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'!

Genetics in an age of fundamentalism

I heard a program the other day on the BBC Radio 4's In Our Time about the origins, rise, and persistence of Chinese Legalism. Introduced in the 4th century BC, and the hallmark of the rule of the first emperor, the philosophy of Legalism was based on laws and their strict implementation.  It was the basis of a brutal, authoritarian state, elements of which have lasted 2500 years.

Here's one description (found here):

...Legalism is a Classical Chinese philosophy that emphasizes the need for order above all other human concerns. The political doctrine developed during the brutal years of the Fourth Century BCE. The Legalists believed that government could only become a science if rulers were not deceived by pious, impossible ideals such as "tradition" and "humanity." In the view of the Legalists, attempts to improve the human situation by noble example, education, and ethical precepts were useless. Instead, the people needed a strong government and a carefully devised code of law, along with a policing force that would stringently and impartially enforce these rules and punish harshly even the most minor infractions. 

                                                                                              L. Kip Wheeler 

To overly simplify, but I'm just trying to make a point, in Legalism, allegiance must be paid to the role of the ruler, rather than to a particular leader.  And, the system of rulership is absolute.  Further, Legalism views people as much easier to control if they are uneducated, and there's no sense in which they are expected to improve themselves.

In contrast, another ancient Chinese philosophy, Confucianism, was much more benevolent, with an optimistic view of human potential; people are basically good, and if taught new things they can be cultivated into better people.  Confucians see authority and leadership as something everyone has the potential to achieve, whereas in Legalism, the ruler dictates and people are expected to follow.

This contrast between people as good and improvable vs inherently evil, the absolute vs the relative, is of course a familiar dialectic, not at all restricted to philosophy of nation states.  Theism vs agnosticism,  laissez faire or free market vs regulation, the US Constitution as fixed or as flexible, cultural relativism vs universal human rights, free will vs predetermination, and of course tabula rasa or blank slate vs inherency, or nature vs nurture.

Confucius

The consistency with which people view the world in either absolute or relative terms is curious to me, and indicates that we aren't necessarily learning from observation, evaluating and interpreting the facts as we see them as we go about choosing our favorite economic system, or whether cultural practices that are alien to our own have any merit.  It seems instead that we've got an a priori view of the world that informs those decisions, an ideology that guides us in what turns out to be a fairly predictable direction.  In a loopy sort of way, those with an absolutist ideology would say that that ideology is genetic (and, indeed, that things like how we vote are genetic), while those with a relativist ideology would disagree, saying it's learned.

But at least our mythology about science is that it's supposed to be fact-driven, not ideological.  Often it is, though how do most people decide whether or not they accept that humans are driving climate change, or that all life evolved from a common ancestor?  Unless we're climate scientists or evolutionary biologists, we generally don't have the knowledge to evaluate the data in any meaningful way.  So these decisions become ideological.  In that sense, facts do not rule, not even in relation to science.

And what about the role of genes in making us who we are?  Ken and I have been sneeringly called "blank slaters" more than once, because we don't embrace the idea that who we are is determined by our genes.  The assumption is that if one doesn't accept that genes are always destiny, one must accept that they never are.

But, there's another way, and it's more subtle, and more nuanced, and that is to recognize that there's a continuum of gene action, from predictable to unpredictable.  Some alleles pretty reliably are associated with a given trait (alleles associated with Tay Sachs or cystic fibrosis), while others are not (APOE4 and dementia, HFE and  hemochromatosis).  With a few exceptions, specific genetic variants can't be predicted from most complex traits, and vice versa.  So, sometimes Legalism might be a good analogy for the relationship between genes and traits -- dictator, strong-arm genes -- and sometimes Confucianism; genes interacting with environment.  But there's also Daoism, another ancient Chinese philosophy, which taught that people were to live in harmony with nature, that government is unnatural, and that the best government is a weak government -- no dictator genes, mostly environment.

It used to be said that one's politics could be predicted from one's stand on genetic determinism, but determinism has become so pervasive that this is no longer true.  Atheist free-market constitutional modernist cultural relativist Bernie Sanders supporters are as likely to be genetic determinists these days as are, well, the opposite.  Determinism has become a pervasive ideology, and this despite a lot of evidence to the contrary.  Philosophers of science have long tried to define and describe how science is done, but I think fundamentally, while science is different from a lot of other human endeavors in that we do have ways of verifying that we're learning things, the role of ideology in what we think we've learned should not be underestimated.  And in many ways, it is heavily affected by emotions and by scientists' personal situations (careers, biases, and so on), even when they try to be 'objective'.  In recent decades, some 'science studies' work has clearly shown this (even if the practitioners have their own sociocultural axes to grind); given human nature, it should be no surprise. 

