Tag Archives: mutation

Does smoking kill by accumulation of mutations or by repeated exposure until the final crack?

We have a new paper at Sci Rep online “High degree of polyclonality hinders somatic mutation calling in lung brush samples of COPD cases and controls“.

It took a long time from my initial grant application at Sander Stiftung in Dec 2009 (where it was rejected), to the field work within the scope of the EvA study (where the PI Loems Ziegler-Heitbrock retired).

Followed by some first analysis together with Francesc at CNAG in Barcelona the final publication now appeared – my gratulations to Gian-Andri and Ivo Gut for their hard work!

Chronic obstructive pulmonary disease (COPD) is induced by cigarette smoking and characterized by inflammation of airway tissue. Since smokers with COPD have a higher risk of developing lung cancer than those without, we hypothesized that they carry more mutations in affected tissue.
We called somatic mutations in airway brush samples from medium-coverage whole genome sequencing data from healthy never and ex-smokers (n=8), as well as from ex-smokers with variable degrees of COPD (n=4). Owing to the limited concordance of resulting calls between the applied tools we built a consensus, a strategy that was validated with high accuracy for cancer data.
However, consensus calls showed little promise of representing true positives due to low mappability of corresponding sequence reads and high overlap with positions harbouring known genetic polymorphisms. A targeted re-sequencing approach suggested that only few mutations would survive stringent verification testing and that our data did not allow the inference of any difference in the mutational load of bronchial brush samples between former smoking COPD cases and controls.

So we would have probably needed a higher genome coverage on our brush sample mix. Or should we have sequenced more single cells as discussed in the paper?

At least, we now know, that sequencing at rather low coverage rate is not a screening tool for expected cancer development. Are there less pre-malignant lesions than expected? When looking at some other papers (Cancer Genome Atlas, esophagus, and more recently colon samples, I can only confirm what Iñigo Martincorena wrote

this study emphasizes how little we know about somatic evolution within normal tissues, a fundamental process that is likely to take place to varying degrees in every tissue of every species.

Somatic mutations accumulates with age. There may be even more mutations in the aging esophagus than in sun-exposed human skin. Lee-Six estimates 43.6 mutations /year, while I still have a gut feeling that there is no gradually accumulation of mutations (until the second hit) but a clonal expansion of a single

Martincorena 2018 https://science.sciencemag.org/content/362/6417/911

bronchial cell, hit by a single smoke stream. With this hypothesis, smoking would not kill by accumulation of deleterious mutations, but by the never ending re-exposure until the ultimate deleterious mutation occurs.

Many more of these timeline studies will be necessary to explain why the lung cancer risk drops immediately after you stop smoking.

One mutation every day

At least some people believe that once it’s published in Nature, it must be superior science – even when it’s rather trivial (or even wrong). There is a category “Brief Communications Arising” but when you are trying to get your comments there you will get this message by email:

In the present case, while we appreciate the interest of your comments to the community, we do not feel that they challenge key data or conclusions of the papers by Pleasance et al., and therefore we cannot offer to consider your paper for publication in our Brief Communications Arising section.

Pleasance et al. is a recent paper accompanied by a press release that tells you Continue reading One mutation every day

How we inherit acquired traits – all about non random mutations in the human genome

This is just a material collection for a forthcoming review. I am collecting links to studies showing an increased mutation rate in CpG islands that may possibly fix gene activation status. Continue reading How we inherit acquired traits – all about non random mutations in the human genome

A longe fuse

Mutation accumulation in the human genome is a largely neglected research field. Most mutations have a very small effect (if any) and may be compensated by environmental improvements. I have already argued in that way in my 2003 Triple T paper and will reiterate it soon in PLOS medicine (just found that James Crow 1997 in PNAS and 2000 in nat gen rev had the same opinion). In principle, the improvement of sanitation and better medical care is leading to a retention of mutations that would be otherwise subject of purifying selection.
Another important factor seems to be the increase of parental age in Western societies. A 20 year old man had about 150 chromosome replications while a 40 year old had about 610 replications. To count the number of your somatic mutations, you need to add all events of your lifetime plus the age of your father at birth minus 9 months … Even with the high fidelity of polymerases, DNA replication remains an error prone process leading eventually to an increase of germline mutations (as may be seen with achondroplasia, Apert syndrome, neurofibromatosis and prostate cancer). With the increasing age of fathers we are now nearly doubling the absolute number of mutations every generation – and we keep them in the pool in contrast to previous centuries. Crow in PNAS 1997 even said

I do regard mutation accumulation as a problem. It is something like the population bomb, but it has a much longer fuse

timebomb.png

Addendum 20 Nov 2013

In another post, I detailed the 3,93 figure derived from cancer tissues. The best human estimate at the moment is in this Cell paper that shows a rate between 2.0 and 3.8 x 10^-8 cells. Sperm sequencing may not represent a good model as there are too many degenerate cells.

