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

Area of Science:

• Genomics
• Animal Genetics
• Reproductive Biology

Background:

• Recessive embryonic lethal (EL) mutations can impact livestock fertility.
• Understanding the burden and impact of these mutations is crucial for cattle breeding programs.

Purpose of the Study:

• To identify and characterize embryonic lethal mutations in Belgian beef and New Zealand dairy cattle using next-generation sequencing.
• To estimate the frequency and impact of loss-of-function (LoF) variants on embryonic survival.

Main Methods:

• Large-scale exome sequencing of over 600 cattle to identify genetic variants.
• Genotyping over 40,000 animals for breed-specific variants.
• Statistical analysis to detect significant depletion of homozygotes for candidate EL mutations.
• Validation of candidate EL mutations through trio analysis.

Main Results:

• Identified a substantial number of genetic variants, including 1377 stop-gain, 3139 frame-shift, and 1341 splice-site variants.
• Cattle exhibit a comparable load of loss-of-function (LoF) variants to humans.
• Confirmed nine novel embryonic lethal mutations segregating at frequencies from 1.2% to 6.6%.
• These mutations collectively cause approximately 0.6% embryonic mortality.

Conclusions:

• Embryonic lethal mutations are a significant factor affecting cattle fertility.
• EL mutations preferentially impact genes involved in fundamental cellular functions.
• The identified mutations provide valuable information for managing breeding to enhance reproductive efficiency.