'DNA spellchecker' means that our genes aren't all equally likely to mutate

A study that examined 17 million mutations in the genomes of 650 cancer patients concludes that large differences in mutation rates across the human genome are caused by the DNA repair machinery.

'DNA spellchecker' is preferentially directed towards more important parts of chromosomes that contain key genes.

The study illustrates how data from medical sequencing projects can answer basic questions about how cells work.

The work, performed by two scientists from the EMBL-CRG Systems Biology Unit in Barcelona, will be published online in Nature on 23rd February.Copying the large book that it is our genome without mistakes every time a cell divides is a difficult job. Luckily, our cells are well-equipped to proof-read and repair DNA mistakes. Now, two scientists at the Centre for Genomic Regulation in Barcelona have published a study showing that mistakes in different parts of our genome are not equally well corrected. This means that some of our genes are more likely to mutate and so contribute to disease than others.

The scientists analysed 17 million 'single nucleotide variants' - mutations in just one nucleotide (letter) of the DNA sequence - by examining 650 human tumours from different tissues. These were 'somatic' mutations, meaning they are not inherited from parents or passed down to children, but accumulate in our bodies as we age. Such are the main cause of cancer. Many result from mutagens, such as tobacco smoke or ultraviolet radiation, and others come from naturally occurring mistakes in copying DNA as our tissues renew.

Ben Lehner and his team had previously described that somatic mutations are much more likely in some parts of the , thus damaging genes that may cause cancer. In a new paper published on 23rd February in Nature, they show that this is because genetic mistakes are better repaired in some parts of the genome than in others. This variation was generated by a particular DNA repair mechanism called "mismatch repair" - a sort of a spellchecker that helps fix the errors in the genome after copying. Lehner and Supek show that the efficiency of this 'DNA spellchecker' varies depending on the region of the genome, with some parts of chromosomes getting more attention than others.

Turning the tables on mutation rates

The work presented by Lehner and Supek sheds new light on a process that was unexplored - what makes some parts of the human genome more vulnerable to damage? "We found that regions with genes switched on had lower . This is not because less mistakes are happening in these regions but because the mechanism to repair them is more efficient", explains Ben Lehner, group leader, ICREA and AXA professor of risk prediction in age-related diseases at the EMBL-CRG Systems Biology unit in Barcelona. The 'mismatch repair' cellular machinery is extremely accurate when copying important regions containing genes that are key for cell functioning, but becomes more relaxed when copying less important parts. In other words, there appears to be a limited capacity for DNA repair in our cells, which is directed where it matters most.

The CRG researchers also found that the rate of mutation differs for around 10% of the human genome in cells originating from different tissues. In particular, liver, colorectal and lymphocyte malignancies present more mutations in some parts of our chromosomes, while breast, ovarian and lung cancers accumulate more mutations in other places. They found that genes that are important and switched on (expressed) in a particular tissue also exhibit less mutations in tumours of that tissue; the effect extends into the surrounding DNA. But what gives the important genes a higher resilience to damage?

"The difference is not in the number of new mutations but in the mechanism that keeps these mutations under control", comments Fran Supek, CRG postdoctoral researcher and first author of the paper. "By studying cancer cells, we now know more about maintaining DNA integrity, which is really important for healthy cells as well", he adds. Once the 'genomic spellchecker' has been disabled in a cell, the scientists observed that genetic information started decaying not only very rapidly, but also equally in all parts of the genome - neither the important nor the less important parts can were repaired well anymore. DNA is known to be switched off in some tumours from the colon, stomach and uterus, producing 'hypermutator' cancer in those organs.

The accumulation of harmful changes in DNA is a normal process occurring in all human cells every time they divide. Therefore this research not only makes an important contribution not only to cancer research, but also may lead to insights into aging and genetic diseases as well.


Explore further

Study sheds new light on aggressive cancer in children

More information: Nature, 23rd February 2015. DOI: 10.1038/nature14173
Journal information: Nature

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JVK
Feb 23, 2015
"... liver, colorectal and lymphocyte malignancies present more mutations in some parts of our chromosomes, while breast, ovarian and lung cancers accumulate more mutations in other places."

That is the basis for the claims I made in the context of nutrient-dependent RNA-directed DNA methylation and RNA-mediated amino acid substitutions that differentiate all cell types in all individuals of all species.

Amino acid substitutions stabilize DNA in organized genomes. Mutations perturb the biophysically constrained chemistry of protein folding that leads from entropic elasticity to anti-entropic epistasis and to the phenotypes exemplified in morphological and behavioral diversity of species from microbes to man.

See for examples: Nutrient-dependent/pheromone-controlled adaptive evolution: a model.
http://www.ncbi.n...24693353

See for criticisms of the model by someone who believes in beneficial mutations: http://www.ncbi.n...24959329

JVK
Feb 23, 2015
See also http://www.eureka...1815.php

The obvious links from food odors to thermodynamic cycles of protein biosynthesis and degradation are typically controlled by nutrient uptake, which links ecological variation to ecological adaptation via species-specific pheromones.

