Thursday, June 22, 2017

Everything is genetic, isn't it?

There is hardly a trait, physical or behavioral, for which there is not at least some familial resemblance, especially among close relatives.  And I'm talking about what is meant when someone scolds you saying, "You're just like your mother!"  The more distant the relatives in terms of generations of separation, the less the similarity.  So you really can resist when told, "You're just like your great-grandmother!" The genetic effects decline in a systematic way with more distant kinship.

The 'heritability' of a trait refers to the relative degree to which its variation is the result of variation in genes, the rest being due to variation in non-genetic factors we call 'environment'.  Heritability is a ratio that ranges from zero when genes have nothing to do with the trait, to 1.0 when all the variation is genetic.  The measure applies to a sample or population and cannot automatically be extended to other samples or populations, where both genetic and environmental variation will be different, often to an unknown extent.

Most quantitative traits, like stature or blood pressure or IQ scores show some amount, often quite substantial, of genetic influence.  It often happens that we are interested in some trait that we think must be produced or affected by genes, but that no relevant factor, like a protein, is known.  The idea arose decades ago that if we could scan the genome, and compare those with different manifestations of the trait, using mapping techniques like GWAS (genomewide association studies), we could identify those sites, genomewide, whose variation in our chosen sample may affect the trait's variation.  Qualitative traits like the presence or absence of a disease (say, diabetes or hypertension), may often be due to the presence of some set of genetic variants whose joint impact exceeds some diagnostic threshold, and mapping studies can compare genotypes in affected cases to unaffected controls to identify those sites.

Genes are involved in everything. . . . .
Many things can affect the amount of similarity among relatives, so one has to try to think carefully about attributing ideas of similarity and cause.  Some traits, like stature (height) have very high heritability, sometimes estimated to be about 0.9, that is, 90% of the variation being due to the effects of genetic variation.  Other traits have much lower heritability, but there's generally familial similarity.  And, that's because we each develop from a single fertilized egg cell, which includes transmission of each of our parent's genomes, plus ingredients provided by the egg (and perhaps to a tiny degree sperm), much of which were the result of gene action in our parents when they produced that sperm or egg (e.g., RNA, proteins).  This is why traits can usually be found to have some heritability--some contribution due to genetic variation among the sampled individuals.  In that sense, we can say that genes are involved in everything.

Understanding the genetic factors involved in disease can be important and laudatory, even if tracking them down is a frustrating challenge.  But because genes are involved in everything, our society also seems to have an unending lust for investigators to overstate the value of their findings or, in particular, to estimate or declaim on the heritability, and hence genetic determination, of the most societally sensitive traits, like sexuality, criminality, race, intelligence, physical abuse and the like.

. . . . . but not everything is 'genetic'!

If the estimated heritability for a trait we care about is substantial, then this does suggest the obvious: genes are contributing to the mechanisms of the trait and so it is reasonable to acknowledge that genetic variation contributes to variation in the trait.  However, the mapping industry implies a somewhat different claim: it is that genes are a major factor in the sense that individual variants can be identified that are useful predictors of the trait of interest (NIH's lobbying machine has been saying we'll be able to predict future disease with 'precision').  There has been little constraint on the types of trait for which this approach, sometimes little more than belief or wishful-thinking, is appropriate.

It is important to understand that our standard measures of genes' relative effect are affected both by genetic variation and environmental lifestyle factors.  That means that if environments were to change, the relative genetic effects, even in the very same individuals, would also change.  But it isn't just environments that change; genotypes change, too, when mutations occur, and as with environmental factors, these change in ways that we cannot  predict even in principle.  That means that we cannot legitimately extrapolate, to a knowable extent, the genetic or environmental factors we observe in a given sample or population, to other, much less to future samples or populations.  This is not a secret problem, but it doesn't seem to temper claims of dramatic discoveries, in regard to disease or perhaps even more for societally sensitive traits.

But let's assume, correctly, that genetic variation affects a trait.  How does it work?  The usual finding is that tens or even hundreds of genome locations affect variation in the test trait.  Yet most of the effects of individual genes are very small or rare in the sample.  At least as important is that the bulk of the estimated heritability remains unaccounted for, and unless we're far off base somehow, the unaccounted fraction is due to the leaf-litter of variants individually too weak or too rare to reach significance.

Often it's also asserted that all the effects are additive, which makes things tractable: for every new person, not part of the study, just identify their variants and add up their estimated individual effects to get the total effect on the new person for whatever publishable trait you're interested in.  That's the predictive objective of the mapping studies.  However, I think that for many reasons one cannot accept that these variable sites' actions are truly additive. The reasons have to with actual biology, not the statistical convenience of using the results to diagnose or predict traits.  Cells and their compounds vary in concentrations per volume (3D), binding properties (multiple dimensions), surface areas (2D) and some in various ways that affect how how proteins are assembled and work, and so on.  In aggregate, additivity may come out in the wash, but the usual goal of applied measures is to extrapolate these average results to prediction in individuals.  There are many reasons to wish that were true, but few to believe it very strongly.

Even if they were really additive, the clearly very different leaf-litter background that together accounts for the bulk of the heritability can obscure the numerical amount of that additivity from sample to sample and person to person.  That is, what you estimated from this sample, may not apply, to an unknowable extent, to the next sample.  If and when it does works, we're lucky that our assumptions weren't too far off.

Of course, the focus and promises from the genetics interests assume that environment has nothing serious to do with the genetic effects.  But it's a major, often by far the major, factor, and it may even in principle be far more changeable than genetic variation.  One would have to say that environmental rather than genetic measures are likely to be, by far, the most important things to change in society's interest.

We regularly write these things here not just to be nay-sayers, but to try to stress what the issues are, hoping that someone, by luck or insight, finds better solutions or different ways to approach the problem that a century of genetics, despite its incredibly huge progress, has not yet done.  What it has done is in exquisite detail to show us what the problems are.

A friend and himself a good scientist in relevant areas, Michael Joyner, has passed on a rather apt suggestion to me, that he says he saw in work by Denis Noble.  We might be better off if we thought of the genome as a keyboard rather than as a code or program.  That is a good way to think about the subtle point that, in the end, yes, Virginia, there really are genomic effects: genes affect every trait....but not every trait is 'genetic'!


Jason Antrosio said...

Thank you for continuing the work of what should have been accomplished a generation ago. I've added the useful observations to my developing blog-post and class notes on Is DNA a Blueprint?

stephen said...

Do the positive exceed the negative effect as opposed to the natural?