Fundamental units as the basis of science
Every science has fundamental units at the bottom of their causal scale, whose existence and properties can be assumed and tested, but below which we cannot go. The science is about the behavior or consequences of these units and their interactions. The fundamental unit's nature and existence per se are simply assumed. Physicists generally don't ask what is inside a photon or electron or neutron (or they say that these 'particles' are really 'waves'). In that sense, fundamental 'causes' are also defined but not internally probed. They don't really attempt to define 'force' except empirically or, for that matter, 'curved space-time'. You simply don't go there! Or, more precisely, if and when you venture into the innards of fundamental units, you do that by defining other even more fundamental units. When string theory tries to delve into unreal dimensions, they leave most other physicists, certainly the day-to-day ones behind. Generally, I think, physicists are usually more clear about this than biologists. The same in mathematics: we have fundamental axioms and the like that are accepted, not proven or tested.
Why is somatic mutation considered to be some sort of side-show in genetics?
What are biology's fundamental units? For historical reasons, evolutionary biology, which became much of the conceptual and theoretical foundation for biology, was about organisms. Before the molecular age, we simply didn't have the technology to think of organisms in the more detailed way we do now, but thought of them instead as a kind of unit in and of themselves.
Thus, the origins of ecology and phylogeny (before as well as after Darwin) were about whole organisms. Of course, it was long known that plants had leaves and animals had organs, and these and their structures and behavior (and pathologies) were studied in a way that was known to involve dissecting the system from its normal context. That is, organs were just integral parts of otherwise fundamental units. This was true even after microscopes were developed, Virchow and others had established the cell theory of life. Even after Pasteur and others began studying bacteria in detail, the bacterium itself was a fundamental unit.
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| Eukaryotic cell; figure from The Mermaid's Tale, Weiss and Buchanan, 2009 |
But this was a major mistake. Dissecting organs to understand them did, when considered properly, allow the identification of digestion, circulation, muscle contraction, and the like. But the focus then, and still today in the genetic age, on the whole organism as a basically fundamental unit has had some unfortunate consequences. We know that genes in some senses 'cause' biological traits, but we treat an organism as a fundamental unit with a genotype, and that is where much trouble lies.
The cell theory made it obvious that you and I are not not just an indivisible fundamental unit, with a genotype as its fundamental characteristic. Theories of organisms, embryology, and evolution largely rest on that assumption, but it is a mistake, and somatic mutation is a major reason why.
The cell theory, or cell fact, really, makes it clear that you and I are clearly not indivisible causal units with a genotype. We know beyond dispute that cell division typically involves at least some DNA replication errors--'errors', that is, if you think life's purpose is to replicate faithfully. That itself is a bit strange, because life is an evolutionary phenomenon that is fundamentally about variation. Perhaps like most things in the physical world, the important issues have to do with the amount of variation.
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| Mitotic spindle during cell division; from Wikipedia, Public Domain |
The number of cell-divisions from conception through adulthood in humans is huge. It is comparable to the number of generations in a species, or even a species' lifespan. Modern humans have been around for, say, 100,000 generations (2 million years), far fewer than the number of cell divisions in a lifetime. In addition, the number of cells in a human body at any given time is in the many billions, and many or even most cells continue to renew throughout life. This is comparable to the species size of many organisms. The point is that the amount of somatically generated variation among cells in any given individual is comparable to the amount of germline variation in a species or even a species' history. And I have not included the ecological diversity of each individual organism, including the bacteria and viruses and other small organisms on, in, and through a larger organism.
By assuming that somatic mutational variation doesn't exist or is trivially unimportant--that is, by assuming that a whole organism is the fundamental unit of life, we are entirely ignoring this rich, variable, dynamic ecology. Somatic mutation is hard to study. There are many ways that a body can detect and rid itself of 'mutant' cells--that is, that differ from the parent cell at their bodily time and place. But to treat each person as if s/he has 'the' genotype of his/her initial zygote is a rash assumption or, perhaps a bit more charitably, a convenient approximation.
Oversimplification, deeper and deeper
In the same way that we can understand the moon's orbit around the earth by ignoring the innards of both bodies, so long as we don't care about small orbital details, we can understand an organism's life and relations to others including its kin, by ignoring the internal dynamics that life is actually mainly about. But much of what the whole organism is or does is determined by the aggregate of its nature and the distribution of its genotypes over its large collections of cells. We have been indulging in avoiding inconvenient facts for several decades now. Before any real reason to think or know much about somatic mutation (except, for example, rearrangements in adaptive the immune system), the grossness of approximation was at least more excusable. But those days should be gone.
Geneomewide mapping is one example, of course. It can find those things which, when inherited in the germline and hence present in all other cells (except where it's been mutated), affect particular traits. Typically, traits of interest are found by mapping studies to be affected by tens, hundreds, or even thousands of 'genes' (including transcribed RNAs, regulatory regions etc.). Each individual inherits one diploid genotype, unique to every person, and then around this is a largely randomly generated distribution of mutant cells. When hundreds of genes contribute, it just makes no sense to think that what you inherit is what you are.
It should also be noted that we have no real way even to identify the 'constitutive' genome of an organism like a person. We must use some tissue sample, like blood or a cheek swab. But those will contain somatic mutations that arose subsequent to conception. We basically don't look for them and indeed each cell in the sample will be different. Sequencing will generally identify the common nucleotide(s) at each site, and that generally will be the inherited one(s), but that doesn't adequately characterize the variation among the cells; indeed, I think it largely ignores it as technical error.
The roles and relevance of somatic mutation might be studiable in comparing large-bodied, long-lived species with small ones in which not many cell divisions occur. They might be predicted to be more accurately described by constitutive (inherited) genomes, than larger species. Likewise plants with diverse 'germ lines', such as the countless meristems in trees that generate seeds, compared to simpler plants, might be illuminating.
How to understand and deal with these realities, is not easy to suggest. But it is easy to say that for every plausible reason somatic mutation must have substantial effects on traits good, bad, and otherwise. And that means that we have been wrong to consider the individual to be a fundamental unit of life.
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