Let's be intelligent about intelligence

A lot of confusion reins over assertions about whether a physical or even behavioral trait is  'genetic'. There are several reasons for this.  One is the difference between mechanism and variation. Every human trait is genetic in the first sense: an organism develops from a fertilized egg because it has genes, and without its genes it could do or even be nothing.  So every trait is 'genetic' in the mechanism sense. But the other meaning of 'genetic' has to do with variation, and that is where the difficulty and often the contention lies.  The assertion that a trait is 'genetic' in this sense means that some people with a trait, or a particular trait measure, have it because of some particular genotype. That is, we all differ in the trait because of causal genetic differences.  Identifying genetic mechanisms or demonstrating that genetic variation is responsible for variation in a trait are genuine challenges.

Searching for genetic mechanisms responsible for, say, heart disease is one of those challenges.  It's difficult scientifically, but unlike with some other traits, the scientific question isn't politically loaded. Many people fervently want to stress the genetic role in intelligence, for example, and it's often for thinly disguised racist or elitist reasons.  A common response to almost any suggestion that an individual's intelligence might not be inborn, due to variants in his/her inherited genotype (meaning built-into the person's DNA sequence), is an accusation that the person is in denial of reality (but see our Dec 14 post about genetics and dialectics).  But who is really denying reality in such cases?  In our view, it is those who misperceive or misuse measures like heritability and have deep, emotional commitment to inborn destiny.

And, again, it's pretty clear that just slightly beneath the surface is often a racist or other discriminatory agenda: "let's identify 'them' and do something about it, to 'improve' them or prevent them from harming everybody else" (Trump's throw the Muslims out campaign, or the reluctance to invest 'our' resources in groups with inferior IQ, or in the worst case, eliminate them). If it's important to understand why people behave as they do (intelligence being just one aspect of behavior; there are of course many others), the argument goes, then one needs to know if it's genetic, that is, built into the genome at conception!  Again, then depending on who such knowledge is important to, individuals in the population can (should, must) be tested.

Of course, it's worth asking carefully whether what's really being looked for are individual differences, or group differences.  Why 'we' (those in power) 'need' (that is, want) to know which of 'their' behaviors are built-in, is unclear, but seems frequently to justify acting in discriminatory ways, favoring some and neglecting others.  In other words, of course intelligence is the result of gene action, but the argument is really about variation rather than mechanism.

But before we address these issues, it is worth providing a quick description of the core of the 'scientific' basis of the argument, which typically rests on a measure called 'heritability' (denoted here by H but typically written h-squared).

Heritability: simple-sounding word, but a slippery measure
When the genetics of intelligence, or most other behavioral traits for that matter, is considered, the proof that they are genetic is usually that their heritability is high.  Heritability has been known for decades to be a rough indirect indicator of genetic mechanistic cause, but it's a very elusive measure. The usual measure of H is basically the ratio of the amount of variation in genes (G) divided by the amount of variation in genes + variation in environment, G/(G+E), all within a particular sample at a particular time.  This is estimated typically by comparing the trait measure in relatives, since close relatives share specifiable fractions of their respective genetic variants.

This figure schematically shows the scatter of genetic similarities, each dot being values of the measure in an offspring compared to the average of its mother and father.  The figure shows the difference in such correlations if environmental effects are great and genetic variation accounts for only 10% of the similarity (left panel), or small where the environments contribute only 10% (right).

From Wikimedia images, taken from Nature

H in itself measures no specific genes or gene-variants, nor any specific environmental variants.  To avoid some confounding or confusing contributors to the trait, various additional types of sample are often studied or comparisons made, such as between adoptees vs biological children, or dizygous vs monozygous twins. Heritability studies also often try to remove correlations among relatives that are due to shared family environments that could, in the computation, falsely appear as genetic.  While these strategies are not useless, they are well-known to be imperfect.

Since the measure H is a ratio that depends on the particular conditions in your particular sample, if one of the terms (G or E) were to change, even within that same sample, the H value would also change. In other words, let the same population (the exact same set of genotypes) experience changed environments, and H will change. In that sense H is not an absolute measure of how genetic a trait is, but of how relatively important it is.  Let us repeat that--heritability is not a definitive measure of the genetic contribution to a trait.  It is about its context in a particular sample.

Every study of traits like IQ test scores, used as hopeful stand-ins for 'intelligence', shows that there is substantial heritability, though usually far below 1.0.  That means that environmental effects are important, usually predominant, even if genetic variation is contributing as well.  That's about all that H measures show.  'Environment' in this sense tells us nothing in itself about what the specific individual contributing factors might be, because they don't behave the way genetic factors do, thanks to the rules of genetic transmission from parent to offspring; environmental factors don't have theoretically specifiable patterns of clustering among people or even among relatives. The apparent environmental component estimated in H studies can also include things like chance, testing inadequacy, measurement error and so on.

The undeniable bottom line is that variation in traits like intelligence test performance is certainly affected by genetic variation because the trait itself is mechanistically affected by genes. But that is a crude and almost useless fact because the genetic component is generally polygenic, meaning that it is affected by large numbers of varying genomic elements, each making very small individual contributions. Here, we conveniently ignore whether current fad factors such as microbiomic or epigenetic effects are relevant, because each of them is variable, in each population or sample, and over time--even in each individual over time--and could in principle be inherited and hence appear in families as being 'genetic'.

What this means is that even each individual's inborn genetic component will be very different, that is, each of us will have different combinations of variants at tens or hundreds (or more) of contributing gene regions.  The predictability of achieved results from genomes, much less individual variants, will be correspondingly small, practically useless, as we've clearly seen for so many other complex traits (GWAS results, for example, even of IQ test scores). If we could measure environments the way we can measure genomic variation, they would be similarly complex with many individual factors involved, most with individually weak effects.  As with genotypes, the complexity of these environmental factors would mean each person is unique and predictions are weak, and that changing circumstances and imprecision in the risk estimates would have a large potential effect on each person's achieved results.  We've discussed these limitations (and the overselling) of genetic association studies many times here.

But, if one is determined to pry into everyone's inherent worth, here's how to do it properly:
Here's an idea: Let society decide that we want to know the real genetic truth about behaviors, not just the mechanisms but the effect of variation among individuals.  To do that, we must pass legislation to ensure that all environmental factors that contribute to behavior--all of them!--are exactly the same for everyone, from conception onward.  Once that is done, variation in test performance will be entirely due to genes, since the environmental variance, E, would be zero, so that H would be 1.0.  Now we can see how strongly genes in general, or individual genetic variants, determined results.  However, we assert with confidence that the result of individual genetic prediction would still be hopelessly complex in most cases (excepting, for example, clearly pathogenic genetic variants, which we know to be rare, and even they are usually not simple).

