Schlagwort-Archive: ageing

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.

Cycling is good for you (and vitamin D is an activity marker)

Vitamin D level is an activity or lifestyle marker, although this has been largely neglected in the medical literature, maybe except Gannage 2000, Hyppönen 2007, Sohl 2013 and Choi 213. A new paper by de Rui in PLoS now shows that

serum 25OHD levels were significantly higher in individuals who engaged in outdoor pastimes … compared to those who did not. In particular, subjects regularly practicing gardening or cycling had higher serum 25OHD levels than those who did not, whereas 25OHD levels differed little between subjects who did or did not undertake indoor activities.

While these are good news for older cyclists Cycling is good for you (and vitamin D is an activity marker) weiterlesen

Would you like to be a centenarian?

I am currently working on a literature survey on the genetics of ageing when I came across a series of nice monographs at the Max Planck Institute in Rostock.

… the Deluge swept away the pluricentenarians. Ernest (1938) mentioned that the semi-divine persons of the Hindu Sagas lived hundred of thousands of years, and that on average each of ten rulers of Ancient Babylon lived about 43,000 years. Would you like to be a centenarian? weiterlesen

Why men die earlier

It took me nearly one hour to locate also this series of pictures on the net after having seen them recently in the talk of a Spanish colleague.
Yes, there are also more serious comments for example in the Behavioural Issues Blog Why men die earlier weiterlesen

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.

Are genes becoming more important with increasing age?

I found an apparent paradox between two studies. John Whitfield did a twin study in Australia and concluded that shared environmental effects decreased with age (from about 50% to 10%) while additive genetic effects increased. The new Sardinian study found higher heritabilities among younger individuals and explained that by an increase of environmental insults with age. Nice said, but who is right?