The human genome has 23 pairs of chromosomes, one inherited from each of our parents. The genome is the blueprint of our genetic makeup. The ovum and the sperm carry these blueprints from our parents. After fertilisation, the combined single cell, with the 23 chromosomes, starts to divide, copying the genetic material over and over to nearly a trillion cells – which make up the human body.
As the cells divide, the DNA is copied with extremely high accuracy thanks to proteins that proofread and correct errors in the DNA. But despite this mechanism, various studies have estimated that there is still an error rate of 0.64-0.78 mutations per billion base pairs per division. But this rate is also minuscule given the large size of the human genome.
‘Copy-paste’ mistakes
The number and effect of these errors vary significantly, depending on the stage of development or the point in the life-cycle at which they occur. An error that occurs in the DNA after birth but during development is called a somatic genetic mutation. Their occurrence is driven by the repeated ‘copy-pasting’ of the genome – which means there will be more somatic genetic mutations the older an individual is and the higher the turnover of the tissue. Turnover is the replacement of old cells with new ones.
Sometimes, a somatic genetic mutation can render a cell fitter than others, which lead to the formation of tumours. So these mutations are called driver mutations.
Given these details, we should think of the human body as a mosaic of cells rather than as a clone of a single cell. In their genomic composition, these cells are similar to each other, but still different enough thanks to a handful of genetic variants. While most of these variants may not have a function, a small number will if they lie in parts of the genome responsible for encoding proteins or regulating them.
Knowledge explosion
Somatic genetic variants are important for a number of normal physiological processes. For example, the immune cells in our body, which produce antibodies, undergo an enormous amount of somatic changes to create diverse proteins. These proteins recognise and bind to specific pathogens, forming a ‘library’ of cells, each with a specific protein. During an infection, the body selects cells from this library, depending on which can bind to a pathogen better, and uses them to make antibodies.
Scientists have known of somatic variants and their role in diseases for many years now, but there has been an explosion in the amount of data and knowledge only recently. This was due to our ability to sequence the genetic material in individual cells. Specifically, using advanced microfluidics and high-throughput sequencers, we can now sequence tens of thousands of cells from a tissue at the same time, opening big windows into the genes in and the functional diversity of cells in the human body.
Cancer’s signatures
Somatic genetic variants play an important role in the development of cancers. We now know that somatic changes can cause a cancer to develop and that cancers can accelerate the development of somatic changes. So they can help with early detection, diagnosis, and prognosis.
Early detection and diagnosis of cancers rely on the fact that certain genetic variations and patterns – called mutational signatures – of genetic variations are characteristic of specific cancers. There are technologies to detect DNA from tumour cells that has ‘escaped’ the cells into blood or fluids, to spot a cancer early. Similarly, certain variations in a cancer could be used as a signature of the disease’s progress and/or to track how a tumour has responded to some course of therapy.
Under-recognised cause
The other major application for somatic changes is in the development of genetic diseases. Many genetic conditions arise from somatic genetic variants. Obviously, these conditions are not inherited from either parent but are due to new genetic variations that have arisen during development. So the severity and distribution of the disease depends on how early or late during development the corresponding mutation occurred.
In fact, somatic genetic variants are an under-recognised cause of many immune disorders that are the result of mutations in a single gene, including primary immunodeficiency disorders. In some instances, somatic changes can be beneficial in a genetic disease – by changing a deleterious change to a normal one, a phenomenon known as revertant mosaicism. For example, around 10% of cases of Wiskott-Aldrich syndrome, a rare genetic immunodeficiency, have been found to have revertant mosaicism, as a result alleviating the severity of the disease in many individuals.
SMaHT Network
The U.S. National Institutes of Health recently launched a programme focused on understanding the breadth of somatic mosaicism and the biological and clinical significance of such somatic events in humans. Called the ‘Somatic Mosaicism across Human Tissues’ (SMaHT) Network, it aims to catalyse our study of the field by discovering somatic variants, developing tools and resources with which to study them, and improving our ability to analyse, interpret, and organise them in different biological and clinical contexts.
In effect, SMaHT should be able to deliver novel biological insights using a data-centric approach. The U.S. government has for now invested $140 million in a SMaHT-led effort to characterise somatic variants in 10-15 tissues from 150 post-mortem samples obtained from deceased individuals.
As we plumb more intricate depths of the cells that we are made of, and their wondrous diversity, we also take strides on the road to usher in innovative approaches to understand and manage the diseases that assail us. The ability to scrutinise our genes at the level of single cells also empowers us to reshape our understanding of the fundamental aspects of evolution.
The authors are senior consultants at the Vishwanath Cancer Care Foundation. All views and opinions are personal.