But this is of course a fantasy: making environmental effects uniform for everyone is obviously impossible, for at least two reasons.  First, we can't make the climate in Maine like that in Florida or California.  We can't have identical schools everywhere, or the same number of books in every home, or the same number of words spoken to each infant at each developmental stage.  And so on.  So maybe a more realistic idea would be to make the environmental variation the same everywhere, so that in a sense it was a kind of uniformly distributed 'error' term in measuring genetic effects.  Of course that can't be done either, for the same sorts of reason.

Secondly, genes don't work on their own, but interact with 'environments' in almost every imaginable way, and certainly in the development of the brain.  That means that separating G and E (as in G+E) is clearly an oversimplification of something very poorly understood.  Even fixing the same environment everywhere would not have the same effect on every genotype.

The bottom line, in reality, is that arguments, usually by those in privilege, that behaviors (and hence their societal value) are inherent, are almost inevitably working some other form of self-advantaging agenda.  Racism is right beneath the surface in much of this, but so are xenophobia and class differences.  So are hopes of producing babies with some desired property.  That's clear from the history of the subject.

Since it's impossible to think that society could make environments uniform for everyone so all that's left is genetic variation, the next most salubrious thing a society could do would be to provide the best environmental conditions for all of its members to thrive in, not expecting everyone to achieve the same but at least to have safe, satisfactory lives.  More socioeconomic equity by the elimination of poverty and privilege would be a solution if such equity were the real objective. Of course since the beginning of history this has been the stated goal of those who bemoan the unfairness of society (though less so of others who say we're inherently unequal and we ought to reward the privileged).  We gain little by peering into individual genomic 'souls' and condemning those found genetically wanting to fates that we, in the elite, decide is best for them (inevitably making sure we stay at the top).

This doesn't seem too cynical a view of the subject: If what those who assert the deep importance of genetics of behavior really want is for society to be fair, the first thing is to understand the environmental effects that obviously are the predominant causes of behavioral variation, and rectify the inequities.  Let society ensure that everyone has the same conditions: no upper class advantages in schools, ballet lessons, Kaplan prep courses for SATs to get them into Princeton, no jobs to get through family or parents' contacts, same number of books in every house, no corner drug dealers nor rats in the hallways in poor neighborhoods......  Or, how about broader 'intelligence' testing ideas, to include smarts like the ability to read defenses in basketball while flying through the air, or work a fork-lift efficiently, or fix one of today's complicated cars....

H is a complex factor that is misused as much as it is used, because there are too many reasons to interpret its computational subtleties in ways that conveniently favor one's own social agenda. Not everyone interprets these issues in this way, but behaviors like intelligence are too juicy for those with such intentions to resist.  But, yes, let's be scientific, and commit to a concerted effort to make H approach 1.0, so that we can really understand the genetic contributions--that is, to make test-score differences really 'genetic'!  Then we could make sense of 'genetic' causes.  But, would any serious thinker believe it would be very useful?

Shelling out for Sheldon....again (but without the nudes)!

In the 1940s and into the 50s, WH Sheldon carried out a project on the science, or even (modestly claimed) the new science of human morphological and behavioral science.  The work became known in various ways, but one important term that described it was somatotyping.  

WH Sheldon, from the Wikipage about him

In this project, students at our most Ivied universities were compelled to pose au naturel for front, side, and back photos, so their shapes and ultimately their personal natures could be studied, scientifically!  It should be noted that Sheldon was, after all, at Major Universities for much of his career, so his work must have been Important.

These were in the Olde Tyme hand calipers and graph paper days, without today's more definitive way of taking measurements (that is, using computers to do the measuring).  Means and variances of body shape were computed and, in the usual way that scientists often show the depth of their insight, divided into categories (finding categories makes such tables seem a lot more insightful than mere lists of measures). 

Sheldon used three basic categories to divide up what is in fact a quantitative pattern: he called them endomorphs, mesomorphs, and ectomorphs.  You can call these skinny, normal, and fat (but don't let a scientist hear you using such ordinary language).  To be really scientific, Sheldon devised a 3-number scale for various traits in an individual to reflect how strongly Mes, Ect, or End the trait was in that person. Your resulting somatotype score was with you all your life, from the womb onward, because it represented your very essence, despite how much you ate or whatever (again, recall, this is science).

The tricorn classification.  Each person a mix of the Big Three possibilities.  Modified from Google images

What they really look like in idealized form.  (This image is all over the web, source hard to determine.)

One might expect this sort of work to have been done by anthropologists, but Sheldon was a psychologist. The idea was not just to study body shape, but that shape is a window to the inner soul--Sheldon called this new science 'Constitutional psychology'.  Of course, you know the stereotypes: the jovial Santa-like fat person, edgy skinny one, and manly Heroic (that is, sexily muscled) mesomorph. Sheldon considered (i.e., studied) women, too, but since women aren't very important he mostly cared about men (that is, professionally speaking).

Sheldon wrote his ideas in book form in 1940, as The Varieties of Human Physique, and the 1954 Atlas of Men, and the work was quite influential, surely because of its rigorous scientific quality (that is, not just because of the nude pictures!).  But, he was working in, and part and parcel of, the racist, sexist, and other 'ist' environment of the eugenics era, where experts' value judgments about human qualities were taken as respectable science.

From The Varieties of Human Physique

Sheldon's work did not come out of nowhere. More than a century before Sheldon, Franz Gall, a comparably prominent scientist, made similar in-depth revelations about personality from identifying cranial somatotypes (that field of science was called 'phrenology').  And in Sheldon's own time was his fellow Ivy Leaguer, Carleton Coon, who made his own set of observations about how personality as revealed by morphology demonstrated the racial characteristics of peoples, and the definitive finding that the Europeans were the superior type.

All this other credit aside, Sheldon's work is out of fashion, and out of sight, somehow viewed as rather crude, and embargoed at least in part because at least one photographed subject would go on to become President, and other future movers and shakers posed for Sheldon's eager eye.

Somatotyping redux. . .

Understanding what made you roly-poly and jovial, or gaunt and neurotic was beyond Sheldon's abilities, cramped by the limited knowledge of the time.  Now, of course, we're well past the Sheldon age.  We're beyond daguerrotypes and have real data from DNA sequencers, fancy 3D cameras, CT scanners, and fMRIs. These Big Data technologies now allow us to penetrate a subject's deepest nature, so to speak, and thus objectively reveal the naked truth.  Currently a number of large projects are afoot aiming to do just that in one way or another.  The mega-study called 'GIANT' to measure stature and other anthropometric states is an example.  Of course, whether their estimated thousands of contributing genome regions makes prediction useful is another matter....