Adaptations across a continuum of increasing organismal complexity link epigenetically-effected brain development in insects to humans during their life history transitions.

The same model organism, S. cerevisiae, sets the stage for explanations of the nutrient-dependent pheromone-controlled RNA-mediated events in:

"Predicting phenotypic variation in yeast from individual genome sequences" http://www.nature...007.html

in:
"From Fertilization to Adult Sexual Behavior"
http://www.hawaii...ion.html

and in: http://www.ncbi.n...10980296

JVK
Feb 23, 2015
RNA-mediated epigenetic regulation of gene expression http://www.nature...863.html

"The mechanisms that distinguish between different types of transcription and that trigger the generation of different classes of small RNAs remain to be fully understood,
although the available evidence indicates a major role for RNA processing events that act co‑transcriptionally to determine whether a nascent transcript becomes a functional mRNA or is marked for processing by RNAi and other surveillance mechanisms."

The co-transscriptional mechanisms involve viral microRNAs and nutrient-dependent microRNAs that typically lead to healthy nutrient-dependent cell type differentiation via the biophysically constrained chemistry of protein folding in species from yeasts to primates.

Anyone who has not yet grasped the facts of RNA-mediated cell type differentiation is probably an evolutionary theorist.

JVK
Feb 24, 2015
Others may be afraid to comment about the obvious misrepresentations made by evolutionary theorists who have attributed 1) gain of function and 2) physiopathology to mutations since the early years of the 20th century. For example, in 2011 Ben Lehner's group reported

"...we considered only mutations in protein-coding regions and those predicted to cause loss-of-function alterations. Variation within regulatory regions and gain-of-function mutations are also expected to contribute to differences in phenotype, and incorporating the analysis of these into our approach could further improve predictions." -- Predicting phenotypic variation in yeast from individual genome sequences http://www.nature...007.html

Reports that link mutations to gain-of-function are still missing, at at time when nutrient-dependent amino acid substitutions are clearly linked to increasing organismal complexity in species from microbes to man.

JVK
Feb 24, 2015
Perhaps the problem stems from Dobzhansky.

In 1964: "...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!" (p. 443) http://icb.oxford...citation

In 1973: "...the so-called alpha chains of hemoglobin have identical sequences of amino acids in man and the chimpanzee, but they differ in a single amino acid (out of 141) in the gorilla." (p.127) http://www.jstor..../4444260

I think there is overwhelming experimental evidence that mutations lead to loss of function and that amino acid substitutions lead to gain-of-function. Does anyone disagree? If not, does anyone agree that evolutionary theorists who have been reporting beneficial mutations are biologically uninformed?

Perhaps there is a middle-ground. If so, why doesn't someone tell us about it?

JVK
Feb 24, 2015
The Israeli school system offers a clear alternative, which probably includes teaching the ridiculous theory of neo-Darwinism, at the same time students learn how ecological variation is linked to ecological adaptation. http://www.educat...olution/

The fact that pseudoscientific nonsense is still being taught by the biologically uninformed, ensures we will have yet another generation of biologically uniformed students in the US.

Compare that to what students will be learning about ecology -- if only in the context of one researcher from Israel: Eshel Ben-Jacob, who has linked physics, chemistry, and the molecular biology of cell type differentiation in species from microbes to humans.

2014 Modeling putative therapeutic implications of exosome exchange between tumor and immune cells http://www.pnas.o...abstract

In 2003, he started with "Bacterial self-organization"

JVK
Feb 24, 2015
http://earthsky.o...ar-death

Excerpt: "Astronomers belive that supernova explosions flood our Milky Way galaxy with high-energy radiation that probably contributed to the radiation background that produces mutation and drives the evolution of life on Earth."

My comment: In the context of the experimental evidence from this news release, what some astronomers supposedly believe is pseudoscientific nonsense akin to what evolutionary theorists supposedly believe.

The link from our sun's biological energy to controlled cell type differentiation via amino acid substitutions that stabilize DNA in the organized genomes of species from microbes to man can probably be compared to the ridiculous misrepresentations of theorists from any discipline.

If Feynman was not still dead, I'm rather certain he would address the evidence. https://www.youtu...X_0jDsrw

JVK
Feb 24, 2015
Re: the sun's biological energy compared to the radiation background that supposedly produces mutation and drives the evolution of life on Earth.

"What is crucially needed is predictions of new tests that will confirm the hypothesis that top-down causation is real, and not just an epiphenomenon. The papers by Jaeger (microbiology) and Noble (physiology) are strong steps forward in this regard. This is perhaps the area where most needs to be done, across the board in all domains. Areas where striking progress is being made in this regard are epigenetics [22] and social neuroscience [23]." http://rsfs.royal...abstract

In a series of published and unpublished works, I have shown the sun's biological energy can be epigenetically linked to what is known about social neuroscience.

Progress has already been made that eliminates nearly all the pseudoscientific nonsense taught by those who believe in definitions and assumptions.

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