Molecular clocks control mutation rate in human cells

November 9, 2015, Wellcome Trust Sanger Institute
DNA
Credit: NIH

Every cell in the human body contains a copy of the human genome. Through the course of a lifetime all cells are thought to acquire mutations in their genomes. Some of the mutational processes generating these mutations do so in bursts and these will often be through external exposures such as sunbathing or tobacco smoking. Other mutational processes, however, may be internal to the cell and generate mutations continuously, at a constant rate over decades. If so the mutations they generate will be "clock-like", with the number of mutations present correlating with the age of the person. In research reported in Nature Genetics two clock-like mutational processes have been found in human cells and the rates at which the two clocks tick in different human cell types have been determined.

These clock-like mutational processes could ultimately be responsible for a large proportion of human and contribute to human ageing.

The genomes of cancer cells held the key to finding these molecular clocks. Previous work on cancer had revealed that often leave a molecular fingerprint, called a mutational signature, on the genome of a cancer cell. To identify the mutational signatures of clock-like mutational processes in the , this study looked at the DNA sequences of 10,250 cancer genomes, from 36 different types of cancer.

The researchers found 33 mutational signatures in the cancer genomes, but only two had clock-like features. These two clock-like processes, termed Signature 1 and Signature 5, showed a correlation between the number of mutations found in each cancer sample and the age of the patient when the cancer was diagnosed.

"This is a hugely exciting finding as it solves a longstanding question. Not only has this study proved that mutational molecular clocks exist, it has also shown that there are two separate clock processes that are constantly degrading DNA," said Dr Ludmil Alexandrov, corresponding author and Oppenheimer Fellow at Los Alamos National Laboratory in the USA. "How fast these clocks tick in a cell may well determine both the ageing of this cell and the likelihood for it to become cancerous."

The molecular clocks generate mutations at a steady rate, the 'ticking' rate of the clock, and accumulate more mutations with age. By investigating 7,329,860 from the cancer genomes, the researchers were able to effectively look back in time, calculating which mutations each cell had had before it became a cancer cell. This showed them how fast the mutational clocks had generated the mutations. This information could help researchers understand the biology of cancer development and even look at the rate that primary cancer cells spread to other parts of the body (metastasis).

"This study is important and could have practical implications for cancer patients. In the future it could lead to clinicians being able to compare the genomes of a primary tumour and any metastases, and determine the length of time it had taken to spread," said Dr Julian Sale, an author on the paper and group leader at the MRC Laboratory of Molecular Biology. "Because the clock continues to tick in the cancer, it may also be possible to help doctors predict for new patients how quickly a cancer may change, for example to become metastatic to other parts of the body or to acquire resistance to a drug. This could help doctors plan the best course of treatment for a patient."

Both Signature 1 and Signature 5 clock-like processes accumulated mutations at a constant rate over time and operate in essentially all cell types in the human body. However they exhibited substantially 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. The fact that they behave differently indicates that they are likely to be due to two different biological processes.

The mutation rate of Signature 1 was highest in cells with high turnover rates, such as stomach and colorectal cells, and appeared to be due to certain methylated cytosine bases transforming into thymine, leading to mismatches in the genome which are converted into mutations when a cell divides. The mutational process for Signature 5 is mysterious. However, unlike Signature 1, the Signature 5 mutation rate did not correlate with the number of cell divisions. More research is needed on both these processes to understand their full roles in the cell.

"This is the first identification and quantification of mutational , and was carried out by looking through the "cracked lens" of . Over the next few years, we hope to perform large-scale sequencing directly of all types of normal to refine these clock-like mutation rates" said Professor Sir Michael Stratton, corresponding author and Director of the Wellcome Trust Sanger Institute. "In addition, further research is particularly needed to understand the nature of the mutational processes generating these clock-like mutations."

Explore further: Researchers discover genetic imprints and signatures left by DNA-damaging processes that lead to cancer

More information: Alexandrov LB et al., (2015) Clock-like mutational processes in human somatic cells. Nature Genetics. DOI: 10.1038/ng.3441

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JVK
3.9 / 5 (15) Nov 09, 2015
Through the course of a lifetime all cells are thought to acquire mutations....


This suggests acquisition of the mutations is like magic, despite experimental evidence that it is biophysically constrained during thermodynamic cycles of protein biosynthesis and degradation that link microRNAs from amino acid substitutions and adhesion proteins to protection of organized genomes from virus-driven genomic entropy.

See: Continuous Histone Replacement by Hira Is Essential for Normal Transcriptional Regulation and De Novo DNA Methylation during Mouse Oogenesis
http://www.scienc...15007777

This suggests virus-driven genomic entropy is biophysically constrained by RNA-directed DNA methylation in the context of nutrient-dependent organism-level thermoregulation and homeostasis.

