieke A1 Gabriela Knubben-Schweizer A1 Ruedi Fries A1 Hubert Pausch YR 2016 UL http://biorxiv.org/content/early/2016/01/15/036889.abstract AB Background Low 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. Recently, several paternal half sibs with low birth weight and size have been noticed in the Fleckvieh cattle population.Results Affected 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 SNP 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 control 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, 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.Conclusions A frameshift mutation in GON4L is associated with autosomal recessive 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.