NGS-based reverse genetic screen for common embryonic lethal mutations compromising fertility in livestock
- Carole Charlier1,5,
- Wanbo Li2,5,
- Chad Harland1,3,
- Mathew Littlejohn3,
- Wouter Coppieters1,4,
- Frances Creagh3,
- Steve Davis3,
- Tom Druet1,
- Pierre Faux1,
- François Guillaume1,6,
- Latifa Karim1,4,
- Mike Keehan3,
- Naveen Kumar Kadri1,
- Nico Tamma1,
- Richard Spelman3 and
- Michel Georges1
- 1Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 4000-Liège, Belgium;
- 2State Key Laboratory for Pig Genetic Improvement and Production Technology, Jiangxi Agricultural University, Nanchang, 330045, Jiangxi Province, P.R. China;
- 3Livestock Improvement Corporation, Newstead, Hamilton 3240, New Zealand;
- 4Genomics Platform, GIGA, University of Liège (B34), 4000-Liège, Belgium
- Corresponding authors: carole.charlier{at}ulg.ac.be, michel.georges{at}ulg.ac.be
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↵5 These authors contributed equally to this work.
Abstract
We herein report the result of a large-scale, next generation sequencing (NGS)-based screen for embryonic lethal (EL) mutations in Belgian beef and New Zealand dairy cattle. We estimated by simulation that cattle might carry, on average, ∼0.5 recessive EL mutations. We mined exome sequence data from >600 animals, and identified 1377 stop-gain, 3139 frame-shift, 1341 splice-site, 22,939 disruptive missense, 62,399 benign missense, and 92,163 synonymous variants. We show that cattle have a comparable load of loss-of-function (LoF) variants (defined as stop-gain, frame-shift, or splice-site variants) as humans despite having a more variable exome. We genotyped >40,000 animals for up to 296 LoF and 3483 disruptive missense, breed-specific variants. We identified candidate EL mutations based on the observation of a significant depletion in homozygotes. We estimated the proportion of EL mutations at 15% of tested LoF and 6% of tested disruptive missense variants. We confirmed the EL nature of nine candidate variants by genotyping 200 carrier × carrier trios, and demonstrating the absence of homozygous offspring. The nine identified EL mutations segregate at frequencies ranging from 1.2% to 6.6% in the studied populations and collectively account for the mortality of ∼0.6% of conceptuses. We show that EL mutations preferentially affect gene products fulfilling basic cellular functions. The resulting information will be useful to avoid at-risk matings, thereby improving fertility.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.207076.116.
- Received March 16, 2016.
- Accepted August 19, 2016.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.