Somatic mutation: does it cut both ways?

I've written journal articles as well as blogposts here at MT, about the known and potential importance of somatic mutation (SoMu) as a cause of disease.  I referred to this in our post on 'precision' medicine yesterday, saying I'd write about it today.  So here goes, an attempt to show why SoMu may be an important causal phenomenon, one I called 'Cryptic causation' in a paper a few years ago in Trends in Genetics.

SoMu's are DNA changes that occur in dividing cells after the egg is fertilized.  Mutations arise every time cells divide after that, throughout life.  Each time a cell divides thereafter, the mutations that arose when it was formed are transmitted to its daughter cells, and this continues throughout life (unless that site experiences another mutation at some point during its lifelong lineage).  The distinction between somatic mutations and germ line mutations goes back to Weissmann's demonstration of the separation of the 'soma' and the 'germ line', the germ line being a developmental clade of cells leading to sperm and egg cells and soma being cells unrelated to these.  A change from parent to offspring that reflects mutation arising in the germ line is the usual referent of the word 'mutation'.   Wherever they arose in the embryogenesis of the gonads, they are treated as if they occurred right at the time of meiosis.  That isn't a real problem, but it is fundamentally distinct from SoMu, because the latter are inherited in the somatic (body) tissue lineage in which they arose, but are not transmitted to offspring.

Normally, we would dismiss somatic mutation as just one of those trivial details that has little to do with the nature of each organism--its traits.  At any given genome location, most of the cells have 'the' genome that was initially inherited.  If a SoMu breaks something in a single cell in some tissue, making that cell not behave properly, so what?  Mostly the cell will die or just while away its life not cooperating, its diffidence swamped out by the millions of neighboring cells, performing their proper duties, in the mutant cell's organ.  It will have no effect on the organism as a whole.

But that is not always so!  In some unfortunate cell, a combination of inherited and somatic variants may lead that individual cell to be hyperviable in the sense of not following the local tissue's restrictions on its growth and behavior.  It can then grow, differentiate, grow more, again and again. We have a name for this: it's called cancer.

Somatic changes may mean that different parts of a given organ have somewhat different genotypes. Some fraction of, say, a lung or stomach, may work more or less efficiently than others.  If the composite works basically well, it won't even be noticed (unless, for example, the somatically mutant clones cause differences, like local spots, in skin or hair pigment).  But when a change in one cell is early enough in embryogenesis, or there is some other sort of phenotype amplification, by which a single mutant cell can cause major effects at the organismal level, the SoMu is very important indeed.

It isn't just cancer that may result from somatic mutation.  Epilepsy is a possible example, where mutant neurons may mis-fire, entraining nearby otherwise-normal neurons to engage in firing, and producing a local seizure.  I suggested this possibility a few years ago in the Trends in Genetics paper, though the subject is so difficult to test that although it is a plausible way to account for the locality of seizures, the idea has been conveniently ignored.

There are theories that mitochondria, of which cells contains hundreds or thousands, may mutate relatively rapidly and function badly.  They are an important way the cell obtains energy, and the mitochondrial DNA is not in the nucleus and is not prowled by mutation-repair mechanisms the way chromosomes are.  Some have suggested that SoMu's accumulate in neurons in the brain, and since the neurons don't replicate much if at all, they can gradually become damaged.  It's been suggested that this may account for some senile dementia or other aging-related traits.

Beware, million genome project!
What has this got to do with the million genome project?  An important fact is that SoMu's are in body tissues but are not part of the constitutive (inherited) genome, as is routinely sampled from, say, a cheek swab or blood sample.  The idea underlying the massive attempts at genomewide mapping of complex traits, and the new culpably wasteful 'million genomes' project by which NIH is about to fleece the public and ensure that even fewer researchers get grants because the money's all been soaked up by DNA sequencing, Big Data induction labs, is that we'll be able to predict disease precisely, from whole genome sequence, that is, from constitutive genome sequence of hordes of people.  We discussed this yesterday, perhaps to excess. Increasing sample size, one might reason, will reduce measurement error and make estimates of causation and risk 'precise'.  That is in general a bogus self-promoting ploy, among other reasons because rare variants and measurement and sample errors or issues may not yield a cooperating signal-to-noise ratio.

So I think that the idea of wholesale, mindless genome sequencing will yield some results but far less than is promised and the main really predictable result, indeed precisely predictable result, is more waste thrown onto mega-labs, to keep them in business.

Anyway, we're pretty consistent with our skepticism, nay, cynicism about such Big Data fads as mainly grabs in tight times for funding that's too long-lasting or too big to kill, regardless of whether it's generating anything really useful.

