The Geography of Faces

How much can you tell about where someone comes from, just from their face?

The other day I was in London and came across a group of young people in Muslim attire who were waving (or in some cases wearing) a particular flag. I thought it was the Iranian flag, but, I thought, they didn't look Iranian. They looked more like Somalis, but it certainly wasn't the blue and white Somali flag. I decided that maybe they were some kind of pro-Iranian demonstrators, but I later worked out that it was the flag of the unrecognised state of Somaliland.

This got me thinking about how reliable these "they look they're from..." judgements are.

Clearly on a basic level, we can usually tell which continent someone's ancestors were from, in terms of the familiar "races" of Europeans, Africans, East Asians etc. But what about shorter distances?


Could you tell, just from looking at them (and setting aside dress, hairstyle, jewellery etc.) whether someone was from Spain as opposed to France? Korea or Japan? Russia or Germany?

I can only speak for England, but there's certainly a vague but widespread belief that every part of Europe has a  distinct 'look'. In the past, people were very fond of talking about that kind of thing; today, we're rather embarrassed by the idea but the belief lives on.

I don't know, but I'd be very surprised if there weren't analogous beliefs in other countries.

But how accurate are these folk beliefs, really?

Supposing you were the world expert on human faces - or suppose you were a supercomputer with face-recognition software and access to Facebook's entire dataset. How accurately could you place someone's origins on the map, on average? To within 1000 km? 100? With what degree of accuracy? In an ideal world, could the ultimate face-placer judge someone as French vs German 75% of the time? 90%? Or only slightly better than chance?

I suspect that if you researched this, you'd find that a supercomputer could do very well, in most parts of the world, but that the majority of actual people are less accurate than they think they are.

Personality Without Genes?

According to a paper just published (but available online since 2010), we haven't found any genes for personality.

The study was a big meta-analysis of a total of 20,000 people of European descent. In a nutshell, they found no single nucleotide polymorphisms (SNPs) associated with any of the "Big 5" personality traits of Neuroticism, Extraversion, Openness to Experience, Agreeableness and Conscientiousness. There were a couple of very tenuous hits, but they didn't replicate.

Obviously, this is bad news for people interested in the genetics of personality. But I wonder if the implications are even wider -

We know that there are SNPs associated with physical traits like height, weight, hair colour, eye colour, and the risk of various diseases. If none of those SNPs are associated with personality, then none of those traits are causally associated with personality.

"Short man syndrome"? A myth. Rod Stewart was wrong about blondes. There's no such thing as a "fat personality". And so on. Maybe that's not surprising, but more generally, the implication would be that the genes we inherit have no direct or even indirect influence on our personality, which is a pretty radical conclusion when you think through it.

I'm making some assumptions here. Maybe some genes are correlated with personality, but the currently popular "Big 5" approach is just a poor way of measuring of personality. It could also be that there are so many interacting genetic and environmental effects on personality that any given effect is tiny by itself, and even bigger sample sizes, or multivariate data analysis, would be needed to detect such effects.

de Moor, M., et al. (2010). Meta-analysis of genome-wide association studies for personality Molecular Psychiatry, 17 (3), 337-349 DOI: 10.1038/mp.2010.128

Genes for Intelligence - Back to Square One

Here's a paper - soon to appear in Psychological Science - which says that Most Reported Genetic Associations with General Intelligence Are Probably False Positives

The authors tried to replicate published associations between particular genetic variants (SNPs) and IQ (specifically the g factor). They looked at three datasets, a total of about 10,000 people, and didn't confirm any of the 12 associations.

As Razib Khan says in his post on this, "My hunch is that these results will be unsatisfying to many people." I'd go further and say that no-one will be happy with these.

For those who believe that IQ is purely environmental and not genetic, any satisfaction they might feel will be short lived because these authors did replicate the recent finding that genetic variants explain about 50% of the variance in IQ. Looking at all SNPs together, there was a strong correlation between "genetic similarity" and similarity in IQ. That independently confirms what the much-criticized twin studies of IQ said - IQ is about 50% heritable.

But for people who do believe in the genetics of intelligence, this shows us that we have no idea what the genes are, and that everything published so far has been pretty much for naught.

There's another implication. We actually do know of many "IQ genes" in that we know genes that, when mutated, cause mental retardation (very low IQ).

