How And Where Do Mutations Occur Throughout The Body?

Posted on 15 September 2021

Genetic mutation is inescapable for organisms living on this planet. The genetic information contained within our cells is constantly being damaged, be it by ultraviolet light and other radiation from space, radiation from the ground, or chemicals produced in essential reactions within the cells themselves. No matter how good our cells are at repairing this damage, sometimes the genetic code becomes altered in what is known as a genetic mutation. Mutations can also be introduced as a result of copying errors when a cell divides, despite the remarkably effective proofreading mechanisms in place. Scientists have estimated that genetic mutations occurring throughout the human body each day number in the trillions.

Why Mutations Haven’t Killed You Yet

The wrong combination of mutations can lead to cancer, yet the vast majority are harmless. There are a few reasons for this. The genetic code is written in such a way that a single ‘letter’ being changed may not actually change the meaning of the code that it is part of. Even if it does, the function of the protein that is encoded may not be affected. If the function of a protein is affected, it is unlikely to have a significant effect on the tissue to which the cell belongs. Finally, cells are able to self destruct in a process called apoptosis if harmful mutations occur.

Although most mutations are harmless, they are also there to stay. Once a mutation slips through the net, that mutation will be passed on to daughter cells during cell division. Those cells will gain and pass on mutations of their own and so on. This means that as we age, not only are our cells more likely to bear mutations that prime them to become cancerous, but our cells also become more and more genetically dissimilar from each other. Even mutations that aren’t ‘pre-cancerous’ are thought to negatively effect the function of cells and tissues and thereby contribute to the ageing process. It therefore benefits us to improve our understanding of these mutations, how and where they occur, and how they relate to the ageing process.

Genes and cancer
It takes more than a single mutation to make a cancer cell. As the number of cells in a tissue that have cancer-driving mutations increases, the probability that one more mutation will result in cancer rises.

Mapping Mutations Throughout The Body

These mutations do not occur at the same rate in all tissues, with cells that divide more rapidly and cells that are exposed to more sources of damage (unsurprisingly) tending to accumulate mutations at a higher rate. Using sequencing technology, it is possible to study the frequency and the nature of genetic mutations within a given tissue. The occurrence of mutations has been mostly studied in cancers, and less is known about the occurrence of mutations in non-cancerous tissues throughout the body. This is what researchers set out to study in a paper published in Genome Biology.

The researchers used RNA sequencing, which is used to read the sequence of the RNA templates copied from the DNA code, in order to catalogue mutations from over 7500 tissue samples across 36 different tissues throughout the body. They then compared mutation rates in different tissues and different individuals, and investigated what factors were associated with greater mutation within a given sample. They also studied the occurrence of cancer-driving mutations in normal tissues.

What Affects The Frequency Of Mutations?

In support of what has already been observed, tissues that had more frequent mutations than average included those most often exposed to mutagens from the environment, and those with a high rates of cell division and turnover. These included tissue samples from the skin, lung, blood, oesophageal mucosa, spleen, liver, and small intestine. On the other end of the spectrum were tissues with low environmental exposure to mutagens and/or low rates of cell division. These tissues, which included brain, prostate, adrenal gland, and several types of muscle tissue (such as heart and skeletal muscle) had lower than average mutation rates.

This graph shows the number of mutations in each tissue according to sequencing depth (the number of unique sequences read). The straight blue line represents the number of mutations that would be expected for a given depth of sequencing. Tissues above this line have more mutations than would be expected, while those below the line have fewer than expected.

Mutations were unsurprisingly more common in tissue samples from older individuals, though the importance of age for different tissues varied. In terms of the number of mutations detected, blood was most strongly affected by age. Strong age-associations were also found in several brain regions, and in the skin when looking specifically at C to T mutations (the most common type of mutation to occur due to ultraviolet light exposure). Gender and ethnicity also affected mutation rates in some tissues. For example, some mutations in adipose (fat), liver, and adrenal gland tissue were more common amongst females, but researchers didn’t find any mutations that were significantly more common in males. They also found a higher rate of aforementioned C to T mutations sun-exposed skin compared to non-exposed skin, but this difference was only present in Caucasians and not African-Americans. This is not surprising considering the protection from UV light afforded by higher melanin content in the skin.

Natural Selection Within Human Tissues

Since mutations are passed on to the cell’s progeny during division, a mutation that is advantageous to the survival and future division of a cell will tend to become more common within a tissue in a process akin to evolution by natural selection. This is a major problem in cancers, where cancer cells will regularly acquire mutations that make them more malignant (such as by allowing them to divide faster or resist destruction by the immune system). In cancers, mutations that may have a significant impact on the cell (such as ‘nonsense mutations’, which result in an unfinished and usually useless protein being produced) are generally selected for. However, the researchers in this study found that in healthy tissues the opposite was true. Nonsense mutations were selected against and were less common compared with mutations with a lower impact on the cell, such as ‘synonymous mutations’ (mutations that do not change the encoded protein in any way). This is probably because in healthy tissue, nonsense mutations are more likely to impair the function of the cell or trigger cell death than less impactful mutations.

Different tissues were also observed to have distinctive ‘patterns of mutation’ – that is to say that some groups of specific mutations are associated with certain tissues. This could suggest that cells in different tissues are subject to different ‘selective pressures’ and go down different evolutionary paths as a result. Differing expression of genes that affect mutation rates, such as DNA repair genes, as well as how the DNA is packaged in different tissues, seem to be associated with these mutation patterns.

The Occurrence Of Cancer-Promoting Mutations

Genetic mutations associated with the development of cancer occurred with varying frequency in different tissues. One might expect tissues with higher overall mutation rates to also have higher rates of cancer-driving mutations, however this was not always the case. Sun-exposed skin had the highest levels of mutations in genes associated with cancer, while brain tissue had among the lowest levels. Interestingly, heart and muscle tissue had higher than expected levels of cancer-associated mutations, despite having lower than average rates of mutation overall.

A graph showing the proportion of mutations occurring in 53 genes known to carry cancer-driving mutations.

Together, these findings help to shed further light on the patterns of mutation that occur in different tissues, a topic that hasn’t yet been studied in great detail. They reinforce our understanding of why these mutations occur at different rates throughout the body, and also reveal genetic changes during ageing that precede the development of cancer.


The somatic mutation landscape of the human body:

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