With millions of DNA markers or even complete DNA sequence, and moving towards a million or more measured subjects, we will finally be able to relate genetic variation to somatotype (that term itself is no longer in general use, because it smacks of old-style pseudoscience).  We're finding the hundreds or thousands of genes that make your somatotype what it is, which must be predictable from birth, of course, or else the study would largely be of rather less crucial importance to society.  One application, that will be vital, is that the FBI, police, or NSA will be able to use DNA samples from the scene of a crime to predict what the perpetrator looks like.  But, surely they will also be able to use DNA samples to predict the dangerous, antisocial, or undesirable somatotypes they should be on the lookout for as well. 

. . . and more, or is it less?
While the new more deeply intrusive methods will allow sets of genes to be found that explain somatotypic variation, the clear signs are that it will soon go much farther, into territory Sheldonians could only make amateurish guesses about.  For that, three facts are key:  

1.  The traits are already clearly known to be affected by variation in huge numbers (hundreds or more) different genome regions.  That's because interactions among many factors are required to assemble complex physical or behavioral traits. 

2. Most functional genome regions are involved in gene regulation or processing--such as signaling among cells that affect a cell's context-specific gene expression. That's how we develop as differentiated organisms with tissues, organs, and the like. 

3.  Most genes are pleiotropic, that is, they are used in more than one developmental or cellular context or function.  Our total repertoire of genes can be as small as it is because even with limited numbers of genes, there are essentially unlimited numbers of combinations of the genes available for different purposes.

These facts are critical to opening, or perhaps reopening, a rigorous new age of Somatotypology!  Based on the points just listed, the logic goes as follows:

If a given gene is used in more than one context, and one of them makes your somatotype, and another makes your personality, then of course if we know the genetic basis of your somatotype score (new, highly computerized versions of the tricorn figure above), then, obviously, your personality will be predictable as well because the same genes will also be involved in determining your behavior!  A morphological window into your soul.  How you look = how you act! A syllogism so seemingly tight it would make Aristotle smile!

Of course, the syllogism happens to be wrong, but we'll let that pass. But you've undoubtedly noticed a major uptick in studies of the genetics of behavior, reviving notions long thought deservedly dead.  Countless newly energized investigators are mapping every sort of behavior, focusing of course on things like intelligence, violence, criminality, liberal politics, ability to make wise pension investments, and (of course) sexuality normal and antisocial.

So why would this neo-Sheldonian revolution make any difference? Do you think we're being far too suspicious or even paranoid that people are going to be suggesting that facial or other physical appearance is diagnostic of behavior based on the above syllogism? This line of thinking is not our invention, even if the first forays are as yet unpublished gleams in some investigators' eyes. 

Yes, readers, DNA-based personality forensics is on the way!  A rebirth of  'Constitutional Psychology' as written in your very genome!  Sheldon could only assume it; science now can prove it.   Sheldon was right, though of course, the new version won't read like Sheldon.  It will be written in impermeable technical, statistical, and genomic language (details and flaws--if any--entombed in Supplemental Information).  And private companies (as well, of course, as the security agencies) will be using this rigorous knowledge to hawk genomic tests for Find-a-Mate or IVF websites.  You and the government will be able to tell who's a robber, rapist, or good candidate for law school or hedge-fund managing....not to mention who qualifies to marry your daughter!

But--and here's the really good part.  Unlike DNA, which you have to needle or swab people to get from them, or find at already-committed crime scenes, all you'll need will be to see someone or get a photo (say from their Facebook page), to scope out the future criminals, sexual abusers, jovial friends, untrustworthy scoundrels and other deviates, and so much more.  Indeed, this time around we'll be able to go a giant step beyond the crude, restricted range of Sheldon's work.  Basically only wealthy white people, mostly men or women merely in search of husbands, attended the Ivies in his day, but now, thanks to more open admissions, we'll be able to show things that have long been intuitively obvious, though only crudely speculated about, in Sheldon's own day.  We'll now dig deeply into the basic personality differences--and consequent relative ranking--of races (just call them 'ethnic groups' if that mask makes you more comfortable), in terms of important behaviors and talents.  This will be a huge advance for (hu)mankind, and for our own national security.

And think of the research money that will be saved!  The DNA sequencers and expensive labs can be dispensed with, once they've shown that all we really need are photos that any old cell phone can take.  So, maybe the threat that all of us will be shelling out once more for Sheldon, since our taxes will be paying for this vital but erstwhile very expensive work, won't come to pass after all.
  

This is the new wave, real science replacing the former pseudo-science. The charts will be far more aesthetically pleasing than Sheldon's old hand-crafted ones, though new reports will probably not include nudes because you can already see as many of those as you want on the web without having to buy an expensive Body Atlas.  However, don't despair about even that, since one can safely predict that scientific specialists will soon turn their penetrating attention groin-ward in their own highly technical studies.

A new wave replaces the old wave in the nature of things.  How long this tide will stay in is hard to predict.  But you don't want to miss its exciting, not to say titillating, messages.

Eugenics is back...and YOU are paying for it!

It didn't take a genius to predict that the fervid ideology driven by genomic technology would lead to a revival of the geneticizing of every human trait, and once behavior was allowed back into the tent that we'd see eugenics not far behind.  And a story in the NYTimes suggests that criminality is already back in apparent good graces. 

The tainted history of using biology to explain criminal behavior has pushed criminologists to reject or ignore genetics and concentrate on social causes: miserable poverty, corrosive addictions, guns. Now that the human genome has been sequenced, and scientists are studying the genetics of areas as varied as alcoholism and party affiliation, criminologists are cautiously returning to the subject. A small cadre of experts is exploring how genes might heighten the risk of committing a crime and whether such a trait can be inherited.    

 It's couched in pious only-for-social-good kind of rhetoric, along with 'oh, no, your genes don't determine your future penal state, only give some suggestions about .....'

But this is eugenics by other names.  Once it is believed that genes affect your risk of being a criminal (or whatever other kind of undesirable), the acknowledged fact that environments can modify that probability tend to be swept away, because your genotype can be measured at birth and used to label you.  If you have an above-average 'tendency' to become a sociopath (of types other than those of the neo-eugenicists in modern genomics--now, as before, in major universities), then you or your kids and friends may be labeled, watched, shadowed, pressured (on pain of things like no insurance or jobs) to take preventive measures (e.g., be doped by psycho-meds).

It's understandable for a host of reasons, all of which were invoked by the first round of eugenecists, because we know that genetic variation affects variation in basically any trait you can name.  But the determinism is usually very weak, and the bulk of social problems, like criminality, could be cured not by professors at prestige universities with large grants, but by more social equity and integration, and so on--things we understand imperfectly but perhaps far better than we understand genes.  But who will know and what will they be allowed to do with that knowledge?  Will there be forms of subtle intimidation applied (insurance, jobs, school admissions, imposed preventive measures....).  And what traits will, incrementally, be added to the test list?  We all know from history--including some contemporary history--how it goes.