While waiting for the next attack on Ben Carson's creationist beliefs, is any evolutionary theorist willing to tell us about de novo methylation?
Captain Stumpy
1.9 / 5 (13) Nov 09, 2015
This suggests acquisition of the mutations is like magic
no it doesn't
your claims are ranging between blatantly false claims (like the quoted) and unsubstantiated conjecture (opinion) to untested claims
http://www.auburn...ion.html

While waiting for the next attack on Ben Carson's creationist beliefs
1- who gives a sh*t about what carson believes?

2- there is NO SCIENCE in the creationist movement. this is not a matter of debate- it is a proven fact validated and upheld by the US Supreme Court

reported for trolling and baiting
anonymous_9001
1.9 / 5 (13) Nov 09, 2015
You can find most everything you need to know about de novo methylation here:

http://m.sciencemag.org/content/286/5448/2287
http://www.scienc...11001582
http://m.genesdev.cshlp.org/content/16/1/6.long
http://www.method...iew.html
JVK
3.9 / 5 (14) Nov 09, 2015
[q[ You can find most everything you need to know about de novo methylation here:

Thanks, but I can't find where the methyl groups come from. Is that why they call it de novo methylation? If they do not know that methylation is nutrient-dependent and RNA-directed, they probably think it magically occurs, which means it might automagically link mutations to evolution, too.

But see for comparison: RNA-directed DNA synthesis and RNA tumor viruses https://books.goo...p-PWZKLk

1- who gives a sh*t about what carson believes?


Thanks for asking. All intelligent people want to know why other intelligent people believe in creation so that they can compare their beliefs to the beliefs of evolutionary theorists who won't address the claims about the resurrected bacterial flagellum. https://www.youtu...fKOozG40
anonymous_9001
2.1 / 5 (14) Nov 09, 2015
Thanks, but I can't find where the methyl groups come from.


The exclusive donor for DNA methyltransferase is SAM, S-Adenosyl methionine, derived from ATP and methionine.

methylation is ... RNA-directed


I'm not sure what you mean here. DNMT1 and DNMT3 bind directly to DNA, identifying CpGs. DNMT2 (renamed TRDMT1) methylates tRNA, but the other two have nothing to do with RNA.
JVK
3.9 / 5 (14) Nov 09, 2015
I'm not sure what you mean here.


Have you considered learning something about RNA-directed DNA methylation?

https://www.googl...directed

When I claim that methylation is nutrient-dependent and RNA-directed, I mean that methylation is nutrient-dependent and RNA-directed. I do not mean that
methylation is ... RNA-directed
because you left out the context of the epigenetic pathway that links nutrients to DNA methylation.

See instead (you FOOL): RNA-directed DNA methylation: an epigenetic pathway of increasing complexity.http://www.ncbi.n...24805120
Captain Stumpy
1.7 / 5 (12) Nov 09, 2015
All intelligent people want to know why other intelligent people believe in creation so that they can compare their beliefs to the beliefs of evolutionary theorists who won't address the claims about the resurrected bacterial flagellum
@jk
1- no, they don't, because intelligent people are not all creationists
logical fallacy

2- beliefs are for religion, not science: Evolution is a Theory (a scientific theory) thus is supported by empirical data, not beliefs
so you posted even more logical fallacies

3- this is a science site, specifically, medical: not a religious forum

reported for religious and pseudoscience creationist proselytizing
JVK
3.9 / 5 (14) Nov 09, 2015
How can anyone be ignorant enough to continue claiming that
Evolution is a Theory (a scientific theory) thus is supported by empirical data, not beliefs
without using the theory to explain how the bacterial flagellum re-evolved over the weekend?

Captain Stumpy might just as well claim that he will belief anything anyone tells him, because he is the most ignorant theorist of all -- one who claims a theory has explanatory power when it explains nothing about biologically-based cause and effect.
JVK
3.9 / 5 (14) Nov 09, 2015
See also: http://medicalxpr...nia.html

Again we see that the speed at which protein biosynthesis and degradation occurs links nutrient-dependent microRNAs to RNA-mediated cell type differentiation, which is perturbed by the viral microRNAs linked to pathology in specific tissue types.

It amazes me that no matter how many examples come forth each day, evolutionary theorists continue to live in a state of denial and hope that someone will still take them seriously.
anonymous_9001
1.9 / 5 (13) Nov 09, 2015
RNA-directed DNA methylation: an epigenetic pathway of increasing complexity.http://www.ncbi.n...24805120


This, unlike most everything else you post, is actually relevant and matches up with terminology you use. Thank you.

If you did this more often, we could have much more fruitful discussions like this (ignoring all the insults).

