Scientists have succeeded in integrating chromosomes in mammals

The study revealed that engineering at the chromosome level can be achieved in mammals.

Researchers engineer the first sustainable chromosomal changes in mice.

In nature, evolutionary chromosomal changes can take a million years, but scientists recently reported a new programmable chromosome fusion technique that has successfully created mice with genetic changes occurring on an evolutionary scale of a million years in the laboratory. The findings may shed light on how chromosomal rearrangements—the elegant bundles of structured genes presented in equal numbers by each parent, matching and exchanging or mixing characteristics to produce offspring—affect evolution.

In a study published in the journal Sciences, the researchers showed that chromosome level engineering is possible in mammals. They have succeeded in creating a laboratory mouse with a new, sustainable karyotype, providing crucial insight into how chromosomal rearrangements affect evolution.

Co-first author Lee Jieun, a researcher at Chinese Academy of Sciences (CAS) Institute of Zoology and State Main Laboratory of Stem Cells and Reproductive Biology. “However, over longer time scales, karyotypic changes resulting from chromosomal rearrangements are common. Rodents have 3.2 to 3.5 rearrangements per million years, while primates have 1.6.”

karyotyped mice

By merging two intermediate-sized chromosomes, researchers have produced the first sustainable engineered karyotype of lab mice. This mouse has two chromosomes fused together. Credit: Wang Qiang

According to Li, even small changes can have a huge impact. In primates, 1.6 changes are the difference between humans and gorillas. Gorillas have two distinct chromosomes, while humans have two fused chromosomes, and the transition between ancestral human chromosomes gave rise to two different chromosomes in gorillas. Individually, fusion or translocation may 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 over a short time scale, Lee believes that the ability to engineer modifications may enrich genetic understanding over millennia, including how to correct skewed or misshapen chromosomes. Other scientists have succeeded in altering chromosomes in yeast, but efforts to transfer the technology to mammals have been unsuccessful.

The challenge, according to first co-author Wang Libin of CAS and the Beijing Institute of Stem Cells and Regenerative Medicine, is that the process entails extracting 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 serve to align and negotiate the hereditary genes of the resulting organism. This is known as genomic course, and it occurs when the dominant gene is marked as active while the recessive gene is marked as inactive. The process can be scientifically manipulated, but the information has not stuck in previous attempts in mammalian cells.

“Genomic imprinting is frequently lost, which means that 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 imprinted regions, we can create a consistent, sperm-like imprinting pattern in cells.”

Without the three naturally imprinted regions, the imprinting pattern designed for researchers could take hold, allowing them to integrate specific chromosomes. They tested it by fusing two of the medium-sized chromosomes – 4 and 5 – from head to tail and two of the largest – chromosomes – 1 and 2 – in two directions, resulting in karyotypes with three different arrangements.

“Primary formations and differentiation of stem cells were slightly affected; however, karyotypes with fused chromosomes 1 and 2 resulted in stunted growth,” Wang said. “The smaller fused chromosome consisting of chromosomes 4 and 5 was successfully passed on to the offspring.”

Karyotypes with fused chromosome 2 at the top of chromosome 1 did not result in any full-term mouse pups, while the opposite arrangement produced pups that grew larger, more restless and slower-bodied, compared to mice with 4 and 5 fused chromosomes. Only mice with 4 and 5 chromosomes fused were able to produce offspring from wild-type mice, but at a much lower rate than standard experimental mice.

Wang said the researchers found that impaired fertility resulted from a defect in how chromosomes separate after alignment. He explained that this discovery demonstrates the importance of chromosomal rearrangements in establishing reproductive isolation, which is a major evolutionary marker for the emergence of a new species.

“Some engineering mice showed abnormal behavior and increased growth after birth, while others showed decreased fecundity, suggesting that although the change in genetic information was limited, animal chromosomal fusion could have profound effects,” LI said. “. “Using a stable haploid embryonic stem cell platform and gene editing in an in vitro mouse model, we experimentally demonstrated that a chromosomal rearrangement event is the driving force behind species evolution and is important for reproductive seclusion, providing a potential pathway for large-scale engineering[{” 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.