One reason for this is that SoMu cannot be detected in the kind of whole genome sequences being ground out by the machinery of this big industry.  If you have SoMu's in vulnerable tissues, say lung or stomach or muscle, you may be at quite substantial increased risk for some nasty disease, but that will be entirely unpredictable from your constitutive genome because the mutation isn't to be found in your blood cells.  Now, thinking about that, sequencing is not so precise after all, is it?

I've tried to point these things out for many years, but except for cancer biologists the potential problem is hardly even investigated (except, in a different sort of fad, by epigeneticists looking for DNA marking that affects gene expression in body cells but that, also, cannot be detected by whole genome sequencing).

In fact, epigenetics is a similar though perhaps in some ways tougher problem.  DNA marking affects gene expression by changing it in local tissues, which reflects cellularly local environmental events and hence constitutive genomics can't evaluate it directly.  On the other hand, epigenetic marking of functional elements can easily and systematically be reversed, also enzymatically in response to specific environmental changes at the cell level.  These are somatic changes in DNA dynamics, but at least SoMu, if detected, basically doesn't get reversed within the same organism and is 'permanent' in that sense, and hence easier to interpret.

But--the mistake may go in the opposite direction!
But I've myself neglected another potentially quite serious problem.  SoMu's arise in the embryonic development of the tissues we use to get constitutive genome sequences.  The lineage leading to blood and other tissues divides from other lineages reasonably early in development.  The genome sequenced in blood is not in fact your constitutive genome!  Information found there may not be in other of your tissues, and hence not informative about your risks for traits involving gene expression.

The push for precision based on genomewide sequencing is misguided in this sense, the opposite of the non-detectability of SoMu's in blood samples.  The opposite may be true: what's is found in 'constitutive' genomes in blood samples may actually not be found in the rest of the body and may not have been in your inherited genome!

This may not be all that easy to check.  First, comparing parent to offspring, one should see a difference, that is, non-transmitted alleles in both parties.  But since neither parent's blood and offspring's blood is entirely their 'constitutive' genomes, it may be difficult to know just what was inherited.  Even if most sites don't change and follow parent-offspring patterns, it doesn't take that many changes to cause disease-related traits (if it did, then why would so much funding be going to 'Mendelian', that is, single gene, usually single-mutation traits)?

One could check sequences in individuals' tissues that are not in the same embryonic fate-map segment as blood, or compare cheek cells and blood, or other things of that nature.  In my understanding at least, lineages leading to cheek cells (ectodermal origin) and blood cells (mesodermal origin) separate quite early in development.  So comparing the two (being careful only to sample white cells and epithelial cells) could reveal the extent of the problem.

It might comfortingly show that little is at issue, but that should be checked.  However, of course, that would be costly and would slow down the train to get that Big Funding out of Congress and to keep the Big Labs and their sequencers in their constituencies in operation.

Still, if we are being fed promises that are more than just ploys for mega-funding in tight times,  or playing out of the belief system that inherited genome sequence is simply all there is to life, or is enough to know about, then we need to become able to look where genetic variation manifests its effects:  at the local cell level.  Even for a true-believer in DNA as everything, a blood-based sequence can only tell us so much--and that may not include the variation that exists in the person's other tissues.

Well, one might wish to defend the Infinite Genomes Project by saying that at least constitutive genome sequences from blood samples get most, or the main, signal by which genetic variation affects risk of traits like disease.  But is that even true?

First, huge genomewide mapping studies routinely, one might say notoriously relative to the genome faith, account for only a fraction, usually small fraction, of the estimated overall genetic contribution as estimated by measures like heritability.  Predictive power is quite limited (and here we're not even considering environments, which cloud the picture greatly).

But second, risk from constitutive genome sequence is, as a rule and especially for complex or late-onset traits that are so important to our health and longevity, accounting only for a fraction of overall risk.  That is, heritability is far below 100%.  So the bulk of risk is not to be found in such sequence data.  And while 'environment' is clearly of major importance, SoMu appears as environment in genomic studies, because the variants are not in constitutive sequences and not shared between parents and offspring in family studies.  This may be especially important for traits that really do seem to involve genes in the cellular mechanism, as so clearly shown by cancers.

Thus, it is not accurate to say that at least we even get the bulk of genetic (meaning inherited) risk accounted for by pie-in-the-sky exhaustive genome sequencing.  Yet, testing for SoMu is not even on the agenda of Big Data advocates.

How much more one would get from a serious approach to SoMu--which would require some serious innovative thinking--remains untested.  It's not on the agenda not because we know its relatively unimportant, but because it's hard to test, and in that sense hard to use to grease the wheels of current projects for which an excuse to keep funding is what is really being sought by the Big Data advocates.  It's safer, even if we know it's got its limits and we don't really know what those limits are.

A real 'genomic' approach should include checking for the problems caused by SoMu--in both directions!