Young-Lim Lee1,2, Aniek C. Bouwman2, Chad Harland1,3, Mirte Bosse2, Gabriel Costa Monteiro Moreira1, Roel F. Veerkamp2, Erik Mullaart4, Nadine Cambisano5, Martien A.M. Groenen2, Latifa Karim5, Wouter Coppieters1,5, Michel Georges1 and Carole Charlier1 1Unit of Animal Genomics, GIGA-R, Faculty of Veterinary Medicine, University of Liège, B-4000 Liège, Belgium; 2Wageningen University and Research, Animal Breeding, and Genomics, 6708 WG Wageningen, The Netherlands; 3Livestock Improvement Corporation, Hamilton 3240, New Zealand; 4CRV B.V., 6842 BD Arnhem, The Netherlands; 5GIGA Genomics Platform, GIGA Institute, University of Liège, B-4000 Liège, Belgium Corresponding authors: younglim.leeuliege.be, michel.georgesuliege.be, carole.charlieruliege.be Abstract

Assisted reproductive technologies (ARTs), including in vitro maturation and fertilization (IVF), are increasingly used in human and animal reproduction. Whether these technologies directly affect the rate of de novo mutation (DNM), and to what extent, has been a matter of debate. Here we take advantage of domestic cattle, characterized by complex pedigrees that are ideally suited to detect DNMs and by the systematic use of ART, to study the rate of de novo structural variation (dnSV) in this species and how it is impacted by IVF. By exploiting features of associated de novo point mutations (dnPMs) and dnSVs in clustered DNMs, we provide strong evidence that (1) IVF increases the rate of dnSV approximately fivefold, and (2) the corresponding mutations occur during the very early stages of embryonic development (one- and two-cell stage), yet primarily affect the paternal genome.

Received March 23, 2023. Accepted August 8, 2023.