Monday, July 29, 2013

What is 'your' genotype? There's no answer because you have millions of them!

No one has a single genotype.  We begin life as a single cell, a fertilized egg containing two human genome copies, one inherited from each parent.  It also contains hundreds or thousands of mitochondrial DNA molecules that were in the egg cell.  They will not all be identical.  Then the initial cell divides to begin the process by which we formed an embryo that grew its many tissues and organs.  This involved billions of cell divisions.

Human blastocyst; Wikimedia

Each time a cell divides, some mutations occur.  These are not germline (sperm or egg) mutations, differences between your parents and you, the usual notion of mutation.  Instead, they are somatic (body cell) mutations.  The embryo forms a tree of cell descent (and, in that sense, so do you), and mutational changes in a cell are inherited when it divides into two daughter cells and their descendant cells throughout the rest of your life.  So that the earlier a mutation occurs in the embryo the greater the number of cells that will have that change.

As a result, each person is a genotypic mosaic.  When people talk about a genotype, they usually and sloppily refer to what would be sequenced in a sample of blood or cheek cells.  Most of this will be the inherited sequence but there will be a mix of cells with rarer changes (that the sequence-reading software may regard as sequencing errors and ignore), and mutations that may be common in other tissues from different embryonic cell branches will not be seen.

Somatic mutations can have no effect or great effect depending on when and where they occur.  You can have a BRCA1 mutation that arose during your development but that was not inherited and/or isn't in the sample that was sequenced to determine 'your' genotype.  Since your cells are always dying and dividing, you don't really have 'a' genotype!

A recent commentary in Science points out the potential importance of somatic mutations and the complexities they introduce into trying to infer genetic causation in medicine.  This is quite important, and is well-explained.  But there is a deeper history to this than covered in the piece.

Indeed, people had realized by the 1970s that somatic mutation was probably a contributor to cancer, because one transformed cell that had misbehaving behavior as a result of mutant genes could grow into a life-threatening tumor.  The idea was bruited in a wonderful and famous paper by Al Knudsen at the University of Texas in Houston (my Dean, where I was at the time) in the early '70s, in relation to the eye cancer retinoblastoma.  He showed the potential joint impact of inherited and somatic variation.  That conceptually led various people to pursue the idea of multistage somatically based tumorigenesis, and work largely by Bert Vogelstein and colleagues at Johns Hopkins established early ways of genomic screens to compare tumor cells with the patient's normal cells to show this.

Many of us were writing about the implications of somatic mutation at that time.  It was explicit in articles, book chapters, and books.  I myself attempted to awaken people to the potentially broader and challenging impact of somatic mutation (e.g., in Trends in Genetics in 2005).  Ranajit Chakraborty and I wrote many papers in the '80s about the way somatic mutation might explain why cancer is not usually present at birth and to account for the age of onset patterns of cancer, and in my 1993 book Genetic Variation and Human Disease (20 years ago!) and elsewhere I provided a speculative account of how this could apply to age-related diseases (most diseases) more widely.

There were and are many other examples and instances of the importance of somatic mutation, in humans and other animals (and plants).  But the bemused human genetics establishment, anchored in early 20th century concepts of simple inheritance, established its juggernaut of GWAS and the idea of relating 'the' genome of a person to his/her fate, paying conveniently little attention to somatic mutation.

Because the situation is so clear in regard to cancer, cancer research has gone to great lengths to understand somatic mutation, as has some smattering of other work here and there, such as attempts to account for some effects of aging in terms of mitochondrial somatic mutation.  In a way, the idea of genomewide 'expression profiling'--looking for cell-specific gene expression in specific tissues--is related to the idea that you can't describe a person from an inherited genotype.

The challenge is outlined well in the current paper, even if the author decided or neglected to cite the earlier literature or note that somatic mutation has been widely ignored out of convenience or culpable unawareness (pick your favorite explanation).  Until we face up to the problem, we will be wastefully pouring funds down the GWAS and sequence database drain. 

The issues are complex.  We know now that the same inherited mutation has variable effects depending on the rest of a person's genotype--and that's why the effectiveness of personalized genomic medicine is heavily misrepresented by various hopeful and/or vested interests.  Similarly, a person's somatic mutations will interact with each other, and with his/her inherited genotype to produce resulting traits, normal as well as disease.  That two-set pattern 'squares' the amount of complication we have to deal with.

Working out how to handle what we know about genotypic variation will not be easy, but we should slow down the train while we try to work out a useful strategy, or at least stop over-promising.  However, the likelihood is that most people who read the article (or, indeed, this post!) will say "Hmm, that's interesting," and then, feeling satisfied about their new awareness, finish their coffee....and go back to business as usual.


Kevin Mitchell said...

Seems like rates of somatic mutation could be estimated from frequency of conditions like piebaldism (if not inherited) or heterochromia or other conditions affecting the pigmentation of skin, hair or eyes (given the known number of loci that could be mutated). If it were prevalent enough to contribute substantially to disease, it seems like the frequency of mosaic coloration should be a lot higher. (Obviously it contributes very substantially to cancer, though often due to some predisposing factor or exposure to a mutagen that increases mutation rate in affected cells).

Ken Weiss said...

I'm just reading a paper on somatic mutation in cancer (Nature, current or last or next issue, I can't tell since my pdf is from the pre-print part of their web page).

On a quick glance-through, there are the usual overstatements and simplifications in this paper, but the idea of identifying SoMus in tumors is something I must say that I've suggested needs to be done as I mentioned, hopefully not too self-servingly, in the post.

Ranajat and my work on modeling age patterns is related to this, perhaps being more informative than has been generally acknowledged....though most people have become so gene-obsessed that informative epidemiological facts like age of onset have slipped into the background.

There are many important issues to be worked out. But the idea that morphology (i.e., presence of tumor or as you note pigmentation type traits) as a function of age as well as numbers of cells at risk, does provide some evidence.

You have pointed out one of the problems (increased SoMu rate that could be due to genetic variation) and there are many others. The Nature authors were sloppily allowed to begin by saying that "All cancers are caused by somatic mutations;" which may or may not be true depending on what the word 'caused by' means--some investigators suggest that retrotransposons are responsible sometimes (are their acts 'mutation'?), and what about viral cancers and inherited mutations?

There's still a lot to learn, and thinking about indicators, as you suggest, is one way.