Human HeLa cancer cell in telophase of mitosis

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A team led by researchers at the Wellcome Trust Sanger Institute have observed the earliest mutations to occur in human life using adult cells for the first time. By analysing the genomes of breast cancer patients, the team were able to identify the mutations that developed during the first cell divisions of a human embryo. They also demonstrated that at the two-cell stage of development, one of the cells becomes dominant and makes up the majority of adult cells in the body. The work was published in Nature this week.

The early stages of embryonic development are still very poorly understood, largely due to the difficulties encountered when trying to study embryos directly within the lab. However, this new study managed to use blood samples from 279 adults with breast cancer to discover 163 mutations that occurred in first three cell divisions of embryonic development.

Once they had identified these mutations, the team used them to calculate what proportion of adult cells came from the first two cells of the embryo. Their results demonstrated that roughly 70% of adult cells resulted from one of the two initial cells, with the second cell making up the remaining 30%. They also found a similarly skewed contribution when focusing on second and third generation cells.

“This is the first time that anyone has seen where mutations arise in the very early human development,” said Young Seok Ju, Ph.D., first author of the paper. “It is like finding a needle in a haystack. There are just a handful of these mutations, compared with millions of inherited genetic variations, and finding them allowed us to track what happened during embryogenesis.”

The researchers then moved from blood samples to cancerous tissue samples that had been surgically removed from the participants during their treatment. In healthy tissues, the cell make-up is the result of multiple somatic cell clone lines which display some genetic variety. Cancerous tumours, on the other hand, are the result of a single mutated cell dividing beyond control and as a result, all cells within the tumour should have the same base genetic code (further mutations may occur during the growth of the tumour). The team therefore theorised that the proposed embryonic mutations should either appear in all cells of the tumour or none of them. Their results showed that this was the case and thereby validated their hypothesis that their mutations occurred in early development.

“Having identified the mutations, we were able to use statistical analysis to better understand cell dynamics during embryo development. We determined the relative contribution of the first embryonic cells to the adult blood cell pool and found one dominant cell – that led to 70% of the blood cells – and one minor cell. We also sequenced normal lymph and breast cells, and the results suggested that the dominant cell also contributes to these other tissues at a similar level,” said Inigo Martincorena, Ph.D., co-author. “This opens an unprecedented window into the earliest stages of human development.”

The study also allowed the team to measure the mutation rate during early embryonic development for the first time. Previous work estimated that on average, one mutation occurred per cell division, but this investigation was able to show that three mutations appeared in daughter cells for each division.

“This is a significant step forward in widening the range of biological insights that can be extracted using genome sequences and mutations,” Professor Sir Mike Stratton, lead author and Director of the Sanger Institute said. “Essentially, the mutations are archaeological traces of embryonic development left in our adult tissues, so if we can find and interpret them, we can understand human embryology better. This is just one early insight into human development, with hopefully many more to come in the future.”

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