Now many researchers have hoped that if a certain gene causes you to have an IQ of, say, 50 when it's completely deleted by a mutation, then more subtle variants in that gene would have minor effects on IQ. Maybe a variant that reduces expression of the gene by 10% would knock off 5 IQ points.

In other words, if big mutations cause big phenotypes, then small mutations in the same place ought to cause small phenotypes. It seems to make sense - but today's IQ literature shows that it's just not true.

That's not just a problem for IQ though. Take autism or ADHD, we know that there are rare, severe mutations that cause these conditions. Many people are hoping that common variation in the same genes might also be interesting - but if IQ is anything to go by, it won't be.

Perhaps this is not so surprising. Breaking your neck and becoming paraplegic is going to seriously impair your ability to play baseball. That doesn't mean that normal variation in baseballing skill has much to do with minor neck injuries.

Chabris, C. F. et al (2011). Most Reported Genetic Associations with General Intelligence Are Probably False Positives Psychological Science

Scientific Databases - or Filters?

A new online database called AutismKB offers a quick way to find the evidence linking genes to autism.

You can read up on it in a paper describing the project.

You can browse by chromosome or gene name, it includes data on all kinds of genetic variants from SNPs to CNVs and it gives each variant a score according to the strength of the evidence. I haven't had a chance to really tell how useful these scores are, but there's an option to create your own score based on how much weight you give different kinds of evidence. The dataset is huge although it doesn't seem to have been updated for a few months.

Overall, it's a new tool and there's sure to be bugs to iron out, but it seems like it could be very useful. I do worry though that this kind of database encourages misleading ways of thinking about autism genetics.

There are numerous genetic variants which have been strongly linked to autism, although none of them account for more a small proportion of cases because these variants are rare. But many (most, actually, is my impression) of them have also been observed in people with other symptoms ranging from ADHD to epilepsy to schizophrenia.

So searching a database of "autism genes" could encourage you to think that these were only autism genes, which is far from true. Genetics, it is becoming increasingly clear, doesn't respect our current concepts of psychiatric illness or our academic specialities. There are few (if any) parts of the genome that can be neatly fenced off and declared exclusive to ADHD experts, schizophrenia researchers or whatever.

But disease-specific databases encourage the illusion that they do exist. It's the same old problem of the filter bubble which many people have warned about in the context of general purpose search engines. Scientists have filter bubbles too.

This is not of course a criticism of AutismKB in particular - the same goes for any similar "disease-gene" database. And to be fair AutismKB does provide links to a schizophrenia database, and a couple of others but you have to dig quite deep to get there. The "main page" of results for any given variant is pure autism.

That's the whole problem with filter bubbles - they make it too easy to hear what you want to hear, compared to getting a new perspective, so you don't even think to look outside the filter.


Xu LM, Li JR, Huang Y, Zhao M, Tang X, and Wei L (2011). AutismKB: an evidence-based knowledgebase of autism genetics. Nucleic acids research PMID: 22139918

The Gene That's "For" Nothing

Scientists like to warn you not to talk about "the gene for" a particular disease or trait.

I've done so in previous posts e.g. this one or this one.

But such scalding is not always very effective. We like simple explanations, so we like to find simple connections between genes and phenotypes.

Which is why a new paper is important. The authors, a large Turkish-American collaboration, found that mutations in a gene, WDR62, are associated with severe brain malformations in 9 patients. But what's interesting is that it doesn't cause any particular malformation.

If you have two faulty copies of this gene, your brain won't be normal, but what goes wrong varies widely amongst different people. Although the 9 cases had some features in common, such as microcephaly (small head and brain), in other respects they differed greatly.

As the authors put it, mutations in WDR62 cause

a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients... had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities.

These are distinct entities, in the sense that you can have any one of them, without having the others. And they are different brain changes. What the authors mean is that everyone assumed that, because they're  different, they must have different genetic causes. They've just shown that this is wrong.

So what is WDR62 "for"? Experiments in mice showed it to be involved in the migration of new neurons from their origin to their final location in the brain. So it's "for" correct neuronal placement, although how it works remains unclear.

WDR62 ought to remind us that there's a long and winding road from gene to phenotype, and that the same gene can, when mutated, cause very different symptoms. This is especially interesting in the light of recent evidence showing that the same mutations can cause a range of behavioural disorders from autism to ADHD to schizophrenia.

