Changing the number of chromosomes an animal has can take millions of generations over the course of evolution in nature — and now scientists have been able to make the same changes in lab mice in a relative instant.
The new technique that uses stem cells and edits genes is a major achievement, and the team hopes it will reveal more about how chromosome rearrangement might affect the way animals evolve over time.
It’s in chromosomes — those strands of proteins and DNA in cells — that we find our genes, inherited from our parents and mixed together to make us who we are.
For mammals such as mice and us humans, chromosomes usually come together. There are exceptions, such as in sex cells.
Unfertilized embryonic stem cells are usually the best starting place to tinker with DNA. However, the lack of that extra set of chromosomes provided by a sperm deprives the cells of an important step in negotiating which genes in which chromosomes are marked as active to do the job of building a body.
This process, called imprinting, was a stumbling block for engineers who wanted to restructure large parts of the genome.
“Genomic imprinting is often lost, meaning the information about which genes should be active disappears in haploid embryonic stem cells, limiting their pluripotency and genetic manipulation,” said biologist Li-Bin Wang of the Chinese Academy of Sciences.
“We recently discovered that by removing three imprinted regions, we were able to establish a stable sperm-like imprint pattern in the cells.”
Without those three naturally imprinted regions, sustainable chromosome fusion was possible. In their experiments, the researchers fused two medium-sized chromosomes (4 and 5) and the two largest chromosomes (1 and 2) in two different orientations, resulting in three different arrangements.
The fusion of chromosomes 4 and 5 was the most successful in terms of the genetic code passed on to the mice’s offspring, although breeding was slower than usual.
One of the 1 and 2 fusions produced no offspring from mice, while the other mice produced offspring that were slower, larger, and more anxious than those from the fusion of chromosomes 4 and 5.
According to the researchers, the declines in fertility are due to how the chromosomes separate after alignment, which doesn’t happen in the normal way. It shows that chromosomal rearrangement is crucial for reproductive isolation – an important part of the ability of species to evolve and stay separate.
“The lab house mouse has retained a standard 40-chromosome karyotype — or the complete picture of an organism’s chromosomes — after more than 100 years of artificial breeding,” said biologist Zhi-Kun Li, also of the Chinese Academy of Sciences.
“Over longer timescales, however, karyotype changes caused by chromosome rearrangements are common. Rodents have 3.2 to 3.5 rearrangements per million years, while primates have 1.6.”
To put this into context, rare jumps in chromosomal rearrangement have helped direct the evolutionary pathways of our own ancestors. Chromosomes that remain separate in gorillas, for example, are fused into one in our human genome.
Those kinds of changes can happen once every few hundred millennia. While the genetic edits done here in the lab were on a relatively small scale, the signs are that they could have some dramatic effects on the animals involved.
It’s still in its infancy — this is a scientific first, after all — but further down the line, there may be the opportunity to correct misaligned or misshapen chromosomes in human bloodlines. We know that in individuals, chromosome fusions and relocations can lead to health problems, including childhood leukemia.
“We have shown experimentally that the chromosomal rearrangement event is the driving force behind species evolution and is important for reproductive isolation, providing a potential pathway for large-scale engineering of DNA in mammals,” says Li.
The research was published in Science.