Molecular Clocks Control Mutation Rate in Human Cells

A copy of the human genome is present in each and every cell in the human body. It is believed that during a person's lifetime all cells acquire mutations. While some of these mutations are through external exposure like tobacco smoking or sunbathing, there are certain other mutational processes that happen internally and occur continuously at a constant rate over years. Such mutations are typically clock-like “ that is for a certain age of a person, there are likely to be certain number of mutations.

In a new research published in Nature Genetics two clock-like mutational processes have been discovered in human cells and the rates at which the two clocks tick in different human cell types have been determined. It is understood that these mutational processes could have a significant role to play in many human cancers and in human ageing.

Previous studies on cancer cells have found that mutations often leave a molecular fingerprint, called a mutational signature, on the genome of a cancer cell. In order to identify the mutational signatures of clock-like mutational processes in the human body, the researchers of this study looked at the DNA sequences of 10,250 cancer genomes, from 36 different types of cancer. 33 mutational signatures were found in the cancer genomes by the researchers of which only two exhibited clock-like features. Named Signature 1 and Signature 5, these signatures showed a correlation between the age of the patient when the cancer was diagnosed and the number of mutations found in each cancer sample.

Dr. Ludmil Alexandrov, Oppenheimer Fellow at Los Alamos National Laboratory in the USA and author of the study said that this finding is very significant as it solves a longstanding question. This study shows that mutational molecular clocks exist and that there are two separate clock processes that are constantly degrading DNA. The rate at which these clocks tick may determine the ageing of this cell and the likelihood for it to become cancerous.

The researchers investigated 7,329,860 somatic mutations from the cancer genomes calculated which mutations each cell had had before it became a cancer cell. It helped them understand the rate at which the mutational clocks had generated the mutations. This information could be crucial to understand biology of cancer development and metastasis.

Dr. Julian Sale, an author on the paper and group leader at the MRC Laboratory of Molecular Biology opined that this study have practical implications for cancer patients. It could lead to clinicians being able to compare the genomes of a primary tumour and any metastases, and find out how long it took to spread. It can also assist doctors in predicting for new patients how quickly a cancer may change, like how fast it can spread or acquire resistance to a drug. It will help doctors in planning the best course of treatment.

It was found that both Signature 1 and Signature 5 clock-like processes accumulated mutations at a constant rate over time and operated in essentially all cell types in the human body. But, it was also seen that they exhibited different mutation rates in the different tumour types and surprisingly they also had different rates to each other, even in the same type of tumour. This suggests that they are likely to be due to two different biological processes.

Signature 1 had the highest mutation rate in cells with high turnover rates, like stomach and colorectal cells, and seemed to be due to certain methylated cytosine bases transforming into thymine, leading to mismatches in the genome that get converted into mutations when a cell divides. The mutational process for Signature 5 is still not very clear. Unlike Signature 1, the Signature 5 mutation rate did not correlate with the number of cell divisions. Further study is needed on both these processes to understand their full roles in the cell.

Professor Sir Michael Stratton, corresponding author and Director of the Wellcome Trust Sanger Institute remarked that it is the first identification and quantification of mutational molecular clocks, and was carried out by looking through the “cracked lens” of cancer genomes. In future research large-scale sequencing of all types of normal cells to refine this clock-like mutation rates is planned.

Reference Links:

https://medicalxpress.com/news/2015-11-molecular-clocks-mutation-human-cells.html

https://www.sanger.ac.uk/news/view/molecular-clocks-control-mutation-rate-human-cells