Addendum 1 Jan 2021

Here is a new nature medicine paper on cell turnover.

What I do not understand – shouldn’t we  have a much higher leukemia rate in the population? Leukemia is only  on the11th place.

Addendum 29 Apr 2021

Another Nature study shows

Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues …

this could be the answer to my previous question

These mutations may result from the interplay between endogenous DNA damage and repair that occurs in cells at all times. The similar mutation burden and signatures in granulocytes and hae- matopoietic stem cells, despite a different divisional load, could also be consistent with a time-dependent rather than a division-dependent accumulation of somatic mutations during haematopoiesis

although it will need independent corroboration before making any conclusion that damage repair is more important than replication.

Evolution in fast motion

Nature genetics as an advance online publication about comparative genome sequencing of E. coli where 13 de novo mutations in 5 strains were monitored over 44 d (or ~660 generations). It is a great study – not only because the author list includes one of my previous coauthors – but for giving a first insight about development of a mutation and fixing its allele frequency. Unfortunately, there is no flowchart and the methods are somewhat vague, what has been sequenced (or resequenced) in which strain at what time . In other words who are the winners? Did they manage that by their own strength or with a little help of some friends? Why rises the allele frequency always to 100% and what about some discrepancy of allele frequency and fitness? We will hopefully see more of these studies, yea, yea.

Genetics making up of Homo sapiens

Lets start a further workup of the evolutionary thread. With the complete human and chimp genome on our harddisks we are now able to compare genome sequence and genome activity of both species. A 2003 review by Sean Carroll summarizes our pre-genome knowledge about pan and homo lineages 6 Million years ago. The most interesting question is which mutations or genome rearrangements (Popesco 2006) are most relevant in the separation of lineages.

BTW I have still doubts about any positive effects of mutations (although this might be possible). Yes, I wonder also where are the exact pan-homo transitions (although the Sahelanthropus tchadensis might be a good candidate). Furthermore, I have doubts in survival of the fittest where non-survival of the non-fittest seem to be more relevant ;-) “Survival of the Sickest” is a CD of Mad Sin and a book of Sharon Moalem 2007.

Neuroanatomy might have provided some clues of a larger frontocortex in homo sapiens although the detailed cytoarchitecture could be as relevant. Noise of neutral substitutions could have confounded previous findings. It is also not clear to me if expansions and contractions of whole gene families are even more relevant. We may also renember that most quantitative traits have a polygenic background.

In any case FOXP2 could be associated with speech and language disorders (Vargha-Khadem 2005) where another prominent gene was now found in the 49 regions that are different between chimp and human but otherwise conserved (Pollard 2006). This new gene called “HAR1” is even expressed in the developing neocortex making it a prime candidate for species differentiation. Is there anybody able to convince me that the 18 fixed mutations in HAR1 have indeed a beneficial effect on brain development? A “leading edge” comment in Cell argues that all substitutions are upgrades from weak to strong base pairing:

Curiously, this weak-to-strong substitution bias in HAR1 extends over 1.2 kb, a region far larger than HAR1 itself. Such changes which also appear to characterize the HARs as a group undoubtely serve to strengthen RAN helices against dissociation…

I would also like to mention that male humans share more identity with male chimps than with female humans, at least on a genetic level, yea, yea.

Addendum

Even blogs have a half-life of less than 1 week. A new PNAS paper by Michael Oldham shows a more integrated view of human brain evolution by examining gene coexpression networks in human and chimpanzee brains. This seems to be another promising approach.

Ethnographic studies at Oktoberfest

Having many years of experience with ethnographic studies at Oktoberfest München, I am fascinated by a new Cell paper that shows distinct behavioral responses to ethanol. This is something that I alread assumed (although I did not known about this particular RhoGAP18B isoform only about ADH deficiency). Will the knowledge of more and more mutations in the lifestyle area raise ethical problems? Yea, yea.