Chinese scientists claim to have engineered the world's first mouse with fully reprogrammed genes
Researchers from the Chinese Academy of Sciences (CAS) claim to have found a novel technique for programmable chromosome fusion successfully producing mice with genetic changes "that occur on a million-year evolutionary scale" in the laboratory.
The findings could shed light on how chromosome rearrangements—the tidy packages of organized genes provided in equal numbers by each parent, which align and trade or blend traits to produce offspring—influence evolution, reported Phys.org on Thursday.
"The laboratory house mouse has maintained a standard 40-chromosome karyotype—or the full picture of an organism's chromosomes—after more than 100 years of artificial breeding," said Li Zhikun, a researcher at CAS's Institute of Zoology.
"Over longer time scales, however, karyotype changes caused by chromosome rearrangements are common. Rodents have 3.2 to 3.5 rearrangements per million years, whereas primates have 1.6," added Li, co-first author of the study.
The mouse, known as Xiao Zhu, or "Little Bamboo," was the world's first mammal with fully reprogrammed genes, according to the South China Morning Post.
The study claims to have provided important insight into how chromosomal rearrangements may affect evolution by showing that chromosome-level engineering is possible in mammals and by effectively deriving a laboratory house mouse with a novel and sustainable karyotype.
According to Li, such small changes can have a big impact. Humans and gorillas are separated by 1.6 changes in primates. Gorillas have two distinct chromosomes, whereas humans have two fused chromosomes, and a translocation between ancestor human chromosomes resulted in two distinct chromosomes in gorillas.
Individually, fusions or translocations can result in missing or extra chromosomes, as well as diseases like childhood leukemia.
While the chromosomes' consistent reliability is useful for understanding how things work on a short time scale, Li believes that the ability to engineer changes could inform genetic understanding over millennia, including how to correct misaligned or malformed chromosomes.
Although attempts to transfer the techniques to mammals have not been successful, other researchers have successfully engineered chromosomes in yeast.
"Genomic imprinting is frequently lost, meaning the information about which genes should be active disappears, in haploid embryonic stem cells, limiting their pluripotency and genetic engineering," said Wang Libin, first author of the study and a researcher with CAS and the Beijing Institute for Stem Cell and Regenerative Medicine.
"We recently discovered that by deleting three imprinted regions, we could establish a stable sperm-like imprinting pattern in the cells."
There are two sets of chromosomes in diploid cells that align and negotiate the genetics of the resulting organism. This is known as genomic imprinting, and it occurs when a dominant gene is marked active while a recessive gene is marked inactive.
The process can be manipulated scientifically, but previous attempts in mammalian cells have failed to stick to the information.
Wang explains that the process requires deriving stem cells from unfertilized mouse embryos, which means the cells only have one set of chromosomes.
Evolutionary indicator of the emergence of a new species
Scientists genetically engineered a kind of mouse with 19 chromosomal pairs, one pair less than is standard in this species, and part of these genetic changes can be passed to offspring, claimed CGTN, a Chinese state-run English-language news channel based in Beijing.
"The initial formations and stem cell differentiation was minimally affected; however, karyotypes with fused 1 and 2 chromosomes resulted in arrested development," Wang said.
"The smaller fused chromosome composed of chromosomes 4 and 5 was successfully passed to offspring."
The researchers discovered that the weakened fertility was caused by an abnormality in how chromosomes separated after alignment, according to Wang.
This finding, he said, proved the significance of chromosomal rearrangement in establishing reproductive isolation, a crucial evolutionary indicator of the emergence of a new species.
The research was first published in Nature.
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.
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