The current step sounds innocent, as it's about crime, as being discussed by NIJ (the National Institute of Justice; the 'J' is supposed to be about justice, but they have the money so they can define that however they want).  Big deal?  After all, how different will genomic surveillance be from communication surveillance that is apparently being expanded? 

The work is going to be done,  since nobody has the will to stop it....and YOU are paying for it.

"and I want no other fame": The tale of the butterfly novelist--Vladimir Nabokov

Lolita may be a story for adults only, but Vladimir Nabokov told another story that can be enjoyed by all.  It appears to be an amateur's triumph, based on a correct guess that was before its time.  No definitive data could have been assembled to tell the tale while Nabokov was alive.  But thanks to the very regular, clocklike way that DNA accumulates variation among descendants over time, the guess seems to have been confirmed with current methods.

Polyommatous blue, by Lilly M.,
Wikimedia Commons

The immediate story is told by Carl Zimmer in the NY Times, but is based on a paper just published in the Proceedings of the Royal Society.  If Lolita was about a man in pursuit of a (too-)young person he obsessively adores, the story of the Polyommatous blue butterflies is one of a man chasing a group of old species that he obsessively adores.

It has long been widely known that Nabokov was a persistent, knowledgeable, dedicated if technically amateur butterfly enthusiast.   It was also long known that he did extensive work on the structures and relationships of the species that came years ago to be known as 'Nabokov blues'.  You can read about this, with maps and illustrations, in a fine book by Kurt Johnson and Steve Coates, Nabokov's Blues: The Scientific Odyssey of a Literary Genius, Zoland Books, 1999.  Johnson is a lepidopterist, expert in these butterflies.

They write "Where South American temperate life-forms had come from became a compelling question from the earliest stages of the continent's exploration." Much of their book, which is a readable, popularized narrative, tells of the efforts by Nabokov and others then and since, to understand the taxonomy--species relationships--among the South American blues and their relatives elsewhere. 

The traits of species available to Nabokov and others did not neatly correlate with their locations in the Andes or down into warmer environments.  That meant that some nearby species seemed too different to have had an evolutionarily recent common ancestor.  And, if they did not, and for the group as a whole, where were their origins then?

This issue had arisen out of the work of many naturalists going back at least to the early 1800s.  From an evolutionary point of view a couple of explanations were plausible.  One is polyphenism: species can have very different morphology or behavior depending on the individuals' local environment or genotypes.  And there is mimicry: distantly related species can come to resemble each other by natural selection. But that will only affect the mimicked trait, leaving the species' other traits less similar.  But in any case how did these butterflies get into the Americas?  There were various suggestions.  One possibility that Nabokov entertained was that the species had expanded into the Americas from Asia, by way of the Bering land bridge--that is, into South America from the north, what is now the Arctic.  The North American ancestral species may then have died out, leaving only their South American descendants.

The story in the Times, like news stories tend to do, makes this seem as if Nabokov got this 'blues' story out of the blue, so to speak, and was insistent on this view.  Indeed, Vila et al. in the Proceedings of the Royal Society paper, do the same:

The radiation of Polyommatus blues in the New World was first appreciated by the famous writer Vladimir Nabokov when he was working as curator in the Museum of Comparative Zoology at Harvard in the early 1940s.

And:

Our results show that Nabokov’s inferences based on morphological characters (primarily of the male genitalia) were uncannily correct in delineating not only species relationships but also the historical ordering of these five key events in the evolution of New World blues.

But even brilliant discoveries occur in a context, and people rarely take immovable positions when the evidence is ambiguous. Johnson and Coates go to great lengths to describe the long history of South American biogeography--the distribution of species over space and how it gets that way.  Ideas of species rafting across vast oceans had been suggested, and when continental drift was discovered, land connections between South America and Asia and Africa provided a possible explanation.  But climate change and a northern connection was another possibility.

There's no taking away from Nabokov that he was diligent and insightful, but others were thinking similar kinds of things, about the biogeography of many different species besides butterflies.  As he said in our title quote, he wanted to be known for this work, and properly so.  But at least Johnson and Coates present the history as one of many widely discussed possibilities by many different investigators--including the Northern origin of South American species generally.  Nabakov appears to have weighed different possibilities, and his preferred hunch, given the set of specimens and knowledge available to him, appears to have been right. 

The new paper uses extensive DNA sequence to resolve these tales in detail, data that of course was unavailable in the past.  The authors draw species-relationship trees based on the degree of sequence identity.  The times of splitting among the species were estimated by the number of DNA sequence differences that had arisen.  Many of the branches were  deep--large numbers of sequence variants, suggesting ancient splits, relative to other nearby species in South America.  Since the nearest relations in these instances were in Asia, the American species must more than once--in different expansion waves--have come from Asia.

Paleoclimatology and continental drift, and known climate tolerance patterns in the butterflies made it possible for the butterflies, over many generations, to expand here from Asia and survive in the warmer climes that existed episodically over an estimated period of 10 million years.  DNA analysis can even work when there has been selection for polyphenism or mimicry.  That's because such selection would distort relationships only at the genes involved in those particular traits, but genomewide variation will accumulate in a pattern that corresponds to the species' histories.  Indeed, DNA evidence could provide evidence for it, by showing that though some species looked similar, they really were not very close relatives overall (genomewide).

Here is an application of genetics that is entirely appropriate, that makes it possible to draw convincing inferences, when morphological or behavioral analysis may not.  A tree of descendant genomes accumulates variation probabilistically, so little can be said from observation of just a few nucleotides.  But these erratic patterns even out when thousands of nucleotides are compared, as these authors did.

Even so, let's keep in mind that genetic analysis is not exactly a scientific miracle.  If genes cause traits, then traits will diverge over evolutionary time in ways that generally reflect underlying genetic divergence.  That is why, in effect, Nabokov was indirectly using genomewide genetics to draw his conclusions--he just couldn't see the genes directly.  This is in essence how Darwin did what he did, too, without a good understanding of what inheritance really was.  But what we now have is explicit genetics to replace Nabokov's inferences from aggregate, implicit genetics. And this can get around problems of phenotypes that don't fit the history.

DNA is more specific and in the sense of time estimation much more rigorously useful than morphology and behavior.  As in forensic applications of genetics, that match sequences to their owners as in crime investigations, analysis that relies on the clear properties of genomes can tell stories that are as powerful as the compelling novels that Vladimir Nabokov wrote.  And he is justly famed for both!

Eugenics and other genetic risks, continued

Again, we return to a topic we said months ago we'd follow up on, but never did.  Holly touched on it here recently in her post about genetics and intelligence -- and, in fact, here's a quick followup on that subject; in particular, scroll down a bit in that link and read the sidebar on what happens to the brains of London cabbies -- and we wrote about it yesterday.  But, as the issues won't go away, and yet another paper is out this week in PNAS by the same characters using the same set of data, we think a topic we began to write about months ago is worth another look.  Especially given our focus this week on randomness and probability, and once again on genetic determinism and eugenics. 

