Scientists engineer first mammal with whole chromosome rearrangements

Chinese scientists have genetically engineered a kind of house mouse with 19 chromosomal pairs, one pair less than is standard in this species.

Chinese scientists have genetically engineered a kind of house 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.

The study published on Friday in the journal Science revealed that chromosome level engineering had been achieved in a mammal for the first time, a result that offered insight into how rearrangements of chromosomes can influence evolution.

Chromosomes are tidy packages of organized genes, provided in equal number from each parent. Their evolutionary changes may take a million years in nature, but in the new study, a novel technique is shown to enable programmable chromosome fusion in the lab.

Rodents have 3.2 to 3.5 chromosomal rearrangements per million years, whereas primates have 1.6. But those 1.6 changes result in the difference between humans and gorillas, since gorillas have two separate chromosomes whereas in humans they are fused, said the paper's co-first author Li Zhikun, researcher from the Institute of Zoology under the Chinese Academy of Sciences (CAS).

"At an individual level, fusions or translocations can lead to missing or extra chromosomes or even to such diseases as childhood leukemia," added Li.

The ability to engineer such changes could inform genetic understanding across millennia, including how to correct misaligned or malformed chromosomes, according to the study.

The Chinese group managed to derive stem cells from unfertilized mouse embryos that contain only one set of chromosomes. In those stem cells, however, the genomic imprinting, a trigger that determines which genes would be expressed, tend to be lost.

The researchers overcame the challenge by deleting three specific imprinted regions, which allowed them to fuse specific chromosomes.

They fused two medium-sized chromosomes – chromosomes 4 and 5 – head to tail, and this revealed that these engineered mice were able to produce offspring with wild-type mice, but at a much lower rate than standard lab mice, according to the study.

Also, the researchers fused chromosomes 1 and 2 in two opposite orientations. In one arrangement, the embryonic development was arrested while in the other, pups grew into larger, more anxious and physically slower adults.

The weakened fertility resulted from an abnormality in the way chromosomes separated after alignment, said the paper's co-first author Wang Libin from the Institute of Zoology.

"This finding demonstrated the importance of chromosomal rearrangements in establishing reproductive isolation, a key evolutionary sign of the emergence of a new species," said Wang.

The technique provides a potential route for large-scale engineering of DNA in mammals, and therefore, renders therapeutic possibilities, said the researchers.

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