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Monday, November 7, 2011

What is a gene "for"?


“Scientists discover gene for autism” (or ovarian cancer, or depression, cocaine addiction, obesity, happiness, height, schizophrenia… and whatever you’re having yourself). These are typical newspaper headlines (all from the last year) and all use the popular shorthand of “a gene for” something. In my view, this phrase is both lazy and deeply misleading and has caused widespread confusion about what genes are and do and about their influences on human traits and disease.

The problem with this phrase stems from the ambiguity in what we mean by a “gene” and what we mean by “for”. These can mean different things at different levels and unfortunately these meanings are easily conflated. First, a gene can be defined in several different ways. From a molecular perspective, it is a segment of DNA that codes for a protein, along with the instructions for when and where and in what amounts this protein should be made. (Some genes encode RNA molecules, rather than proteins, but the general point is the same). The function of the gene on a cellular level is thus to store the information that allows this protein to be made and its production to be regulated. So, you have a gene for haemoglobin and a gene for insulin and a gene for rhodopsin, etc., etc. (around 25,000 such genes in the human genome). The question of what the gene is for then becomes a biochemical question – what does the encoded protein do?

But that is not the only way or probably even the main way that people think about what genes do – it is certainly not how geneticists think about it. The function of a gene is commonly defined (indeed often discovered) by looking at what happens when it is mutated – when the sequence of DNA bases that make up the gene is altered in some way which affects the production or activity of the encoded protein. The visible manifestation of the effect of such a mutation (the phenotype) is usually defined at the organismal level – altered anatomy or physiology or behaviour, or often the presence of disease. From this perspective, the gene is defined as a separable unit of heredity – something that can be passed on from generation to generation that affects a particular trait. This is much closer to the popular concept of a gene, such as a gene for blue eyes or a gene for breast cancer. What this really means is a mutation for blue eyes or a mutation for breast cancer.

The challenge is in relating the function of a gene at a cellular level to the effects of variation in that gene, which are most commonly observed at the organismal level. The function at a cellular level can be defined pretty directly (make protein X) but the effect at the organismal level is much more indirect and context-dependent, involving interaction with many other genes that also contribute to the phenotype in question, often in highly complex and dynamic systems.

If you are talking about a simple trait like blue eyes, then the function of the gene at a molecular level can actually be related to the mutant phenotype fairly easily – the gene encodes an enzyme that makes a brown pigment. When that enzyme is not made or does not work properly, the pigment is not made and the eyes are blue. Easy-peasy.

But what if the phenotype is in some complex physiological trait, or even worse, a psychological or behavioural trait? These traits are often defined at a very superficial level, far removed from the possible molecular origins of individual differences. The neural systems underlying such traits may be incredibly complex – they may break down due to very indirect consequences of mutations in any of a large number of genes.

For example, mutations in the genes encoding two related proteins, neuroligin-3 and neuroligin-4 have been found in patients with autism and there is good evidence that these mutations are responsible for the condition in those patients. Does this make them “genes for autism”? That phrase really makes no sense – the function of these genes is certainly not to cause autism, nor is it to prevent autism. The real link between these genes and autism is extremely indirect. The neuroligin proteins are involved in the formation of synaptic connections between neurons in the developing brain. If they are mutated, then the connections that form between specific types of neurons are altered. This changes the function of local circuits in the brain, affecting their information-processing parameters and changing how different regions of the brain communicate. Ultimately, this impacts on neural systems controlling things like social behaviour, communication and behavioural flexibility, leading to the symptoms that define autism at the behavioural level.

So, mutations in these genes can cause autism, but these are not genes for autism. They are not even usefully or accurately thought of as genes for social behaviour or for cognitive flexibility – they are required, along with the products of thousands of other genes, for those faculties to develop.

But perhaps there are other genetic variants in the population that affect the various traits underlying these faculties – not in such a severe way as to result in a clinical disorder, but enough to cause the observed variation across the general population. It is certainly true that traits like extraversion are moderately heritable – i.e., a fair proportion of the differences between people in this trait are attributable to genetic differences. When someone asks “are there genes for extraversion?”, the answer is yes if they mean “are differences in extraversion partly due to genetic differences?”. If they mean the function of some genetic variant is to make people more or less extroverted, then they have suddenly (often unknowingly) gone from talking about the activity of a gene or the effect of mutation of that gene to considering the utility of a specific variant.

This suggests a deeper meaning – not just that the gene has a function, but that it has a purpose – in biological terms, this means that a particular version of the gene was selected for on the basis of its effect on some trait. This can be applied to the specific sequence of a gene in humans (as distinct from other animals) or to variants within humans (which may be specific to sub-populations or polymorphic within populations).