Bilgüvar K, et al (2010). Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature, 467 (7312), 207-10 PMID: 20729831

Potential Personal Genomics

A while ago I wrote about how new findings in genetics could herald a new kind of "eugenics", based not around selective breeding to ensure that "bad" genes aren't passed on, but rather based on using fetal genetic testing to choose which variants enter the gene pool in the first place.

I said-

In the near future, we might be able to routinely sequence the genome of any unborn child shortly after conception

But I didn't realize that this may be really very near indeed. Two recent reports have shown that it's possible to sequence fetal DNA from a maternal blood sample. In one case it was used to diagnose a 35 week fetus with a genetic deletion on chromosome 12 seemingly associated with autism, developmental delay and shortness.

In this case it was inherited from the father (which is why they decided to test for it), but this approach could equally be used to screen for the de novo mutations that account for much disease, as I discussed in the last post.

This is big. Currently, the main way to get fetal DNA is through amniocentesis, i.e. inserting a needle into the womb. It's a substantial and not entirely safe medical procedure. A blood sample would be an order of magnitude cheaper and safer, but most of all it would be something you could do at home.

No longer would you need to go to a hospital and discuss everything with a doctor. You could take some blood, send it off anonymously to a sequencing company, and get the results in an email. It would take it out of the hands of professionals and open up a space for individual choice.

The cost of whole-genome sequencing has been falling exponentially and many think it will fall below the $1000 mark within a few years. Combine that with fetal DNA testing and we might see moderately well-off parents able to sequence fetal DNA within the next decade.


When this happens I think the personal genomics industry will suddenly become extremely "hot". At the moment you can sequence your own DNA for a few thousand $ if you want. The results may be interesting but they're of little obvious use. Whatever your genes are, you're stuck with them.

But as soon as we're talking about potential human genomes, it'll kick things up a notch. Media interest and political controversy is sure to follow. Personally I think it'll the debate will begin in earnest when we start seeing selective abortions on the basis of genes for "normal" variants rather than "disease" genes.

It's one thing to not want a child with blindness, or a high risk of leukaemia. But as a society I don't think we're ready for not wanting a child because they're predicted to be a B student rather than an A student, or brunette rather than blonde. At some point soon, though, we'll have to decide what we think about that.

Peters D, Chu T, Yatsenko SA, Hendrix N, Hogge WA, Surti U, Bunce K, Dunkel M, Shaw P & Rajkovic A (2011). Noninvasive prenatal diagnosis of a fetal microdeletion syndrome. The New England journal of medicine, 365 (19), 1847-8 PMID: 22070496

Srebniak M, Boter M, Oudesluijs G, Joosten M, Govaerts L, Van Opstal D, & Galjaard RJ (2011). Application of SNP array for rapid prenatal diagnosis: implementation, genetic counselling and diagnostic flow. European journal of human genetics : EJHG, 19 (12), 1230-7 PMID: 21694736

The Google of Negative Results

A new online resource has been launched which offers us the chance to find out what isn't happening in science.

BioNOT is a free searchable database of negative findings in biology and medicine.

Text mining approaches to the scientific literature have become increasingly popular as a way of helping researchers to make sense of a growing number of papers. But they've tended to focus on positive findings and skim over negative ones. In this sense they're following in the tradition of scientists themselves, unfortunately.

It's also hard to search for negative findings on PubMed, because if you type in, say, vaccines NOT associated with autism in the hopes of finding papers showing that vaccines don't cause autism, it will think you are trying to search for "vaccines" and don't want to see any papers mentioning the words "associated with autism". So you end up with 160,000 hits about vaccines with no reference to autism at all. There are ways around this but it's surprisingly tricky.

BioNOT uses text mining to mine null findings from a large database which includes everything you can find on PubMed and also a large number of full text articles (some behind paywalls).

Authors Agarwal et al of Wisconsin say that this will help to map out the "incidentalome" (a brilliant word I'd never heard before) for a given disease or trait i.e. the regions of the genome that turned out not to be associated with it. It should work for anything, though, not just genes.

However the BioNOT system isn't perfect. The authors note that it is rather over-enthusiastic in finding negative sentences.

A quick try on the system bears this out. I searched for 5 HTTLPR, the claimed "happiness gene". This revealed many papers finding no link between the gene and various things. But it also threw up false positives (how ironic), such as:

young rhesus monkeys were split into two groups... those having, or not, the short variant of the 5 -HTTLPR polymorphism

This is just telling us about the methods of a study. It's not a null finding, but it set the BioNOT alarm bells ringing, presumably because it contained the word "not".

