Like archeologists digging into the earth, layer by layer, until they reach the earliest artifacts, genomic scientists at Wellcome Trust Sanger Institute traced the mutational histories of human adults—all the way back to the two-cell stage of embryonic development. The scientists found that mutational rates very early in development are higher than previously estimated. The scientists also discovered that the earliest mutations can skew subsequent development, such that the doublings of a so-called dominant cells can convey a new mutation to a disproportionally large proportion of the adult body.

These findings were detailed March 22 in the journal Nature, in an article entitled “Somatic Mutations Reveal Asymmetric Cellular Dynamics in the Early Human Embryo.” The article describes how the Wellcome Trust Sanger Institute team used whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations.

“We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures,” wrote the article’s authors. “We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio.”

Essentially, the researchers found that the first two cells in an individual’s development contribute differently to the whole body. One cell gives rise to about 70% of the adult body tissues, whereas the other cell has smaller contribution, leading to about 30% of the tissues. These skewed contribution dynamics can also occur in some cells in the second and third generations.

The early mutations, originally pinpointed in normal blood cells from cancer patients, were then sought in cancer samples that had been surgically removed from the patients during treatment. Unlike normal tissues composed of multiple somatic cell clones, a cancer develops from one mutant cell. Therefore, each proposed embryonic mutation should either be present in all the cancer cells in a tumor or in none of them. This proved to be the case, and by using these cancer samples, the researchers were able to validate that the mutations had originated during early development.

“Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer,” the authors of the Nature article explained. “They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues.”

Their study, the authors suggested, provides insights into the mutation rates, mutational processes, and developmental outcomes of cell dynamics that operate during early human embryogenesis.

“This is the first time that anyone has seen where mutations arise in the very early human development. It is like finding a needle in a haystack,” said Young Seok Ju, M.D., Ph.D., first author from the Wellcome Trust Sanger Institute and the Korea Advanced Institute of Science and Technology (KAIST). “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.”

“Having identified the mutations, we were able to use statistical analysis to better understand cell dynamics during embryo development,” added Inigo Martincorena, Ph.D., from the Sanger Institute. “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. This opens an unprecedented window into the earliest stages of human development.”

During this study, the researchers were also able to measure the rate of mutation in early human development for the first time, up to three generations of cell division. Previous researchers had estimated one mutation per cell division, but this study measured three mutations for each cell doubling, in every daughter cell.

Mutations during the development of the embryo occur by two processes—known as mutational signatures 1 and 5. These mutations are fairly randomly distributed through the genome, and the vast majority of them will not affect the developing embryo. However, a mutation that occurs in an important gene can lead to disease such as developmental disorders.

“This is a significant step forward in widening the range of biological insights that can be extracted using genome sequences and mutations,” concluded Sir Michael Stratton, Ph.D., lead author on the paper and director of the Sanger Institute. “Essentially, the mutations are archeological 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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