A nonsense mutation in the COL7A1 gene causes epidermolysis bullosa in Vorderwald cattle.

Hubert Pausch,Henning Hamann,Jens Tetens,Cord Drögemüller,Ruedi Fries,Christine Wurmser,Simon Ammermüller

doi:10.1186/s12863-016-0458-2

Abstract

BackgroundThe widespread use of individual sires for artificial insemination promotes the propagation of recessive conditions. Inadvertent matings between unnoticed carriers of deleterious alleles may result in the manifestation of fatal phenotypes in their progeny. Breeding consultants and farmers reported on Vorderwald calves with a congenital skin disease. The clinical findings in affected calves were compatible with epidermolysis bullosa.ResultsPedigree analysis indicated autosomal recessive inheritance of epidermolysis bullosa in Vorderwald cattle. We genotyped two diseased and 41 healthy animals at 41,436 single nucleotide polymorphisms and performed whole-genome haplotype-based association testing, which allowed us to map the locus responsible for the skin disease to the distal end of bovine chromosome 22 (P = 8.0 × 10−14). The analysis of whole-genome re-sequencing data of one diseased calf, three obligate mutation carriers and 1682 healthy animals from various bovine breeds revealed a nonsense mutation (rs876174537, p.Arg1588X) in the COL7A1 gene that segregates with the disease. The same mutation was previously detected in three calves with dystrophic epidermolysis bullosa from the Rotes Höhenvieh cattle breed. We show that diseased animals from Vorderwald and Rotes Höhenvieh cattle are identical by descent for an 8.72 Mb haplotype encompassing rs876174537 indicating they inherited the deleterious allele from a recent common ancestor.ConclusionsAutosomal recessive epidermolysis bullosa in Vorderwald and Rotes Höhenvieh cattle is caused by a nonsense mutation in the COL7A1 gene. Our findings demonstrate that deleterious alleles may segregate across cattle populations without apparent admixture. The identification of the causal mutation now enables the reliable detection of carrier animals. Genome-based mating strategies can avoid inadvertent matings of carrier animals thereby preventing the birth of homozygous calves that suffer from a painful skin disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0458-2) contains supplementary material, which is available to authorized users.

Highlights

The widespread use of individual sires for artificial insemination promotes the propagation of recessive conditions
We show that a haplotype encompassing the deleterious allele, unexpectedly, segregates in Rotes Höhenvieh cattle
Phenotypic manifestation and inheritance of a painful skin disease in Vorderwald cattle Twenty-five Vorderwald calves (17 male, 6 female, 2 of unknown sex) with congenital skin lesions were born between the years 2004 and 2015

Summary

Introduction

The widespread use of individual sires for artificial insemination promotes the propagation of recessive conditions. Inadvertent matings between unnoticed carriers of deleterious alleles may result in the manifestation of fatal phenotypes in their progeny. Breeding consultants and farmers reported on Vorderwald calves with a congenital skin disease. The breeding population consists of less than 10,000 cows of which 50% are artificially inseminated [1]. In spite of the small number of breeding animals, the effective population size (Ne) of Vorderwald cattle is relatively high (Ne = 130) [1]. Most genetic disorders in cattle populations follow an autosomal recessive inheritance likely because the widespread use of individual bulls for artificial insemination promotes the propagation of recessive alleles [8,9,10].

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