Even so, what I said before still stands. Not all methylation is RNA-directed. The enzymes I mentioned earlier are mammalian and do not involve RNA and RdDM is only in plants. So, RNA-directed methylation is not fitting for a model that's supposed to apply to all organisms when only one kingdom has it.
Captain Stumpy
1.7 / 5 (12) Nov 09, 2015
might just as well claim that he will belief anything anyone tells him, because he is the most ignorant theorist of all
@jk
i am not a theorist any more than you are a diagnostician or microbiologist

and i don't "belief"[sic] things that can't be validated with evidence, which means, i don't "belief"[sic] in most of what you regurgitate here on PO/MEDx
it explains nothing about biologically-based cause and effect
Tell us, jk: what makes something a "scientific Theory"?
do you know? i'll help
A scientific theory is a well-substantiated explanation of some aspect of the natural world that is acquired through the scientific method and repeatedly tested and confirmed through observation and experimentation
https://en.wikipe...c_theory

thus, to refute a "theory" you must show it to be false
you have YET to do that to Evolution Theory, princess-mensa
JVK
3.9 / 5 (14) Nov 10, 2015
to refute a "theory" you must show it to be false


http://elifescien...4/e04837 Amino-acid sequence similarity predicts TF DNA-binding specificity

Mutations predict virus-driven genomic entropy.

If "...genomic conservation and constraint-breaking mutation is the ultimate source of all biological innovations and the enormous amount of biodiversity in this world." -- there is no experimental evidence to support that ridiculous claim. http://www.amazon...99661731

But no one can show that the ridiculous theory is false.

Fortunately, unless someone is addressing a biologically uninformed science idiot, there is no reason to discuss established scientific facts compared to ridiculous theories.
Captain Stumpy
1.7 / 5 (12) Nov 10, 2015
to refute a "theory" you must show it to be false
http://elifesciences.org/content/4/e04837
@ might i just add this, from your link
Flies look very different from humans, but both are descended from a common ancestor that existed over 600 million years ago. Some differences between animal species are due to them having different genes: stretches of DNA that contain the instructions to make proteins and other molecules.
it doesn't refute the Theory of Evolution, IT SUPPORTS IT WITH EVIDENCE

so, you failed epically to prove Evolution false...

ROTFLMFAO

princess mensa, Suuuper jeeynyus

are you sure you weren't a coyote in a previous life?
JVK
3.9 / 5 (14) Nov 10, 2015
You wrote:
so, you failed epically to prove Evolution false...


I wrote:
But no one can show that the ridiculous theory is false.


What kind of biologically uninformed science idiot parrots my claim and adds "IT SUPPORTS IT WITH EVIDENCE"

Not being able to prove that pseudoscience is nonsense does not mean that everything known to serious scientists about physics, chemistry, biology and molecular epigenetics can be dismissed by citing Lenski's experiments, which linked ecological variation to ecological adaptation via innate immune system differences in the cell types.

Biologically uninformed science idiots who report immune system adaptations in the context of mutations and evolution is a problem that all serious scientists have tried to deal with since 1964 when Dobzhansky wrote: "Biology, molecular and organismic" http://taxonomy.t...1964.pdf

Every other serious scientist gave up on fools like you and Andrew Jones.
JVK
3.9 / 5 (14) Nov 10, 2015
Re: "Biology, molecular and organismic" http://taxonomy.t...1964.pdf

"Ingram and others found that hemoglobin S differs from A in the substitution of just a single amino acid, valine in place of glutamic acid in the beta chain of the hemoglobin molecule."

Also:
"The notion has gained some currency that the only worthwhile biology is molecular biology. All else is "bird watching" or "butterfly collecting." Bird watching and butterfly collecting are occupations manifestly unworthy of serious scientists! I have heard a man whose official title happens to be Professor of Zoology declare to an assembly of his colleagues that "a good man cannot teach zoology. A good man can teach, of course, only molecular biology.

Such pronunciamentos can be dismissed as merely ridiculous. They are, however, caricatures of opinions entertained by some intelligent and reasonable people, whose views deserve an honest and careful consideration and analysis."
JVK
3.9 / 5 (14) Nov 10, 2015
Re: "...some intelligent and reasonable people, whose views deserve an honest and careful consideration and analysis."

That was more than 50 years ago, and you have continued to ignore all the scientific progress that links atoms to ecosystems via metabolic and genetic networks that link the epigenetic landscape to the physical landscape of DNA via RNA-mediated events that determine cell type differentiation in all living genera.

The fact that you follow me on phys.org and medicalxpress.com and plague the discussion groups with your foolishness exemplifies what may be the ultimate level of ignorance that can be achieved by any theorist who has lived at any time during the past 50 years.

If anyone ever erects a monument to honor ignorance, you will be the model represented in the sculpture or your name will be one of those engraved.

"James Stumpy" -- Biologically uninformed science idiot

In any case, you have already made history.

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