So BioNOT is only a first step, but it's an important one.


Agarwal S, Yu H, & Kohane I (2011). BioNOT: A searchable database of biomedical negated sentences. BMC bioinformatics, 12 (1) PMID: 22032181

The Teen Happiness Gene?

Whether you were happy with life as a teenager could be down to a certain gene, says a new study.

In a large study of American adolescents, the AddHealth project, teens who carried the long form of the 5HTTLPR locus were more likely to say they were satisfied or very satisified with their lives (at age 18 to 26). People with two long variants were the most cheerful, with short/long carriers in the middle and short/short being the least so.

The effect was significant controlling for ethnicity (p=0.013), however looking at the data shows that this effect was largely driven by the unhappy teens who reported being "Dissatisfied" or "Neither" on the 5 point scale of life satisfaction - but there were only a small number of these, because the great majority said they were "Satisfied" or "Very Satisfied". Still, there you go.

Incidentally, Neuroskeptic readers may remember AddHealth because of its role in the "black women are ugly" race row from earlier this year.

This study is the latest in a long, long line of attempts to correlate 5HTTLPR with happiness, depression, stress and so on. A few months ago I discussed the history of this busy little gene and covered a meta-analysis of no fewer than 54 papers which claimed that there was indeed a link, with the short allele increasing the risk of depression in response to stressful events.

However many studies failed to find one, and worryingly the three largest studies were all negative which is a classic tell-tale sign of publication bias - maybe people were only bothering to publish smaller studies if they did find a link and hence were "exciting findings". This is quite possible because so many researchers collect DNA as part of psychology studies these days. When the 5HTTLPR story got big (about 5 years ago) I know a lot of people decided to jump on the bandwagon by looking at it in the context of their old data.

Personally I have no idea whether 5HTTLPR is associated with anything. I used to think it probably did, but now I'm just confusion. There have been so many studies and so much inconsistency that it's very hard to know. What worries me is that I'm not sure whether we'll ever get a consensus. We've already had a gigantic study (over 80,000 people) showing no link and many meta-analyses coming to different conclusions.

What will it take to settle the issue? An even bigger study? Would 200,000 people do it? A million? I don't know.

De Neve JE (2011). Functional polymorphism (5-HTTLPR) in the serotonin transporter gene is associated with subjective well-being: evidence from a US nationally representative sample. Journal of human genetics, 56 (6), 456-9 PMID: 21562513

Men, Women and Spatial Intelligence

Do men and women differ in their cognitive capacities? It's been a popular topic of conversation since as far back as we have records of what people were talking about.

While it's now (almost) generally accepted that men and women are at most only very slightly different in average IQ, there are still a couple of lines of evidence in favor of a gender difference.

First, there's the idea that men are more variable in their intelligence, so there are more very smart men, and also more very stupid ones. This averages out so the mean is the same.

Second, there's the theory that men are on average better at some things, notably "spatial" stuff involving the ability to mentally process shapes, patterns and images, while women are better at social, emotional and perhaps verbal tasks. Again, this averages out overall.

According to proponents, these differences explain why men continue to dominate the upper echelons of things like mathematics, physics, and chess. These all tap spatial processing and since men are more variable, there'll be more extremely high achievers - Nobel Prizes, grandmasters. (There are also presumably more men who are rubbish at these things, but we don't notice them.)

The male spatial advantage has been reported in many parts of the world, but is it "innate", something to do with the male brain? A new PNAS study says - probably not, it's to do with culture. But I'm not convinced.

The authors went to India and studied two tribes, the Khasi and the Karbi. Both live right next to other in the hills of Northeastern India and genetically, they're closely related. Culturally though, the Karbi are patrilineal - property and status is passed down from father to son, with women owning no land of their own. The Khasi are matrilineal, with men forbidden to own land. Moreover, Khasi women also get just as much education as the men, while Karbi ones get much less.

The authors took about 1200 people from 8 villages - 4 per culture - and got them to do a jigsaw puzzle. The quicker you do it, the better your spatial ability. Here were the results. I added the gender-stereotypical colours.

In the patrilineal group, women did substantially worse on average (remember that more time means worse). In the matrilineal society, they performed as well as men. Well, a tiny bit worse, but it wasn't significant. Differences in education explained some of the effect, but only a small part of it.

OK.

