From chimpanzees to humans and back: will chromosome fusion help cross us with apes?

The main molecule of life (DNA) consists of only four types of monomers, denoted by the letters A, T, G, and C. Point mutations occur when one or more letters change into another, drop or double. Sometimes, however, larger-scale rearrangements occur in nature: a chromosome can be lost, doubled up, replaced by another. In this case, we are talking about the movement of tens and hundreds of millions of “letters” of DNA.

“At its core, a chromosome is a long string of DNA conveniently packaged for storage and use. The genomes of different organisms have different numbers of chromosomes. For example, humans have 46 chromosomes (or 23 pairs), while chimpanzees have 48 chromosomes. Normally, during evolution, chromosomal rearrangements can occur over a very long period of time. For example, the fusion of two chromosomes or the transfer of one part of one chromosome to another, Antonina Akimenko, geneticist at the Atlas biomedical conglomerate, told socialbites.ca.

mice mus musculusIt normally has 20 pairs of chromosomes, which scientists use for experiments. Using the CRISPR/Cas9 genetic editing system, the authors of the study, published in Science, cut off all the “extra” segments at the ends of chromosomes.

These include telomeres that protect DNA from damage during division, as well as centromeres located in the middle of the chromosome and involved in DNA replication during cell division. The scientists also tagged the chromosomes with special sequences. And then nature did everything: cells have special proteins that “heal” damaged chromosomes. They stuck them where the scientists marked.

In some experiments, the authors glued the fourth and fifth chromosomes (short), in others the first and second (long). As a result, mouse cells contained 19 pairs of chromosomes. They transplanted kernels with such a set into eggs. From them developed embryos, which were later carried out by surrogate mothers. Some mice were able to not only survive but reproduce.

“In the study discussed, the scientists engineered genetically engineered mice with fused chromosomes 4 and 5 that, although their fertility was limited, were able to survive and inherit the resulting fused chromosome. Mice with fused chromosomes 1 and 2 either died at the embryonic stage or died at the embryonic stage,” Akimenko said. “It’s worth noting that it differs markedly from ordinary mice in behavior and is unable to mate with them,” he said.

The work of scientists was the first to describe the success of such large-scale manipulations with chromosomes. Modern genetic engineering makes it possible to artificially introduce point mutations, including for the treatment of hereditary diseases. However, previously it was only possible to change chromosomes for simple organisms such as yeast. This is because they contain one set of chromosomes while more complex organisms have two or more sets in their cells.

“The authors of this groundbreaking study used haploid mouse stem cells, which contain only one set of chromosomes. They were difficult to obtain, but they made it easy to make changes to their DNA. The first challenge was that if there are two sets of chromosomes in the body, if one of them is damaged, the cell will replicate the preserved copy of the damaged region. It’s about being able to use it to make it into a state, ”Pavel Volchkov, head of the MIPT genome engineering laboratory, told Gazeta.ru.

The second difficulty, according to the scientist, is associated with genomic imprinting. Diploid organisms contain two pairs of genes from two parents. Some genes become active if inherited from the mother and others from the father. This genomic imprinting must be turned off for the mouse to survive and all its genes to function more or less normally. This is exactly what the authors did by deleting the three DNA regions responsible for imprinting from the mouse genome.

Volchkov added that while the results of this study are an incredible feat for chromosome engineering, there are still many problems in born mice.

The work of scientists from China is of fundamental importance not only to biology. It could advance research into many genetic diseases in humans: chromosomal imbalances are seen in some types of cancer as well as inherited diseases.

“A change in chromosomes leads to serious consequences – Down syndrome, Edwards, Wolf-Hirshhorn syndrome and other chromosomal diseases with about seven faces. The method demonstrated by scientists to replace chromosomes will probably help in the future to understand how to correct defective chromosomes in humans and, accordingly, to defeat some chromosomal diseases, ”explained Akimenko.

Introducing point mutations is comparable to changing a few letters in a text. The fairy tale about turnips will not change much if the family pulls carrots or pumpkins. But if you add a chapter about Freddy Krueger’s life to War and Peace, you will have to rewrite all four volumes for this character to find a place in the 19th century. The result is a brand new book. The same is true for DNA: a small mutation rarely has major consequences for the entire species. It often affects its owner: it turns it red or allows it to digest lactose in adulthood. But if parts of chromosomes are mixed, even new species, such as humans, can emerge.

“Chromosomal rearrangements are of paramount importance for reproductive isolation, an essential component in the formation of new species. Chimpanzees are humans’ closest living relatives. Human and chimpanzee ancestors split about 6.5–7.5 million years ago. Human and chimpanzee genomes have undergone many changes, including chromosomal rearrangements, since their ancestors split. For example, the second chromosome in humans arose due to the fusion of two ancestral chromosomes corresponding to chromosomes 2a and 2b in chimpanzees,” said Akimenko.

Akimenko also stressed that there is no talk of crossing a chimpanzee with a human, but experiments to create chimeras are ongoing.

“Getting a combined chromosome in a test tube, if possible, does nothing by itself. The essence of this work is not that scientists have succeeded in combining two chromosomes. And we have created a mammalian organism with a similar set of chromosomes that can live and reproduce normally and pass the change on to offspring. the fact that they managed to produce.

Creating human-animal chimeras is another topic scientists are working on. In particular, human stem cells are introduced into the embryo of an animal such as a macaque. The life of chimeric embryos is preserved for a very short time for later examination and must then be destroyed for ethical reasons. “There’s a lot of ethical debate in this area,” Akimenko said.

This work can make research that was previously incredible almost routine. Turning a human back into a chimpanzee wouldn’t work, but creating new species in general has become a viable task that won’t have to spend millions of years.