When did Lyndon Johnson propose the Great Society in the US?  It was in the mid 1960's, when we saw communism as a huge threat.  We reacted by becoming more like our 'enemy'.  Is it too simplistic to suggest that the same could be happening now, when our 'enemy' is religious fundamentalism?  

How do we know what we think we know?

Two stories collided yesterday to make me wonder, yet again, how we know what we think we know.  The first was from the latest BBC Radio 4 program The Inquiry, an episode called "Can we learn to live with nuclear power?" which discusses the repercussions of the 2011 disaster in the Fukushima nuclear power plant in Japan. It seems that some of us can live with nuclear power and some of us can't, even when we're looking at the same events and the same facts.  So, for example, Germans were convinced by the disaster that nuclear power isn't reliably safe and so they are abandoning it, but in France, nuclear power is still an acceptable option.  Indeed most of the electricity in France comes from nuclear power.

Why didn't the disaster convince everyone that nuclear power is unsafe?  Indeed, some saw the fact that there were no confirmed deaths attributable to the disaster as proof that nuclear power is safe, while others saw the whole event as confirmation that nuclear power is a disaster waiting to happen.  According to The Inquiry, a nation's history has a lot to do with how it reads the facts.  Germany's history is one of division and war, and nuclear power associated with bombs, but French researchers and engineers have long been involved in the development of nuclear power, so there's a certain amount of national pride in this form of energy.  It may not be an unrelated point that therefore many people in France have vested interests in nuclear power.  Still, same picture, different reading of it.

Cattenom nuclear power plant, France; Wikipedia

Reading ability is entirely genetic
And, I was alerted to yet another paper reporting that intelligence is genetic (h/t Mel Bartley); this time it's reading ability, for which no environmental effect was found (or acknowledged).  (This idea of little to no environmental effect is an interesting one, though, given that the authors, who are Dutch, report that heritability of dyslexia and reading fluency is higher among Dutch readers -- 80% compared with 45-70% elsewhere -- they suggest because Dutch orthography is simpler than that of English.  This sounds like an environmental effect to me.)

The authors assessed reading scores for twins, parents and siblings, and used these to evaluate additive and non-additive genetic effects, and family environmental factors.  As far as I can tell, subjects were asked to read aloud from a list of Dutch words, and the number they read correctly within a minute constituted their score.  And again, as far as I can tell, they did not test for nor select for children or parents with dyslexia, but they seem to be reporting results as though they apply to dyslexia.

The authors report a high correlation in reading ability between monozygotic twins, a lower correlation between dizygotic twins, and between twins and siblings, and a higher correlation between spouses, which to the authors is evidence of assortative mating (choice of mate based on traits associated with reading ability).  They conclude:

Such a pattern of correlation among family members is consistent with a model that attributes resemblance to additive genetic factors, these are the factors that contribute to resemblance among all biological relatives, and to non-additive genetic factors. Non-additive genetic factors, or genetic dominance, contributes to resemblance among siblings, but not to the resemblance of parents and offspring.  Maximum likelihood estimates for the additive genetic factors were 28% (CI: 0–43%) and for dominant genetic factors 36% (CI: 18–65%), resulting in a broad-sense heritability estimate of 64%. The remainder of the variance is attributed to unique environmental factors and measurement error (35%, CI: 29–44%).

Despite this evidence for environmental effect (right?), the authors conclude, "Our results suggest that the precursors for reading disability observed in familial risk studies are caused by genetic, not environ- mental, liability from parents. That is, having family risk does not reflect experiencing a less favorable literacy environment, but receiving less favorable genetic variants."

The ideas about additivity are technical and subtle.  Dominant effects, that is, non-additive interactions among alleles within a gene in the diploid copies of an individual, are not inherited as additive ones are (if you are a Dd and that determines your trait, only one of those alleles, and hence not enough to determine the trait, is transmitted to any of your offspring).  Likewise, interactions (between loci), called epistasis, is also not directly transmitted.

There are many practical as well as political reasons to believe that interactions can be ignored.  In a practical sense, even multiple 2-way interactions make impossible sample size and structure demands.  But in a political sense, additive effects mean that traits can be reliably predicted from genotype data (meaning, even at birth): you estimate the effects of each allele at each place in the genome, and add them to get the predicted phenotype.  There is money to be made by that, so to speak.  But it doesn't really work with complex interactions.  Strong incentives, indeed, to report additive effects and very understandable!