Back in October, we, and many others, blogged about the paper by Fowler et al. that reported that genes largely determine political ideology.  The data set Fowler et al. mined for that paper, have mined before, and mine again for their PNAS paper this week, is the 2,600 subjects included in the National Longitudinal Study of Adolescent Health, a study of 20,000 adolescents in grades 7-12 in 1994, and followed up in 2001-2002 when students were 17-24 years old, and a subset more recently followed up with biomarkers, including DNA.  The study was designed to look at the effects of social context on health behaviors like seat belt use, drug use, sexual activity, nutrition and so on.  

The small subset who donated DNA were genotyped for 7 candidate polymorphisms. 

The initially targeted candidates are the dopamine transporter (DAT1), the dopamine D4 receptor (DRD4), the serotonin transporter (5HTT), monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), the dopamine D2 receptor (DRD2), and the dopamine D5 receptor (DRD5).

Why these particular genes were   chosen is not something we could easily find but presumably it has to do with previous reports of their association with particular behaviors.

A cursory literature review shows that using these genetic data, researchers have, to date, found 'the warrior gene', that is, an association with DAT1 or DRD2 and gang behavior and serious delinquency, a link with low grades and DAT1, a dopaminergic gene, and that "students with a single, DRD4 variant had significantly lower grades in English and math, but only marginally lower grades in history and science", the genetic basis of victimization, the genetic basis of our place in a social network, that is, popularity, an association with genes and smoking behavior, as well as the links with political behavior and ideology reported by Professor Fowler et al.  And, the new study by Fowler et al. reports that people who share the same DRD2 allele associated with alcoholism tend to be friends.  

Ok, let's just take the DRD4 gene.  This gene that has been associated with numerous behaviors previously, including attention deficit disorder (the association is with a 48 basepair VNTR, or variable number of tandem repeats, in exon 3), novelty-seeking (that exon 3 VNTR again), externalizing behavior in toddlers (exon 3 VNTR), temperament in children with the exon 3 repeat allele if they are given poor quality parenting (or 'differential susceptibility to child rearing'), aggression at age 4 (long repeat), attachment disorganization in infants (48 bp repeat), to cite just a few of the studies reporting an association of behavior with this long repeat in this dopamine receptor gene.  And there are plenty more.

The idea, as proposed by Hamer et al. in 1996 in the precedent-setting Novelty Seeking study, was that the number of repeats in the gene affects the structure of the receptor, thus how dopamine binds to it, and so the efficiency of neurotransmission.

But now there's this, a 2010 genomewide association study by Verweij et al.:

Variation in personality traits is 30–60% attributed to genetic influences. Attempts to unravel these genetic influences at the molecular level have, so far, been inconclusive. We performed the first genome-wide association study of Cloninger's temperament scales in a sample of 5117 individuals, in order to identify common genetic variants underlying variation in personality. Participants’ scores on Harm Avoidance, Novelty Seeking, Reward Dependence, and Persistence were tested for association with 1,252,387 genetic markers. We also performed gene-based association tests and biological pathway analyses. No genetic variants that significantly contribute to personality variation were identified, while our sample provides over 90% power to detect variants that explain only 1% of the trait variance. This indicates that individual common genetic variants of this size or greater do not contribute to personality trait variation, which has important implications regarding the genetic architecture of personality and the evolutionary mechanisms by which heritable variation is maintained.

No association with DRD4 and Novelty Seeking.  And no association with DRD4 and Novelty Seeking was found in 2 samples in New Zealand, and while some studies in birds have shown an association with a DRD4 variant and exploratory behavior, it isn't consistently reported.  A study of one of these repeat polymorphism has shown that the effect of the variation depends on your socioeconomic status: negative for low SES, positive for high SES.  Context determines what the genotype determines.

Now, all the usual caveats that we mention over and over again apply here -- the definition of the trait may vary enough between studies that they are comparing apples and oranges, and the association may in fact be real in some populations and not in others.  But GWAS should find genes with large effects, and the Verweij et al. study did not.

What if that's because the trait is due not just to a single gene but to gene-and-environment interaction? Would a GWAS still pick it up?  This would depend in part on the size of the study sample and the amount of environmental variation among those sampled.  GWAS detects net results, basically, especially if the environmental factors are not known or measured.  Large effects found in a GWAS may be because there was some tractably invariant environment among the sampled people, that may not be present in another sample, and the same allele may not have its purported effect in those data.

The association of this gene with political ideology could be real.  Or it could be a chance positive result due to multiple testing or other statistical aspects of the sample.  Or it could be real....but only ephemeral, changing rapidly with societal context.  The notion that we can predict these kinds of things very meaningfully is one we should be very circumspect about.  Even after extensive (and expensive), very technically sophisticated studies (unlike many of the behavior one-gene studies mentioned here), we can't make good predictions of very clearly genetically-affected traits like how tall you are or whether you'll have diabetes (and if so, what its particular characteristics, severity, response to treatment, etc. will be).

Every trait you can name probably has at least some heritability; that is, genetic variation contributes to variation in the trait.  Heritability is usually substantial.  But so are chance and the various aspects of lifestyle and environment.  High heritability means that genes are relative important in the population, but does not mean that an individual genotype predicts that person's trait reliably.  GWAS experience, which is now extensive, shows that high penetrating power of single (or even a few) genetic variants is not common.  Often, the trait definition is crude (like 'intelligence' or 'IQ', or 'asthma' or 'autism' or even obesity), but the definitions are changeable and cultural, the measures sometimes arbitrary, and people can have the same value for different reasons.  People with high intelligence measures can have better ability to memorize, or to learn quickly from one exposure to a fact or challenge, or to integrate repetitive exposure, or to do mental work by visualization or by other means, and so on.  

Change the environment or the measuring criterion and you can change the result.  Different approaches to modifying the achieved trait, like therapy for a disease, can apply differently to different people with similar measurement value.  People with similar glucose levels have different ways in which the 'same' trait is manifest during their respective lives.  This should be obvious, since diabetes and IQ have both increased substantially in recent decades, but the underlying genetic variation hasn't.


This is in rough terms why things can be genetically affected in real and substantial ways but, we would say, not genetically determined.  Again, the problem lies in overstating the latter and putting it into policy.  This is where the idea of 'eugenics', that is, of using ideas about inherited worth to make policy to 'improve' the human species and its genome, become heavily sociopolitical rather than scientific.  Historically this has led to discrimination against individuals and against whole groups.  One might be tempted to say that it's 'right wing' to believe in genetic determination of traits like ability or behavior, or the inherent value of one race vs another.  But this would be vague at best and misleading at worst.


