Somatic mutations: a genomic revolution hiding inside our cells

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Last Updated29/08/2023

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 due to our ability to sequence the genetic material in individual cells.

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 due 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 minuscule given the large size of the human genome.

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 i.e. there will be more somatic genetic mutations the older an individual is and the higher the turnover of the tissue.
Sometimes, a somatic genetic mutation can render a cell fitter than others, which leads to the formation of tumours.
- So these mutations are called driver mutations.
In their genomic composition, these cells are similar to each other, but still different enough due to a handful of genetic variants.

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.
Specifically, using advanced microfluidics and high-throughput sequencers, we can now sequence tens of thousands of cells from a tissue at the same time.
This opens big windows into genes and the functional diversity of cells in the human body.

Somatic genetic variants play an important role in the development of cancers.
Somatic changes can cause 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 patterns called mutational signatures of genetic variations are characteristic of specific cancers.
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.

The other major application for somatic changes is in the development of genetic diseases.
Many genetic conditions arise from somatic genetic variants.
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, alleviating the severity of the disease in many individuals.

The U.S. National Institutes of Health recently launched a programme called the ‘Somatic Mosaicism across Human Tissues’ (SMaHT) Network focused on understanding the breadth of somatic mosaicism
It aims to catalyse our study of the field by
- Discovering somatic variants
- Developing tools and resources with which to study them
- 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.

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.
It also empowers us to reshape our understanding of the fundamental aspects of evolution.