TY  - JOUR
A1  - Charlier, Carole
A1  - Li, Wanbo
A1  - Harland, Chad
A1  - Littlejohn, Mathew
A1  - Coppieters, Wouter
A1  - Creagh, Frances
A1  - Davis, Steve
A1  - Druet, Tom
A1  - Faux, Pierre
A1  - Guillaume, François
A1  - Karim, Latifa
A1  - Keehan, Mike
A1  - Kadri, Naveen Kumar
A1  - Tamma, Nico
A1  - Spelman, Richard
A1  - Georges, Michel
T1  - NGS-based reverse genetic screen for common embryonic lethal mutations compromising fertility in livestock
Y1  - 2016/10/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 1333 
EP  - 1341 
DO  - 10.1101/gr.207076.116 
VL  - 26 
IS  - 10 
UR  - http://genome.cshlp.org/content/26/10/1333.abstract 
N2  - 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. 
ER  -