To caricature affiliations, we can say that it's not just rapid right-wing behavior genetics that we should be wary of.  The rabid left has left its own trail.  While the Nazis were gassing people who were inherently 'inferior', the Soviets were starving people because, under the influence of one Trofem Lysenko, they believed life was improvable by experience alone rather than by inheritance (a view generally attributed originally to Lamarck in 1813).  In both cases, categorical beliefs about the role of inheritance led to disaster on a major scale.


That is why, despite the fact that of course genetic variation contributes to all biological variation, we should be very careful about making pronouncements that could be used for societal policy.  Today that policy might be favorable to you....but what about tomorrow?  Even if nothing untoward is being done with genetic data these days, prevention is the better part of valor.

Of course, if you want to make strong statements about the genetic determinants and evolution of ostrich knees, feel free, because only a few 'experts' in the world will care one way or the other.

School's Out! (But is my joy based in biology?)

It’s the last day of the semester. Students are submitting their final exams to me today and it’s only fitting that I submit my final thoughts to them (and to you) about what I learned this semester about the Biology of Behavior (Anthropology 261).

First of all, it’s mind boggling that after spending an entire semester studying the subject there are students on one hand…

Here’s me with arms outstretched to the sides, palms up.

… who believe that behavior is mostly determined by genes and that one day we’ll be able to explain it all with genetics, and then there are students on the other hand who are super critical of science and also think that behavior is entirely learned.

You’re wondering what this “behavior” is that I’m talking about.

Me too.

Here’s me wincing vulnerably with blushing cheeks.

That’s problem number one. What is behavior? It’s not really clear. Not after a course like this. Maybe my students will illuminate this for me in their final essay in which they categorize human behaviors according to their own taxonomies. But I haven’t read their essays yet.

Here’s me feeling fight-or-flight grading anxiety with tingly palms and armpits.

Problem number two. Everybody, even the most extreme, was on board with Nature PLUS Nurture (as opposed to Nature VERSUS Nurture). So, many of the class discussions boiled down to popular debates, as opposed to more nuanced debates that would have been more productive. But because we couldn’t become experts at this introductory level, it was difficult to get to the nitty-gritty. What we concluded was that the debate about human behavior in the popular media is full of false dichotomies, irrational fears of improbable/impossible future science, and irrelevant debates as a result of both.

Problem number three has to do with normal versus abnormal behavior. People seem to think that because a behavioral disorder can be traced back to genes, then therefore variation in that behavior at the normal level in unaffected people can also be explained by genes.

Here’s me making a wrong answer buzzer sound. Errrrrrr!

So did we figure out why humans do what they do? Well, considering the two choices [(A) It’s instinct. It evolved by natural selection or (B) We learned it. It’s a product of our environment.] The question of why becomes obscured by the possibility that we may not have a choice.

The former choice, A, implies that we can’t help our behavior…We have excuses for behaving badly and we can’t take moral credit for behaving nicely either.

The latter, B, puts the emphasis on culture and its importance…either at the individual level or beyond. Our bad behavior is our own fault or due to our parents, friends, environment, circumstances. Our good behavior is our own doing or it is shaped by parents, friends, environment, circumstances, and by government laws and religion.

So no matter what the answer is, it’s probably going to offend somebody.

Then there are all the behaviors that are neither “bad” nor “good.” The ones that are just what folks do or do not do at various times of their lives, in various circumstances, under various conditions, according to various individual biologies and histories.

Here’s me shrugging my shoulders and throwing my hands up in the air.

The bottom line that everyone agreed on (I hope) is that all behavior is biological even if it’s learned because we are biological beings. Everything we do, learn, say, feel, think is a biological process. Our genes don’t have to determine it for it to be biological. And, it’s all biological unless you invoke supernatural explanations. Human behavior is biological and this goes for whether or not we intend to do what we do.

So what are the determinants of human behavior that all somehow derive from biological processes?

We made a flow chart over the course of the semester and this is the result. Because there are no arrows pointing to any behaviors, this is not a chart of the determinants of human behavior. Instead it is the “Determinants of the determinants of human behavior.” Smart alecs will notice that there are no quantum variables on here and that’s because we didn’t get that small/big this semester.

Hey, at least it’s better than the flow chart for the American strategy in Afghanistan.

Now could you say that explaining human behavior is easier than explaining the American strategy in Afghanistan? That's a good question! But this flow chart may have caused you to wonder, what’s the point of trying to explain human behavior if it’s at least this complex?

Well, there are behavioral disorders we can hope to treat or cure. And there are evolutionary puzzles that we want to solve!

So how’s the treatment of disorders going? One recent example is the search for the genes for stuttering. That the genes linked to stuttering are involved in metabolism is, first of all, surprising to most until they think about how metabolic processes are linked to neurological development. Okay. So what’s the gene? There are three genes where stutterers in the study population had mutations: GNPTAB, GNPTG , NAGPA. So they found the genes for stuttering? Not exactly. Only 6% of stutterers in the sample had these mutations. Only 6%! The other 94% of stutterers are stuttering with perfectly normal versions of these genes. Plus, there are some people in the sample of non-stutterers (albeit a very few, <0.5%). style="">At least for the 6% who do have known mutations, they could see drug treatments soon.

Now, about those evolutionary riddles we’re all dying to solve…

That’s where maternal effects come into play. This is when mom’s genotype or phenotype influences her offspring’s phenotype and maternal effects are known for things like body size, immune function, predator resistant morphology (like spikes or wings). Known triggers are things like resources, density of conspecifics, temperature, parasites, and predators. And these are adaptive! Relatively little is known about maternal effects on behavior, however, it has been reported recently that mother crickets, just by their being around wolf spiders, influence how their offspring react to predators.

Here’s me crouching down and imitating a cricket immobilizing itself as predator-defense.

Mothers who have been exposed to predators have offspring that are better at surviving in the presence of predators than offspring of mothers who have not been exposed to predators.

Here’s me spit-taking my morning coffee because this is just so incredibly mind-blowing.

So if Nature VERSUS Nurture is so passé. And if it all does boil down to biological underpinnings and genes even if the genes don’t dictate things. Then why the rage and the frustration over explaining human behavior? Why the fears that we’re going down the horrific eugenics path by continuing to search for genes for behavior when we probably can’t find genes that determine variation in any of the behaviors that we find especially interesting in normal people?

I think that what offends people most about biological studies of behavior is the simple fear that it might be explained. Learning about human nature and coming up with the explanations for ourselves, by ourselves, is one of the thrills of being a human. It’s something that we want to experience over our lifetimes, not learn from someone else’s simple rules. It’s the idiosyncrasies and the surprises along the way that can be so beautiful and meaningful and those moments are threatened if a scientist tells us how to size up a person with an equation.

What I learned this semester is that people are defensive about science explaining our personalities, our selves. But what I also learned is that no matter how hard it tries, science cannot explain even the average Joe’s behavior or personality with genes or otherwise.

