Changing the number of chromosomes in an animal in nature can take millions of generations during evolution—and now scientists have been able to make the same changes in laboratory mice in a relative instant.
The new technology with stem cells and gene editing is a major achievement that the team hopes will reveal more about how rearranging chromosomes can affect the way animals evolve over time.
In the chromosomes—those strands of protein and DNA in cells—we find our genes, inherited from our parents and mixed together to make us who we are.
In mammals like mice and us humans, chromosomes typically come in pairs. There are exceptions, for example in sex cells.
Unfertilized embryonic stem cells are usually the best starting point for tinkering with DNA. However, the absence of this extra set of chromosomes provided by a sperm cell robs the cells of an important step in negotiating which genes in which chromosomes are marked as active to perform the task of building the body.
This process — called imprinting — was a stumbling block for engineers looking to rearrange large swaths of the genome.
“Genomic imprinting is often lost, meaning that information about which genes should be active disappears in haploid embryonic stem cells, limiting their pluripotency and genetic engineering,” says Biologist Li-Bin Wang from the Chinese Academy of Sciences.
“We recently discovered that by deleting three imprinted regions, we could establish a stable sperm-like imprinting pattern in the cells.”
Without these three naturally imprinted regions, permanent 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 most successful in passing the genetic code to the mouse offspring, although breeding was slower than normal.
One of the 1 and 2 fusions produced no mouse offspring, while the other produced mouse offspring that were slower, larger, and more fearful than those from the fusion of chromosomes 4 and 5.
According to the researchers, the decline in fertility is due to how the chromosomes separate after alignment, which doesn’t happen normally. It shows that chromosomal rearrangement is crucial reproductive isolation – an important part of the species that can evolve and remain separate.
“The laboratory house mouse has retained a standard karyotype of 40 chromosomes — or the full picture of an organism’s chromosomes — after more than 100 years of artificial breeding,” says biologist Zhi-Kun Li, also from the Chinese Academy of Sciences.
“Over longer periods of time, 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 in context, rare leaps in chromosome rearrangement helped guide the evolutionary paths of our own ancestors. Chromosomes that remain separate in gorillas, for example, are fused into one in our human genome.
These types of changes can occur once every few hundred millennia. While the genetic changes made here in the lab were on a relatively small scale, the evidence suggests they could have some dramatic effects on the animals involved.
It’s still in its infancy – this is a scientific first, after all – but later there may be the possibility of correcting misaligned or malformed chromosomes in human bloodlines. We know that chromosome fusions and misalignments in individuals 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 important for reproductive isolation, offering a potential pathway for large-scale generation of DNA in mammals,” says Li
The research was published in Science.