# Reverse genetics to describe a recessive defect in different breeds

Didier Boichard, Cécile Grohs

► To cite this version:

Didier Boichard, Cécile Grohs. Reverse genetics to describe a recessive defect in different breeds. 68. Annual Meeting of the European Association for Animal Production (EAAP), Aug 2017, Tallinn, Estonia., 2017, Book of Abstracts of the 68th annual meeting of the Federation of Animal Science (EAAP). hal-01604566

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Submitted on 2 Jun 2020

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Chasing deleterious recessives in Italian Holstein dairy cattle

P. Ajmone Marsan¹, M. Milanesi¹, S. Capomaccio², L. Colli¹, S. Biffani³, J.T. Van Kaam⁴, R. Finocchiaro⁴, R. Negrini¹, C.J. Rubin⁵, A. Nardone⁶, N.P.P. Maciotta⁷ and J.L. Williams⁸

¹Università Cattolica del Sacro Cuore, Zootechnics, Via Emilia Parmense 84, 29122 Piacenza, Italy, ²Università degli Studi di Perugia, Dipartimento Medicina Veterinaria, Via San Costanzo, 06123 Perugia, Italy, ³Associazione Italiana Allevatori, Via Molini 36, Roma, Italy, ⁴Anafi - Associazione Nazionale Allevatori Frisona Italiana, Via Bergamo, 26100 Cremona, Italy, ⁵Science for Life Laboratory Uppsala, Uppsala University, Husargtan, Uppsala, Sweden, ⁶Università della Tuscia, Department for innovation in biological, agro-food and forest systems (DIBAF), Via de Lellis, Viterbo, Italy, ⁷Università degli studi di Sassari, Dipartimento di Agraria, Via Enrico de Nicola, Sassari, Italy, ⁸University of Adelaide, School of Animal and Veterinary Sciences, Faculty of Sciences, Roseworthy, Roseworthy, Australia; paolo.ajmone@unicatt.it

Deleterious recessive variants have been searched in Italian Holstein dairy cattle combining High Density SNP genotypes from more than 1000 progeny tested bulls and exome sequence data from 18 animals sampled from the extremes of the male and female fertility effective daughter performance deregressed proof (EDP) distribution. SNP data were used to identify high linkage disequilibrium haplotype blocks. Haplotypes significantly lacking one class of homozygotes, compared to HWE expectation were classified as Homozygous Haplotype Deficient (HHD). In parallel, variants with a putative deleterious effect were identified from exome data. Candidate deleterious variants mapping within HHD were identified and further investigated in silico to assess their conservation across vertebrates and gene function. Thirteen candidate deleterious variants resided in nucleotides or genomic regions highly conserved across vertebrates and occurred in genes functionally linked to fertility or defects in mouse and human. These are pursued as candidates to influence fertility and fitness in Italian Holstein animals and are being validated to evaluate their use in genome-informed breeding programs.

Reverse genetics to describe a recessive defect in different breeds

C. Grohs¹, P. Michot², S. Chahory³, M.C. Deloche², S. Barbey⁴, M. Boussaha¹, C. Danchin-Burge⁵, S. Fritz², D. Boichard¹ and A. Capitan²

¹GABI, INRA, AgroParisTech, Université Paris Saclay, 78350 Jouy-en-Josas, France, ²Allice, 149 rue de Bercy, 75595 Paris, France, ³ENVÀ, Université Paris-Est, Ophtalmology, 7 Avenue du Général de Gaulle, 94704 Maisons-Alfort, France, ⁴INRA, Domaine Expérimental du Pin, 61310 Exmes, France, ⁵Idele, 149 rue de Bercy, 75595 Paris, France; cecile.grohs@inra.fr

Cattle breeds have a narrow genetic basis favoring emergences of recessive defects. In recent years, detection of cases by dedicated observatories (e.g. ONAB in France) combined with homozygosity mapping based on high density SNP genotyping data have proven to be efficient tools, leading to the characterization of more than 130 genetic defects in cattle. However, considering that more than 4,900 defects have been identified in human, this might be only the tip of the iceberg. Indeed, this approach relies on the observation of affected animals with distinctive symptoms, and mutations resulting in non-specific symptoms or symptoms with little economic importance are likely to be missed. The increasing availability of whole-genome sequences has opened new research avenues such as reverse genetics for the identification of mutations impacting animal's health. Recently, using this top-down strategy, we described 2,489 putative deleterious mutations in 1,923 genes, segregating at a minimal frequency of 5% in at least one of 15 breeds studied. The genes observed to be enriched in this study were mainly associated with nervous, visual and auditory systems, suggesting that those genes have not been taken into account for production purposes. Among them, we identified an ancestral deleterious variant in retinitis pigmentosa-1 (RP1) gene causing progressive retinal degeneration in several breeds. ONAB used the well-established and motivated network of partners to investigate the phenotypic consequences of the frameshift candidate variant. Clinical and functional analysis were performed and permit us to validate the causal mutation. Large scale genotyping showed that the mutated variant is very frequent in Normande breed (27%) but also segregates in other breeds at lower frequency (1.5% in Holstein). The conserved sequence haplotype suggests that the mutation is around 3,800 years old.