So what’s the big deal? Relax. You’ll always be somewhat of an enigma. And so will I.

Here’s me lifting my arms behind my head, leaning back, grinning, and sighing contently.

School’s Out!

The long history of Gay Pairee

An article in the Easter Sunday New York Times Magazine shows that homosexual behavior is found in hundreds of species of animals--even insects. That this merits an article, with lots of hand-wringing as to whether gay behavior is right or wrong, natural or otherwise, or indeed even worthy of explanation reveals a lot more about our culture than it does about nature. In short, it shows that our obsession with sexual preference is myopically ethnocentric.

Sexual preference is doubtlessly based on many genetic and environmental factors. Rather than being a rigid threshold, or a yes-no phenomenon, it is some sort of continuum that involves emotional preferences, social constraints or learning, as well as actual copulation and reproduction. This is so obvious it should not have to be discussed and trees don't need to be killed to print stories about it (of course, some of those trees might be 'homosexual'!).

The most important point is going to be the one least heeded because it threatens many vested, often fervid, beliefs about humans and evolution. That's that homosexuality is a problem that human evolutionary anthropology (as well as 'Darwinian medicine') have to explain. The problem is darwinian, or any other fundamentalism, masquerading as 'theory'. Darwinian fundamentalism assumes that what's here and organized must be so because of natural selection. No room for incidental traits, nor a wasted calorie.

From an evolutionary point of view it is no surprise of any kind that homosexual behavior would exist in other species, nor that it would have many manifestations. After all, even within humans it is like that. There is not a whiff of evidence that homosexual behavior is favored per se by natural selection, and clearly if the distribution of interactions and genital use shifted too much towards the homosexual, then it would be selected against (or some modified form of reproduction would replace the 'standard' forms--which, by the way, are themselves hugely variable).

The spectrum of sex and gender behavior, contrary to the oft-expressed shock that homosexuality could even exist (since all behaviors must be here because they're adaptive, and how could homosexuality be adaptive?), is no threat of any kind to properly understood evolutionary theory. If there were a single allele (a variant in a single gene) that inevitably conferred exclusive homosexuality upon its bearers, then our theory predicts it would disappear since if its bearers didn't engage in reproduction it could not be transmitted to the next generation. If complex genotypes confer an increased chance of gay behavior that reduced the bearers' number of offspring, it could proliferate only by chance, or by raising the reproductive success of closely related kin, though that's problematic because they, too, would carry the 'bad' gene. Theories of such 'kin selection' are elegantly mathematical but hard to prove.

On the other hand, sex-related behavior is manifestly complex, a mix of environmental, genetic, and chance effects. Given that, most 'gay' genotypes are unique--every case different, with very little net selection against any specific contributing allele. Just like other perplexing complex traits, they really aren't 'genetic' in the meaningful sense of the word, and fluidity in behaviors is simply tolerated by the weak selective constraints typical of nature.

But this kind of behavior may be interesting in its own right, if it could be stripped of the Just-So story kind of science that engages in excessive theorizing and hand-wringing, and we recognized our culture-bound reasons for even thinking it was particularly interesting. That we cling to fundamentalistic, or tribal, 'theory' is a failure of anthropology to educate scientists about themselves, or a reflection of a deep need for simple organizing principles to live by. And besides blinkered scientists, an understanding of anthropology should suffice to show that some people in a given culture, such as ours, may claim to be revolted by gay behavior but that other perfectly respectable cultures do not share that view. One doesn't have to like, or dislike, variations in sex or gender behavior to realize that such a personal view, to which everyone may have a right, is not mandated by any ultimate truths, and there's certainly no legitimate justification for religious bigotry in this respect.

An important bottom line is that this is not a human-specific problem in any evolutionary sense. The genetic permissiveness in regard to sexual preference is probably so complex that it has virtually no longterm evolutionary consequences or implications. If this is a sociobiological problem, it's hard to see how. Clearly, even in non-social species this has not happened, and homosexuality was present in early animal ancestors, so we've inherited that capability countless eons ago. It is not particularly important to species success, and not tightly monitored by natural selection.

Above all, there is no justification for human exceptionalism. To the extent that homosexual patterns are important to human society, it is not an evolutionary question but a cultural one. Its nature, variation, and impact might be interesting to study on their own, as phenomena that vary from culture to culture. If gay men help care for their brother's children it's an interesting aspect of social structure that is essentially irrelevant to the genetic aspects per se. The genetic mechanisms involved in behavioral differences might be of physiological interest, but they do not explain the phenomenon.

The same holds for many other aspects of social and behavioral traits to which human exceptionalism and lots of 'theory' have been applied. And it's why many people consider 'evolutionary psychology' to be a made-up kind of junk science, if it insists on tight 'darwinian' explanations for things for which the evidence such as discussed in the Times article shows simply isn't there. And it's time to stop geneticizing social behavior, even if, of course, genetic mechanisms are involved.

As anthropologists realized more than a century ago, social facts are best explained in terms of social facts (again, even if a minority of cases, or of behavioral extremes, have specific genetic explanations). Treating social behaviors as if they needed evolutionary explanations in the sense of Darwinian selection adds value judgments that are far more a reflection of preconceived notions of modern society (that is, of the scientists who are peering into behavior with Gotcha! hubris). Unfortunately, we know from clear and repeated history that such value judgments often provide the excuse for discrimination against people, with the upper classes deciding who's good and who's bad.

The cystic fibrosis gene 20 years later

There's a Genetics "News Focus" piece in today's Science magazine called "The Promise of a Cure: 20 Years and Counting", written by Jennifer Couzin-Frankel. We can't link to it, but we will describe it a bit because it relates to several of the issues we've written about ourselves this week.

The piece is about cystic fibrosis (CF), the gene for which was found 20 years ago, and announced with great excitement and hope for a cure. Gene therapy was the immediate focus, and many labs began the hunt for a method to deliver healthy copies of the gene into the lungs of people with CF. However, years into the search, it became apparent that gene therapy, at least as it was being tried, was not going to work, and research turned to better treatment and drug therapies. In the last 20 years, life expectancy for people with CF has risen by about 10 years, to 37. This isn't due to anything genetics has taught scientists, but to more aggressive and earlier treatment to keep lungs clear.

Even if the early promise of a cure hasn't yet been fulfilled,

in a funny way, "science has benefited more from the CF gene than CF has benefited from the science," says John Riordan, a biochemist

now at the University of North Carolina at Chapel Hill and one of the co-discoverers of the CF gene. Much has been learned about the genetics and physiology of CF, and new approaches to gene therapy may be on the horizon. Millions of dollars have been spent over the last decade or so on developing new drugs to treat the disease, and two are now in clinical trials. At least 1000 different mutations in the CF gene have been reported over 20 years; this isn't unusual, even for 'simple' single gene diseases. One of these mutations is quite common, while many have been seen only once; again, this is the usual case. As we wrote in our post on June 15, one of the speakers at the Bristol meeting described instances when it is useful to know a causative allele for determining therapy, and indeed both of the new drugs now in trials are targeted toward one of the known mutations for CF--one is meant to be helpful in patients with the most common mutation, while the other targets those with a mutation that explains the disease in only a few percent of patients.

