New insights into how the human body develops from one cell into trillions, and the genetic mutations that cells pick up along the way, have been generated by two studies from scientists at the Wellcome Sanger Institute, the University of Cambridge and their collaborators.
The studies, published in Nature, are the first to analyse somatic mutation in normal tissues across multiple organs within and between individuals. Researchers were able to retrace human development, including in a 78-year old individual, all the way back to the first cell division, as well as confirm that the mutation rate in the germline cells is much lower than in the other tissues of the body.
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This fundamental knowledge will help to establish baselines for human development and how we acquire mutations throughout life, in both the cells of our body and the genetic code that is passed on to the next generation. Knowing what ‘normal’ development and ageing looks like will in turn help to better understand the onset of disease.
In recent years, technological and experimental advances have allowed researchers to study somatic mutation in healthy tissue. This has been achieved by taking micro-biopsies of just a few hundred cells, which are then genome sequenced to an incredibly high degree of accuracy.
From the very first cell division, an individual’s cells experience damage to their genome. Most of this damage is repaired by the cell, but some changes to the letters of DNA, known as somatic mutations, persist. Through cell division, these mutations are then passed on to the next generation of cells by progenitor cells. When two cells share the same mutations, this implies a shared ancestry and these markers can be used to trace development back through time.
The genetic code that is passed on via sperm and egg cells during reproduction, known as the germline, has long been thought to be protected from the mutational processes that occur in the rest of the body as we age. This helps to ensure that individuals start life with a genome that is ‘intact’, or free from the mutations acquired by the parents during their lives.
For these studies, samples of normal tissue from three adult individuals were supplied by researchers at the MRC Cancer Unit, University of Cambridge and a commercial provider. Researchers at the Wellcome Sanger Institute used laser microdissection to cut out tiny biopsies of just a few hundred cells, covering a wide range of tissues from each donor. These biopsies were then whole genome sequenced so that somatic mutations within and between individuals could be compared.
In one study, researchers created a family tree of cell lineages for each individual stretching all the way back to the fertilised egg of each person. By analysing genomes from the different tissues they could use mutations shared by cells to trace how the tissues of the body had formed from a single cell.
This analysis revealed significant variation between individuals in which cells went on to form particular tissues. For example, the two progenitor cells created by the division of the fertilised egg cell contributed relatively equally to the body of one individual, but in another donor 93 per cent of their cells were descended from just one of the original progenitors.
Source: Sanger Institute