Pedigree-based de novo rate estimation for structural variation in the cattle germline

Lee, Y.L.; Moreira, Gabriel Costa Monteiro; Karim, Latifa; Mullaart, Erik; Coppieters, Wouter; Veerkamp, R.F.; Groenen, M.; Bosse, M.; Bouwman, A.C.; Georges, Michel; Charlier, Carole


De novo mutations (dnm’s) are an important source of genetic diversity and hold paramount significance in understanding evolution and disease genetics. Although dnm’s are often assumed to arise from parental germline, recent studies revealed that a significant proportion of the de novo single-nucleotide variants (dnSNVs) arose during early development, resulting in mosaicism. Structural variations, including deletions, duplications, and inversions, are expected to affect more base-pairs of the genomes than SNVs, due to their larger event size. Nevertheless, the rate of de novo structural variations (dnSVs), and the degree of post-zygotic dnSVs in cattle has not been investigated. Here, we exploited multi-generational pedigrees, where 131 deeply sequenced Dutch Holstein Friesian cattle trios are complemented with large half-sibs and grand-offspring data. Overall, we identified 21 dnSVs (16 deletions, 5 duplications, 1 inversion), in a size range of 56bp to 1.2Mb. Of these, 17 were late germline dnSVs, unravelling the germline dnSV rate of 0.13 dnSV per generation (95% CI 0.07-0.19; 1 dnSV per 7.7 births). Strikingly, 16 out of 17 of the germline dnSVs were of paternal origin, underlining male germlines as a main contributor for bovine dnSVs. Furthermore, we found 4 mosaic dnSVs, accounting for nearly ~20% of the total dnSVs, confirming previous report in bovine dnSNVs. Using the allelic imbalance in the offspring and imperfect linkage in the grand-offspring, we concluded that all mosaic dnSVs arouse in early cleavage cell divisions, before the primordial germ cell specification, hence affecting both germline and somatic tissues. Our study highlights the value of unique bovine pedigree structure for genetics studies.