RT Journal
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
JF Genome Research 
JO Genome Research 
YR 2016 
FD October 01 
VO 26 
IS 10 
SP 1333 
OP 1341 
DO 10.1101/gr.207076.116 
UL http://genome.cshlp.org/content/26/10/1333.abstract 
AB 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.