2022-09-01| R&D

First Sustainable Chromosome Changes in Mammals

by Nai Ye Yeat
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Researchers from the Chinese Academy of Sciences (CAS) announced that they have successfully fused two chromosomes in mice and shown that the new karyotype can be transmitted to offspring. This is also the first time a million-year scale chromosomal evolution has occurred in the laboratory, suggesting the feasibility of chromosome-level engineering in mammals.

The article, “A sustainable mouse karyotype created by programmed chromosome fusion,” was published in Science on 25 Aug. 

Related article: How Are Chromosomes Packed During Cell Division?

How Is Chromosome Fusion So Important?

Most species have a fixed number of chromosomes. However, chromosomes may have split up and fused together; its rearrangement is quite common indeed. For instance, rodents have 3.2 to 3.5 rearrangements per million years, whereas primates have 1.6.

Such seemingly small changes may have huge impacts, leading to profound physiological and behavioral changes, and even become an essential driver of speciation. Human chromosome 2 was formed by the fusion of two chromosomes that remain separate in gorillas. While on an individual level, chromosomal fusions or translocations can result in infertility, aneuploidy, and childhood leukemia.

Thus, the goal is to precisely manipulate chromosomes in higher eukaryotes, especially mammalian ones, in the needs of both medical and evolutionary perspectives. 

Challenges of Chromosomal Level Modification

According to co-first author Wang Libin, a researcher from CAS and the Beijing Institute for Stem Cell and Regenerative Medicine, the main challenge is that the process requires deriving stem cells from unfertilized mouse embryos, which means the cells contain only a single set of chromosomes. As in diploid cells, there are two sets of chromosomes that align and negotiate the phenotypes of the resulting organism called genomic imprinting, where a dominant gene may be marked active while a recessive gene is marked inactive. 

However, genomic imprinting is frequently lost in haploid embryonic stem cells, meaning the information about which genes should be active disappears, thus their pluripotency and genetic engineering were largely limited. Nevertheless, the team finally came up with a solution by deleting three imprinted regions. As a result, a stable sperm-like imprinting pattern in the cells is achieved.

Next, the researchers fused the two largest mouse chromosomes (chromosomes 1 and 2) and two medium-sized chromosomes (chromosomes 4 and 5) separately to investigate thefeasibility of chromosome fusion. Karyotypes carrying large chromosomes fused displayed arrested mitosis, polyploidization, and embryonic mortality. On the other hand, the smaller one could be passed on to homozygous offspring but at a much lower rate than standard lab mice. The team concluded it as a result of an abnormality when chromosomes separated after alignment.

All in all, the study highlighted that the chromosomal rearrangement event is important for reproductive isolation while also key behind species evolution, providing a potential route for large-scale DNA engineering in mammals.

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