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

Simone Jung,Martin C. Langenmayer,Hubert Pausch,Gabriela Knubben-Schweizer,Christine Wurmser,Hermann Schwarzenbacher,Krzysztof Flisikowski,Lubica Misurova,Angelika Schnieke,Ruedi Fries

doi:10.1186/s12711-016-0207-z

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 a low birth weight and a small size were born in 2013 in the Fleckvieh cattle population.ResultsAffected calves were strikingly underweight at birth in spite of a normal gestation length and had craniofacial abnormalities such as elongated narrow heads and brachygnathia inferior. In spite of a normal general condition, their growth remained restricted during rearing. We genotyped 27 affected and 10,454 unaffected animals at 44,672 single nucleotide polymorphisms and performed association tests followed by homozygosity mapping, which allowed us to map the locus responsible for 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 1-bp deletion (g.15079217delC, rs723240647) in the coding region of the GON4L gene that segregated with the dwarfism-associated haplotype. We showed that the deletion induces intron retention and premature termination of translation, which can lead to a severely truncated protein that lacks domains that are likely essential to normal protein function. The widespread use of an undetected carrier bull for artificial insemination has resulted in a tenfold increase in the frequency of the deleterious allele in the female population.ConclusionsA frameshift mutation in GON4L is associated with autosomal recessive proportionate dwarfism in Fleckvieh cattle. The mutation has segregated in the population for more than 50 years without being recognized as a genetic disorder. However, the widespread use of an undetected 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12711-016-0207-z) contains supplementary material, which is available to authorized users.

Highlights

Low birth weight and postnatal growth restriction are the most evident symptoms of dwarfism
Phenotypic manifestation of dwarfism Twenty-seven calves (16 males and 11 females) with a strikingly low birth weight (~15 kg) and a small size in spite of a normal gestation length were detected among the descendants of an artificial insemination bull that was used for more than 290,000 inseminations
A frameshift variant in the GON4L gene was associated with autosomal recessive proportionate DW in Fleckvieh cattle

Summary

Introduction

Low birth weight and postnatal growth restriction are the most evident symptoms of dwarfism. Several paternal half-sibs with a low birth weight and a small size were born in 2013 in the Fleckvieh cattle population. Genome-wide association studies using dense molecular markers detected several quantitative trait loci (QTL) for growth-related traits in cattle [1,2,3]. Sequence variants associated with mature height may affect the size and weight of newborn calves [2, 3, 5]. Birth size and weight vary between breeds, parities and male and female calves [6, 7]. Calves with a strikingly low birth weight and small size in spite of a normal gestation length are commonly referred to as “dwarfs”

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