A reverse genetic approach identifies an ancestral frameshift mutation in RP1 causing recessive progressive retinal degeneration in European cattle breeds.

Pauline Michot,Andrew Marete,Aurélien Capitan,Didier Boichard,Sébastien Fritz,Dimitri Dagios,Sarah Barbey,Coralie Danchin-Burge,Sabine Chahory,Lucie Genestout,Elise Donzel,Aurélie Allais-Bonnet,Cécile Grohs,Matthieu Chambrial,Abdelhak Aboukadiri,Marie-Christine Deloche,Mekki Boussaha

doi:10.1186/s12711-016-0232-y

Abstract

BackgroundDomestication and artificial selection have resulted in strong genetic drift, relaxation of purifying selection and accumulation of deleterious mutations. As a consequence, bovine breeds experience regular outbreaks of recessive genetic defects which might represent only the tip of the iceberg since their detection depends on the observation of affected animals with distinctive symptoms. Thus, recessive mutations resulting in embryonic mortality or in non-specific symptoms are likely to be missed. The increasing availability of whole-genome sequences has opened new research avenues such as reverse genetics for their investigation. Our aim was to characterize the genetic load of 15 European breeds using data from the 1000 bull genomes consortium and prove that widespread harmful mutations remain to be detected.ResultsWe listed 2489 putative deleterious variants (in 1923 genes) segregating at a minimal frequency of 5 % in at least one of the breeds studied. Gene enrichment analysis showed major enrichment for genes related to nervous, visual and auditory systems, and moderate enrichment for genes related to cardiovascular and musculoskeletal systems. For verification purposes, we investigated the phenotypic consequences of a frameshift variant in the retinitis pigmentosa-1 gene segregating in several breeds and at a high frequency (27 %) in Normande cattle. As described in certain human patients, clinical and histological examination revealed that this mutation causes progressive degeneration of photoreceptors leading to complete blindness in homozygotes. We established that the deleterious allele was even more frequent in the Normande breed before 1975 (>40 %) and has been progressively counter-selected likely because of its associated negative effect on udder morphology. Finally, using identity-by-descent analysis we demonstrated that this mutation resulted from a unique ancestral event that dates back to ~2800 to 4000 years.ConclusionsWe provide a list of mutations that likely represent a substantial part of the genetic load of domestication in European cattle. We demonstrate that they accumulated non-randomly and that genes related to cognition and sensory functions are particularly affected. Finally, we describe an ancestral deleterious variant segregating in different breeds causing progressive retinal degeneration and irreversible blindness in adult animals.Electronic supplementary materialThe online version of this article (doi:10.1186/s12711-016-0232-y) contains supplementary material, which is available to authorized users.

Highlights

Domestication and artificial selection have resulted in strong genetic drift, relaxation of purifying selection and accumulation of deleterious mutations
It can be anticipated that the genetic defects reported so far represent only the tip of the iceberg and that many recessive mutations resulting in embryonic mortality or in non-specific symptoms, which can be confounded with those of common diseases, remain to be discovered
The purpose of this study was twofold: (i) to characterize the genetic load of 15 beef and dairy breeds using whole-genome sequencing data from the 1000 bull genomes consortium [12] and (ii) to prove that widespread harmful mutations remain to be detected in our cattle populations by characterizing the effect of a frameshift mutation in the retinitis pigmentosa-1 (RP1) gene, which segregates in Normande cattle and other European breeds

Summary

Introduction

Domestication and artificial selection have resulted in strong genetic drift, relaxation of purifying selection and accumulation of deleterious mutations. With the advent of high-throughput genotyping and next-generation sequencing, efficient methods have been developed to identify the underlying mutations in record time and with a limited number of available cases [6, 7] Such approaches rely on the observation of affected animals with distinctive symptoms. In addition to the influence of genetic drift and hitch-hiking, the frequency of some deleterious mutations, which would be detrimental in the wild, may have been involuntarily increased by artificial selection on behavior, coat color, morphological or production traits. This is the case for example for double-muscling, which causes dystocia [8, 9], and for a series of mutations under balancing selection [10, 11]

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