Although we have never worked on cystic fibrosis, we well remember the excitement with which the finding of the CF gene was announced, and the belief that gene therapy was the next frontier. It was very sobering and discouraging to many when gene therapy turned out to be much trickier than anticipated (will stem cell therapy, so much hyped today, be equally recalcitrant?). Much has been learned about cystic fibrosis in the 20 years since the gene was identified, and it's still possible that genetics will contribute to treatment or even a cure. But, it's a cautionary tale.

The tale is also informative about the various strategies and approaches. The first step, at least as far as genetics goes, is to identify the causal gene(s). Once this is done, specific studies can be done focused on patients (and, where needed comparative control individuals), to identify the spectrum of mutations at the gene(s) and their clinical effects. This makes it possible to focus molecular and cell biology on the genes effects. Mapping or genomewide association studies contribute little more.

One difficulty in gene therapy is getting a good experimental animal model, and this was frustratingly true for CF; in future years, hopefully cell-culture rather than transgenic animal models will be developed (perhaps based on expression manipulation in stem cells of various kinds). This array of knowledge and tools can then lead to therapy that is 'genetic' in that it is directed against the genetic physiology, but is not necessarily genetic either in terms of germ-line alterations to protect future generations, nor not even necessarily related directly to the specific mutation, to DNA or mRNA, etc. It can 'simply' be an attack on the pathophysiology that might take any number of forms.

The motivation of GWAS to identify previously unknown pathways fall somewhere in the middle ground. Mapping (in families, not association studies) found the CF gene, which showed that ion channel biology was involved. Once that happened, mapping studies were no longer needed, and new variation in the CFTR gene could be found by sequencing affected persons. Once a pathway has been found by mapping or any other method, the pathway can be studied directly.

A cogent contemporary question is when can we assume that most pathways have been identified by mapping? Pathways often involve many genes, any one of which could be mutated to have a major effect. If it is highly penetrant and viable, it should be findable in families, in which case 'linkage' analysis is the statistically best approach. Or, well-designed but not massively large genomewide association studies in appropriate samples could identify the offending pathway member.

So long as any gene in the network has mutations with detectable effect, the network is found and its remaining members can then be studied molecularly and in affected people. One might expect that this would be the case for most important gene networks and hence most diseases. In this sense, the new wave of very large genomewide association studies probably is not going to be all that useful, even if it certainly will make important findings now and then. It is here that the discussion of the relative importance of the investment in large GWAS should be.

The Science article also points out both the idea that once found, study of causal genes probably can lead to effective treatments, as well as that it takes time. Media hyperbole doesn't help, or put another way, isn't necessary for support to be given to research on genes that really are important. Likewise, not all avenues need to be followed up if they are very costly, once it becomes possible to focus on known causal genes. Existing resources can be more focused. And currently, there are hundreds of disease-related genes where this could be the case.

A gene 'for' depression that isn't

A new study published in the Journal of the American Medical Association today, and receiving a lot of media attention (e.g., here and here) questions a long-held result of a gene 'for' depression (well, long for a genetic finding for a complex disease--first reported in Science in 2003). This finding was significant because before it was published (and since), psychiatric illnesses had been notoriously and frustratingly immune to genetic dissection. This result was convincing enough that people were encouraged to think that genes for behavior were now going to be findable.

The new study, by Neil Risch and Kathleen Merikangas and others (by no means skeptics about the possibility of explaining complex disease with genetics, though they have cautioned in the past that gene by environment interaction is important), is a 'meta-analysis' of 14 studies that attempted to replicate the original finding, but were less successful. Risch, Merikangas et al. reanalyzed the data and did not find an association between the serotonin gene and depression, though they confirm that life events are significantly correlated with this mood disorder.

Regular readers won't be surprised to hear that we aren't surprised by these results. We are interested, though, in the first two sentences of the JAMA paper:

The successful statistical identification and independent replication of numerous genetic markers in association studies have confirmed the utility of the genome-wide approach for the detection of genetic markers for complex disorders. However, recent genome-wide association studies have also indicated that most common genetic risks, at least when studied individually, are modest in magnitude, with relative risks in the range of 1.3 or less.

It's almost required these days for a genetics paper to start out by proclaiming the success of GWAS--so like most geneticists, these authors are in the GWAS camp....but then they aren't. Indeed, it's now becoming fashionable to want to have it both ways: GWAS have been a great success, but actually they haven't, so we need a lot more money to do other things--like whole genome sequencing on everyone. And that, in essence, is another form of GWAS but on a grander scale because one still must make statistical associations between variants and disease phenotypes.

The individual sequences of Watson and Venter that are on display (with others in the pipeline) already show thousands of previously unknown protein-changing variants, plus additional thousands of 'novel' SNPs of unknown function. So the push for huge studies of this type are still based on technophilic wing-and-prayer promises to a great extent. But nobody is willing to say: pull the plug on these approaches and try something more likely to identify meaningful causes, including meaningful genetic causes, of complex traits. Too many vested interests are at stake.

In response to an article we published a few years ago in the Int. J. of Epidemology (2006 Jun;35(3):562-71), Merikangas basically said that discovery was serendipitous and even if our skepticism was justified the money should keep flowing because, eventually, something would be found. This is not a novel argument and indeed goes back to the basic Baconian idea of induction: keep observing and the theory will emerge from the data. To us in this current context it's an ultimate form of self-interested last resort.

But, this discussion is a road we've traveled down a number of times already in this blog. This new paper certainly won't deter researchers from continuing to search for genes 'for' complex diseases like depression, schizophrenia or autism and neither will we. Biologically, these traits may not be particularly different from physical traits like obesity, diabetes, or cancer. But behavioral traits are different in two very important ways that are relevant to issues of science policy: First, they are exceedingly susceptible to cultural environmental experience and effects. Even when these interact with genetic variation, it is the cultural factors that are not only clearly preponderant but also most malleable. Secondly, they are socially sensitive in the sense of potential for real abuse. We can't forget history, which is rife with arguments about biological inherency that are used to discriminate against classes of people, be they nationalities or 'races'.

At some point, surely even the most dedicated gene hunters will acknowledge that this approach isn't working for complex disease, and will begin to rethink the problem. Network-based thinking, that is, treating systems of interacting genes as wholes, could be a way out, if it has to do with therapy. But probably not if it means simply identifying every variant each person may have in the countless genes in relevant networks.