Secondly, all these various effects are estimated from samples, not derived from basic theory about molecular-level physiology, and often they are hardly informed by the latter at all.  This means that replication is not to be expected in any rigorous sense.  For example, dominance is estimated by the deviation of average traits in AA, Aa, and aa individuals from being in 0, 1, 2 proportions if (say) the 'a' allele contributed 1-unit of trait measure.  Dominance deviations are thoroughly sample-dependent.  It is not easy to interpret those results when samples cannot be replicated (the concepts are very useful in agricultural and experimental breeding contexts, but far less so in natural human populations). And this conveniently overlooks the environmental effects.

This study is of a small sample, especially since for many traits it now seems de rigueur to have samples of hundreds of thousands to get reliable mapping results, not to mention a confusingly defined trait, so it's difficult, at least for me, to make sense of the results.  In theory, it wouldn't be terribly surprising to find a genetic component to risk of reading disability, but it would be surprising, particularly since disability is defined only by test score in this study, if none of that ability was  substantially affected by environment.  In the extreme, if a child hasn't been to school or otherwise learned to read, that inability would be largely determined by environmental factors, right?  Even if an entire family couldn't read, it's not possible to know whether it's because no one ever had the chance to learn, or they share some genetic risk allele.

In people, unlike in other animals, assortative mating has a huge cultural component, so, again, it wouldn't be surprising if two illiterate adults married, or if they then had no books in the house, and didn't teach their children that reading was valuable.  But this doesn't mean either reading or their mate-choice necessarily has any genetic component.  

So, again, same data, different interpretations  
But why?  Indeed, what makes some Americans hear Donald Trump and resonate with his message, while others cringe?  Why do we need 9 Supreme Court justices if the idea is that evidence for determination of the constitutionality of a law is to be found in the Constitution?  Why doesn't just one justice suffice?  And, why do they look at the same evidence and reliably and predictably vote along political lines?

Or, more uncomfortably for scientists, why did some people consider it good news when it was announced that only 34% of replicated psychology experiments agreed with the original results, while others considered this unfortunate?  Again, same facts, different conclusions.

Why do our beliefs determine our opinions, even in science, which is supposed to be based on the scientific method, and sober, unbiased assessment of the data?  Statistics, like anything, can be manipulated, but done properly they at least don't lie.  But, is IQ real or isn't it?  Are behavioral traits genetically determined or aren't they?  Have genome wide association studies been successful or not?

As Ken often writes, much of how we view these things is certainly determined by vested interest and careerism, not to mention the emotional positions we inevitably take on human affairs.  If your lab spends its time and money on GWAS, you're more likely to see them as successful.  That's undeniable if you are candid.  But, I think it's more than that.  I think we're too often prisoners of induction, based on our experience, training, predilections of what observations we make or count as significant; our conclusions are often underdetermined, but we don't know it.  Underdetermined systems are those that are accounted for with not enough evidence.  It's the all-swans-are-white problem; they're all white until we see a black one. At which point we either conclude we were wrong, or give the black swan a different species name.  But, we never know if or when we're going to see a black one.  Or a purple one.

John Snow determined to his own satisfaction during the cholera epidemic in London in 1854 that cholera was transmitted by a contagion in the water.  But in fact he didn't prove it.  The miasmatists, who believed cholera was caused by bad air, had stacks of evidence of their own -- e.g., infection was more common in smoggy, smelly cities, and in fact in the dirtier sections of cities.  But both Snow and the miasmatists had only circumstantial evidence, correlations, not enough data to definitively prove their were right.  Both arguments were underdetermined.  As it happened, John Snow was right, but that wasn't to be widely known for another few decades when vibrio cholerae was identified under Robert Koch's microscope.

"The scent lies strong here; do you see anything?"; Wikipedia

Both sides strongly (emotionally!) believed they were right, believed they had the evidence to support their argument. They weren't cherry-picking the data to better support their side, they were looking at the same data and drawing different conclusions.  They based their conclusions on the data they had, but they had no idea it wasn't enough.  

But it's not just that, either.  It's also that we're predisposed by our beliefs to form our opinions.  And that's when we're likely to cherry pick the evidence that supports our beliefs.  Who's right about immigrants to the US, Donald Trump or Bernie Sanders?  Who's right about whether corporations are people or not?  Who's right about genetically modified organisms?  Or climate change?  Who's right about behavior and genetic determinism?  

And it's even more than that! If genetics and evolutionary biology have taught us anything, they've taught us about complexity.  Even simple traits turn out to be complex.  There are multiple pathways to most traits, most traits are due to interacting polygenes and environmental factors, and so on. Simple explanations are less likely to be correct than explanations that acknowledge complexity, and that's because evolution doesn't follow rules, except that what works works, and to an important degree that's what is here to be examined today.  

Simplistic explanations are probably wrong.   But they are so appealing.