NGS-based reverse genetic screen for common embryonic lethal mutations compromising fertility in livestock - INRAE - Institut national de recherche pour l’agriculture, l’alimentation et l’environnement
Journal Articles Genome Research Year : 2016

NGS-based reverse genetic screen for common embryonic lethal mutations compromising fertility in livestock

Carole Charlier
  • Function : Author
Wanbo Li
  • Function : Author
Chad Harland
  • Function : Author
Mathew Littlejohn
  • Function : Author
Wouter Coppieters
  • Function : Author
Frances Creagh
  • Function : Author
Steve Davis
  • Function : Author
Tom Druet
  • Function : Author
Pierre Faux
François Guillaume
  • Function : Author
Latifa Karim
  • Function : Author
Mike Keehan
  • Function : Author
Naveen Kumar Kadri
  • Function : Author
Nico Tamma
  • Function : Author
Richard Spelman
  • Function : Author
Michel Georges
  • Function : Author

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.

Domains

Animal genetics

Dates and versions

hal-04189529 , version 1 (28-08-2023)

Identifiers

Cite

Carole Charlier, Wanbo Li, Chad Harland, Mathew Littlejohn, Wouter Coppieters, et al.. NGS-based reverse genetic screen for common embryonic lethal mutations compromising fertility in livestock. Genome Research, 2016, 26 (10), pp.1333-1341. ⟨10.1101/gr.207076.116⟩. ⟨hal-04189529⟩

Collections

INRAE
14 View
0 Download

Altmetric

Share

More