Studies offer insight into how the human body develops and acquires mutations throughout life

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 today (25 August 2021) in Nature, are the first to analyze 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.

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 fertilized egg of each person. By analyzing 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 fertilized 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.

Dr Tim Coorens, a first author of the studies from the Wellcome Sanger Institute, said: “By examining the history of each cell, we’ve been able to retrace the development of a 78-year-old person all the way back to the first cell division. It was surprising to find how much variation there was in human development between individuals, and especially between tissues in the same person. It’s not as straightforward as the same set of cells contributing to the heart or kidneys, say, in every person. What our study makes clear is that human embryology is not set in stone.”

In the other study, scientists analyzed the genomic data to compare the mutational landscape in 29 different tissues. Researchers at Newcastle University supplied samples from a further 11 men, from which a further 162 micro-biopsies were taken to explore germline mutation in greater detail.

Such analysis is able to detect patterns of mutation, known as mutational signatures, that can be attributed to particular biological processes or substances the body is exposed to that alter the genome, such as alcohol or tobacco.

The team found ubiquitous mutational signatures across all of the tissues studied, including two that result from the normal functioning of human cells, called SBS1 and SBS5. Other signatures were specific to certain tissues, such as SBS18, which may be indicative of oxidative damage. There was substantial variability in the mutational landscape between tissues in the same individual.

Notably, the mutation rate for spermatogonia – immature sperm cells derived from stem cells in the testes – was found to be much lower than for other cells in the body.

Dr Raheleh Rahbari, a senior author of the studies from the Wellcome Sanger Institute, said: “This study advances our understanding of the diversity of mutation rates and processes within the human body. It has long been suspected that the germline acquires fewer mutations than other cells, in order to preserve the genome that will be passed on to the next generation. Here we reveal for the first time that low germline mutation rate is not the result of selection of sperm with fewer mutations during conception or development, but is a global feature of the male germline compared to other cells. But what is not clear is how spermatogonia, which must divide to create vast numbers of sperm cells, maintain such a low mutation rate.”

The studies will help to establish baselines of normal development and how we acquire mutations throughout life.

Exploring the human body via the mutations cells acquire as we age is as close as we can get to studying human biology in vivo. Our life history can be found in the history of our cells, but these studies show that this history is more complex than we might have assumed.”

Dr Luiza Moore, First Study Author, Wellcome Sanger Institute

Professor Sir Mike Stratton, a senior author of the studies and Director of the Wellcome Sanger Institute, said: “These studies explore the landscape of mutations that normally occur during the course of life in every cell of the human body, providing new insights into human development and important differences between cell types.”