Scientists successfully fuse chromosomes in mammals

Study reveals that chromosome-level engineering can be achieved in mammals.

Researchers engineer first stable chromosomal changes in mice.

In nature, evolutionary chromosomal changes can take a million years, but scientists have recently reported a new technique for programmable chromosome fusion that has successfully created mice with genetic changes that occur on a million-year evolutionary scale in the laboratory. The findings may shed light on how chromosomal rearrangements — the regular bundles of structured genes provided in equal numbers by each parent that align and trade or mix characteristics to produce offspring — affect evolution.

In a study published in the journal science, researchers show that chromosome-level engineering is possible in mammals. They successfully created a laboratory house mouse with a new and stable karyotype, providing crucial insights into how chromosome rearrangements can affect evolution.

“The laboratory house mouse has maintained a standard 40-chromosome karyotype—or the complete picture of an organism’s chromosomes—after more than 100 years of artificial breeding,” said co-first author Li Zhikun, a researcher at the Chinese Academy of Sciences (CAS ). ) Institute of Zoology and State Main Laboratory of Stem Cells and Reproductive Biology. “Over longer time scales, however, karyotype changes caused by chromosomal rearrangements are common. Rodents have 3.2 to 3.5 rearrangements per million years, while primates have 1.6.

Karyotyped mice

By fusing two medium-sized chromosomes, researchers produced the first stable engineered karyotype for laboratory mice. This mouse carries two chromosomes fused together. Credit: Wang Qiang

According to Li, even small changes can have a massive impact. In primates, 1.6 differences are the difference between humans and gorillas. Gorillas have two distinct chromosomes, while humans have two fused chromosomes, and a translocation between ancestral human chromosomes resulted in two different chromosomes in gorillas. Individually, fusions or translocations can result in missing or extra chromosomes, as well as diseases such as childhood leukemia.

While the consistent reliability of chromosomes is useful for learning how things work on a short time scale, Li believes that the ability to engineer modifications could enrich genetic understanding over millennia, including how to correct misplaced or missing chromosomes. malformed. Other scientists have successfully altered chromosomes in yeast, but attempts to transfer the technology to mammals have failed.

The challenge, according to co-first author Wang Libin of CAS and the Beijing Institute of Stem Cells and Regenerative Medicine, is that the process involves extracting the stem cells from unfertilized mouse embryos, meaning the cells have only one pair of chromosomes.

There are two sets of chromosomes in diploid cells that line up and negotiate the genetics of the resulting organism. This is known as genomic imprinting and occurs when a dominant gene is marked active while a recessive gene is marked inactive. The process can be scientifically manipulated, but the information has not stuck in previous attempts in mammalian cells.

“Genomic imprinting is often lost, meaning that the information about which genes should be active is lost, in haploid embryonic stem cells, limiting their pluripotency and genetic engineering,” Wang said. “We recently discovered that by deleting three embedded regions, we can create a stable pattern of sperm-like embedding in cells.”

Without the three naturally embedded regions, the researchers’ designed embedding model could be applied, allowing them to join specific chromosomes. They tested it by fusing two medium chromosomes – 4 and 5 – head to tail and the two largest chromosomes – 1 and 2 – in two orientations, resulting in karyotypes with three different arrangements.

“Initial formations and differentiation of stem cells were minimally affected; however, karyotypes with fused chromosomes 1 and 2 resulted in arrested development,” Wang said. “The smaller fused chromosome composed of chromosomes 4 and 5 was successfully passed on to offspring.”

Karyotypes with chromosome 2 fused on top of chromosome 1 did not lead to any full-term mouse pups, while the reverse arrangement produced pups that grew into adults that were larger, more restless, and physically slower, compared to mice with 4 and fused fused. 5 chromosomes. Only mice with fused chromosomes 4 and 5 were able to produce offspring with wild-type mice, but at a much lower rate than standard laboratory mice.

The researchers found that the impaired fertility resulted from an abnormality in the way chromosomes separated after alignment, Wang said. He explained that this discovery showed the importance of chromosomal rearrangement in establishing reproductive isolation, which is a key evolutionary sign of the emergence of a new species.

“Some engineered mice showed abnormal behavior and excessive growth after birth, while others showed reduced fertility, suggesting that although the change in genetic information was limited, fusing the animals’ chromosomes could have profound effects,” said LI. “Using a fixed haploid embryonic stem cell platform and gene editing in a laboratory mouse model, we experimentally demonstrated that the event of chromosomal rearrangement is the driving force behind species evolution and important for reproductive isolation, providing a potential route to large-scale engineering of[{” attribute=””>DNA in mammals.”

Reference: “A sustainable mouse karyotype created by programmed chromosome fusion” by Li-Bin Wang, Zhi-Kun Li, Le-Yun Wang, Kai Xu, Tian-Tian Ji, Yi-Huan Mao, Si-Nan Ma, Tao Liu, Cheng-Fang Tu, Qian Zhao, Xu-Ning Fan, Chao Liu, Li-Ying Wang, You-Jia Shu, Ning Yang, Qi Zhou and Wei Li, 25 August 2022, Science.
DOI: 10.1126/science.abm1964

The study was funded by the Chinese Academy of Sciences and the National Natural Science Foundation of China. 

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