title: A reverse genetic approach identifies an ancestral frameshift mutation in RP1 causing recessive progressive retinal degeneration in European cattle breeds.
abstract: Domestication 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.
  
  
  
  We 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.
  
  
  
  We 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.
authors: UMR 1313 GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.|ALLICE, 149 rue de Bercy, 75595, Paris Cedex 12, France.
authors: Pauline
authors: P
authors: Michot
authors: Ecole Nationale Vétérinaire d'Alfort, Unité d'Ophtalmologie, Université Paris-Est, 7 avenue du Général de Gaulle, 94704, Maisons-Alfort Cedex, France.
authors: Sabine
authors: S
authors: Chahory
authors: UMR 1313 GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.|Center for Quantitative Genetics and Genomics, Aarhus University, Aarhus, Denmark.
authors: Andrew
authors: A
authors: Marete
authors: UMR 1313 GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.
authors: Cécile
authors: C
authors: Grohs
authors: Ecole Nationale Vétérinaire d'Alfort, Unité d'Ophtalmologie, Université Paris-Est, 7 avenue du Général de Gaulle, 94704, Maisons-Alfort Cedex, France.
authors: Dimitri
authors: D
authors: Dagios
authors: Ecole Nationale Vétérinaire d'Alfort, Unité d'Ophtalmologie, Université Paris-Est, 7 avenue du Général de Gaulle, 94704, Maisons-Alfort Cedex, France.
authors: Elise
authors: E
authors: Donzel
authors: UMR 1313 GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.
authors: Abdelhak
authors: A
authors: Aboukadiri
authors: UMR 1313 GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.|ALLICE, 149 rue de Bercy, 75595, Paris Cedex 12, France.
authors: Marie-Christine
authors: MC
authors: Deloche
authors: ALLICE, 149 rue de Bercy, 75595, Paris Cedex 12, France.|UMR 1198, Biologie du Développement et Reproduction, INRA, 78350, Jouy-en-Josas, France.
authors: Aurélie
authors: A
authors: Allais-Bonnet
authors: Origenplus, 38 rue de la Mérillière, 61300, L'Aigle, France.
authors: Matthieu
authors: M
authors: Chambrial
authors: UE 326, Domaine Expérimental du Pin-au-haras, INRA, 61310, Exmes, France.
authors: Sarah
authors: S
authors: Barbey
authors: Labogena DNA, Domaine de Vilvert, 78350, Jouy-en-Josas, France.
authors: Lucie
authors: L
authors: Genestout
authors: UMR 1313 GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.
authors: Mekki
authors: M
authors: Boussaha
authors: IDELE, 149 rue de Bercy, 75595, Paris Cedex 12, France.
authors: Coralie
authors: C
authors: Danchin-Burge
authors: UMR 1313 GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.|ALLICE, 149 rue de Bercy, 75595, Paris Cedex 12, France.
authors: Sébastien
authors: S
authors: Fritz
authors: UMR 1313 GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.
authors: Didier
authors: D
authors: Boichard
authors: UMR 1313 GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France. aurelien.capitan@jouy.inra.fr.|ALLICE, 149 rue de Bercy, 75595, Paris Cedex 12, France. aurelien.capitan@jouy.inra.fr.
authors: Aurélien
authors: A
authors: Capitan
mesh_terms: D000818:Animals; D001947:Breeding; D002417:Cattle / Q000235:genetics*; D002418:Cattle Diseases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D016368:Frameshift Mutation; D005787:Gene Frequency; D005808:Genes, Recessive; D040741:Genetic Load; D005838:Genotype; D008297:Male; D010641:Phenotype; D012160:Retina / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics*; D059386:Reverse Genetics
chemical_list: D005136:Eye Proteins