This was a large study, and the results are statistically very strong. However, there's a curious result that the authors don't discuss in the paper - the matrilineal group just did much better overall. Looking at the men, they were 10 seconds faster in the matrilineal culture. That's nearly as big as the gender difference in the patrilineal group (15 seconds)!

The individual variability was also much higher in the patrilineal society, for both genders.

Now, maybe, this is a real effect. Maybe being in a patrilineal society makes everyone less spatially aware, not just women; that seems a bit of a stretch, though.

There's also the problem that this study essentially only has two datapoints. One society is matrilineal and has low gender difference in visuospatial processing. One is patrilineal and has a high difference. But that's just not enough data to conclude that there's a correlation between the two things, let alone a causal relationship; you would need to study lots of societies to do that.

Personally, I have no idea what drives the difference, but this study is a reminder of how difficult the question is.

Hoffman M, Gneezy U, List JA (2011). Nurture affects gender differences in spatial abilities. Proceedings of the National Academy of Sciences of the United States of America PMID: 21876159

New Mutations - New Eugenics?

True or false: you inherit your genes from your parents.





Mostly true, but not quite. In theory, you do indeed get half of your DNA from your mother and half from your father; but in practice, there's sometimes a third parent as well, random chance. Genes don't always get transmitted as they should: mutations occur.



As a result, it's not true that "genetic" always implies "inherited". A disease, for example, could be entirely genetic, and almost never inherited. Down's syndrome is the textbook example, but it's something of a special case and until recently, it was widely assumed that most disease risk genes were inherited.



Yet recent evidence suggests that many cases of neurological and psychiatric disorders are caused by uninherited, de novo mutation events. Here are two papers from the last few weeks about schizophrenia(1,2) - but the story looks similar for autism, intellectual disabilities, some forms of epilepsy, ADHD, and others. Indeed they're often the same mutations.



Biologically, a given mutation is what it is, whether it's de novo or inherited. But on a social and a psychological level, I think there are crucial differences, and in particular I think that if it turns out that de novo mutations are important in disease, we're going to see attempts to take these variants out of circulation - far more so than in the case of the very same genes, were they inherited.



The old eugenics movement was based on the idea that if we stop people with bad genes from breeding - by sterilization, voluntary or otherwise, say - we'll be able to eliminate diseases and other undesirable traits. This idea is now generally regarded as extremely unethical, but many of its opponents have shared with the eugenicists the belief that it could work.



But if de novo mutations are what cause the majority of disease, then this approach would be pointless. Sterilizing certain people, or encouraging the healthy ones to have more children, would never be able to eliminate the 'bad genes' because new ones are being created every generation, pretty much at random.



So the de novo paradigm ought to be welcomed by opponents of eugenics. It wasn't just morally wrong - it was biologically misguided too.



But hang on. This is the 21st century. We have in vitro fertilization (IVF), and you can analyze the genes of an IVF embryo before you decide to make it into a child. In the near future, we might be able to routinely sequence the genome of any unborn child shortly after conception.



From there, it would be a small step to allowing parents to decide not to have children with de novo mutations.



This would be, in its effects, a form of eugenics - in the sense that it would produce the effect that the old eugenicists wanted. No more 'bad' genes, or not nearly as many. Opinions will differ as to whether it's morally different. But I would have said that politically, it's a lot more likely to happen.



I can't see forced sterilization returning any time soon. But if you were expecting a baby and you knew that it was not just carrying your and your partner's DNA, but had also suffered a mutation - might you not want to avoid that?



Psychologically, it matters that it did not inherit the gene. It would be a big step to decide that your child should not inherit one of your own genes. Of course, some genes are obviously harmful, like one that raises the risk of cancer, but think about the grey areas - a gene for social anxiety, mild autistic symptoms, obesity, a personality trait.



You might well feel that carrying that gene is what makes you, you; and so it would be natural for your child to have it. You might decide that if it was good enough for you (and all your ancestors), it's good enough for your children. You might well resent the very idea that it's a 'bad' gene at all, as an attack on your own self-worth.



But none of that applies if it's a de novo mutation. Indeed, quite the opposite - all those same considerations would probably lead you to want your children to carry as close as possible to a carbon copy of your DNA, with no random changes. It was good enough for you.



My point is that I think there will be much more support for the idea of genetic screening against de novo mutations than against inherited genes. More people will want it, it will be more socially acceptable, and more widely used. I'm not saying this would be a good or a bad thing, just making a prediction. In the future, diseases and traits that are primarily caused by de novo mutations will increasingly selected against.