A sustainable mouse karyotype created by programmed chromosome fusion
Li-Bin Wang, Zhi-Kun Li, Leyun Wang, Kai Xu, Tiantian Ji, Yihuan Mao, Sinan Ma, Tao Liu, Cheng-Fang Tu, Qian Zhao, Xuning Fan, Chao Liu, Liying Wang, You-Jia Shu, Ning Yang, Qi Zhou, Wei Li
Abstract
Chromosome engineering has been attempted successfully in yeast but remains challenging in higher eukaryotes, including mammals. Here, we report programmed chromosome ligation in mice that resulted in the creation of new karyotypes in the lab. Using haploid embryonic stem cells and gene editing, we fused the two largest mouse chromosomes, chromosomes 1 and 2, and two medium-size chromosomes, chromosomes 4 and 5. Chromatin conformation and stem cell differentiation were minimally affected. However, karyotypes carrying fused chromosomes 1 and 2 resulted in arrested mitosis, polyploidization, and embryonic lethality, whereas a smaller fused chromosome composed of chromosomes 4 and 5 was able to be passed on to homozygous offspring. Our results suggest the feasibility of chromosome-level engineering in mammals.