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

Genetics Selection Evolution

Research Article

Aurélie Allais-Bonnet¹  Dimitri Dagios²  Elise Donzel²  Sabine Chahory²  Coralie Danchin-Burge³  Lucie Genestout⁴  Matthieu Chambrial⁵  Sarah Barbey⁶  Cécile Grohs⁷  Mekki Boussaha⁷  Didier Boichard⁷  Abdelhak Aboukadiri⁷  Sébastien Fritz⁸  Pauline Michot⁸  Aurélien Capitan⁸  Marie-Christine Deloche⁸  Andrew Marete⁹ 

[1] ALLICE, 149 rue de Bercy, 75595, Paris Cedex 12, France;UMR 1198, Biologie du Développement et Reproduction, INRA, 78350, Jouy-en-Josas, France;Ecole Nationale Vétérinaire d’Alfort, Unité d’Ophtalmologie, Université Paris-Est, 7 avenue du Général de Gaulle, 94704, Maisons-Alfort Cedex, France;IDELE, 149 rue de Bercy, 75595, Paris Cedex 12, France;Labogena DNA, Domaine de Vilvert, 78350, Jouy-en-Josas, France;Origenplus, 38 rue de la Mérillière, 61300, L’Aigle, France;UE 326, Domaine Expérimental du Pin-au-haras, INRA, 61310, Exmes, France;UMR 1313 GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France;UMR 1313 GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France;ALLICE, 149 rue de Bercy, 75595, Paris Cedex 12, France;UMR 1313 GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France;Center for Quantitative Genetics and Genomics, Aarhus University, Aarhus, Denmark;

关键词: Ingenuity Pathway Analysis;    Deleterious Mutation;    Frameshift Mutation;    Genomic Selection;    Pupillary Light Reflex;   

DOI  :  10.1186/s12711-016-0232-y

 received in 2016-05-02, accepted in 2016-07-26,  发布年份 2016

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2016