1. Genome-wide next-generation DNA and RNA sequencing reveals a mutation that perturbs splicing of the phosphatidylinositol glycan anchor biosynthesis class H gene (PIGH) and causes arthrogryposis in Belgian Blue cattle
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Tom Druet, Christophe Richard, Corinne Fasquelle, Latifa Karim, Carole Charlier, Wanbo Li, Nico Tamma, Michel Georges, Eric Pailhoux, Arnaud Sartelet, Wouter Coppieters, Sartelet, Arnaud, Li, Wanbo, Université de Liège, Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Walloon Ministry of Agriculture (Rilouke), Belgian Science Policy Organization (SSTC Genefunc PAI), and University of Liege
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bovin ,Glycosylphosphatidylinositols ,PIGH gene ,Arthrogryposis syndrome ,Genome-wide association study ,Genome ,Exon ,Belgium ,arthrogryposis syndrome ,pigh gene ,splice site mutation ,glycosylphosphatidyl inositol deficiency ,belgian blue cattle breed ,Biologie de la reproduction ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,2. Zero hunger ,Genetics ,Arthrogryposis ,0303 health sciences ,Reproductive Biology ,Splice site mutation ,Belgian Blue Cattle breed ,Biologie du développement ,Chromosome Mapping ,High-Throughput Nucleotide Sequencing ,04 agricultural and veterinary sciences ,Exons ,Development Biology ,vache ,adn génomique ,race bovine blanc bleu belge ,Research Article ,Biotechnology ,Genotype ,RNA Splicing ,Locus (genetics) ,Biology ,Polymorphism, Single Nucleotide ,DNA sequencing ,Glycosylphosphatidyl inositol deficiency ,03 medical and health sciences ,Animals ,Gene ,030304 developmental biology ,Sequence Analysis, RNA ,0402 animal and dairy science ,Intron ,Membrane Proteins ,[SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology ,Sequence Analysis, DNA ,040201 dairy & animal science ,Introns ,Haplotypes ,Cattle ,RNA Splice Sites ,Splice-site mutation ,séquençage adn ,Genome-Wide Association Study - Abstract
Background Cattle populations are characterized by regular outburst of genetic defects as a result of the extensive use of elite sires. The causative genes and mutations can nowadays be rapidly identified by means of genome-wide association studies combined with next generation DNA sequencing, provided that the causative mutations are conventional loss-of-function variants. We show in this work how the combined use of next generation DNA and RNA sequencing allows for the rapid identification of otherwise difficult to identify splice-site variants. Results We report the use of haplotype-based association mapping to identify a locus on bovine chromosome 10 that underlies autosomal recessive arthrogryposis in Belgian Blue Cattle. We identify 31 candidate mutations by resequencing the genome of four cases and 15 controls at ~10-fold depth. By analyzing RNA-Seq data from a carrier fetus, we observe skipping of the second exon of the PIGH gene, which we confirm by RT-PCR to be fully penetrant in tissues from affected calves. We identify - amongst the 31 candidate variants - a C-to-G transversion in the first intron of the PIGH gene (c211-10C > G) that is predicted to affect its acceptor splice-site. The resulting PIGH protein is likely to be non-functional as it lacks essential domains, and hence to cause arthrogryposis. Conclusions This work illustrates how the growing arsenal of genome exploration tools continues to accelerate the identification of an even broader range of disease causing mutations, therefore improving the management and control of genetic defects in livestock. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1528-y) contains supplementary material, which is available to authorized users.
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