While geneticists may know what they mean by the shorthand of “genes for” various traits, it is too easily taken in different, unintended ways. In particular, if there are genes “for” something, then many people infer that the something in question is also “for” something. For example, if there are “genes for homosexuality”, the inference is that homosexuality must somehow have been selected for, either currently or under some ancestral conditions. Even sophisticated thinkers like Richard Dawkins fall foul of this confusion – the apparent need to explain why a condition like homosexual orientation persists. Similar arguments are often advanced for depression or schizophrenia or autism – that maybe in ancestral environments, these conditions conferred some kind of selective advantage. That is one supposed explanation for why “genes for schizophrenia or autism” persist in the population.

Natural selection is a powerful force but that does not mean every genetic variation we see in humans was selected for, nor does it mean every condition affecting human psychology confers some selective advantage. In fact, mutations like those in the neuroligin genes are rapidly selected against in the population, due to the much lower average number of offspring of people carrying them. The problem is that new ones keep arising – in those genes and in thousands of other required to build the brain. By analogy, it is not beneficial for my car to break down – this fact does not require some teleological explanation. Breaking down occasionally in various ways is not a design feature – it is just that highly complex systems bring an associated higher risk due to possible failure of so many components.

So, just because the conditions persist at some level does not mean that the individual variants causing them do. Most of the mutations causing disease are probably very recent and will be rapidly selected against – they are not “for” anything.


Jamain S, Quach H, Betancur C, RĂ¥stam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T, & Paris Autism Research International Sibpair Study (2003). Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature genetics, 34 (1), 27-9 PMID: 12669065

18 comments:

  1. What a coincidence, I had just finished reading an article written by Stephen Jay Gould in 1999 on the same topic, when I stumbled upon a reference to your blog post on twitter. Luckily, the article is available freely on google books: search for "the without and within of the smart mice" in 'I have landed' by Gould.

    So, you are right saying that we should not say "a gene for". Unfortunately, it seems that people haven't learned much since 1999 :-)

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  2. Yes, I'd say Gould was spot on there. Dawkins tends to defend the construct, but it seems too easily misconstrued to me.

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  3. In the case of natural selection arguments for autism and depression etc., would you not leave the door open for natural selection arguments for a milder version of these disorders? (i.e., some aspergers' traits that are helpful for engineering and computer programming; low self-esteem that could help in, say, group cohesiveness)

    The myostatin gene for whippets illustrates this point exactly. One mutated copy of the MTSN gene and one normal copy produced faster whippets. However, two copies of the mutated gene produced 'bully' whippets with gross excess muscle. The former could be helpful, the latter not.

    http://www.sciencedaily.com/releases/2007/05/070504151942.htm

    Could disorders be a case of a harmful variation on an evolutionarily helpful trait?

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  4. Darian, you raise a good point. It is conceivable that the situation you propose could hold. The important point, though, is that any "benefit" would have to be at the level that natural selection cares about, not just what we think of as an advantage in human culture. It comes down to number of offspring. If the kind of scenario you envisaged pertained then you would expect the "unaffected" relatives of people with autism or schizophrenia to have more children on average - to offset the selective penalty when the variants actually cause disease. There is no evidence that they do (in fact there is evidence that they do not).

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  5. But can you repair poor wiring? A brain wiring problem is what the creator of Brain Balance has theorized to be at the root of all neuro-behavioral disorders for years, and it's what he based the Brain Balance program on! The program uses sensory, cognitive, and motor exercises to repair the wiring issues in brain communication and improve rhythm and timing. You can read more about it at www.brainbalancecenters.com .

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  6. It wasn't so long ago, 2009 in fact, that media all over the world were in a frenzy over a new research study that found that some of the genes associated with autism are also very common genes, leading to the obvious conclusion that these genes in particular must be good for something:

    http://www.newscientist.com/article/dn17041-gene-variant-found-in-65-of-autism-cases.html

    "The variant is carried by around 60 per cent of people without autism."

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  7. I wouldn't be citing the work of Stephen Jay Gould to support an argument, not since the recent re-examination of Gould's interpretation of Morton's work on skulls was published in PLoS Biology:
    http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001071

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  8. Lili, just because Gould was not always right does not mean he never made a good point! As for the autism studies, the media frenzy over the initial associations with a couple common variants was premature - these variants do not replicate across studies and, even if they did, the association might be caused because they tag rare mutations. We now know over a hundred different genes where mutations (rare ones) can cause autism - these are very quickly selected against. The most probable explanation for why autism persists at a high rate is that new mutations arise quite frequently and that so many genes are required to build a human brain.

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  9. "...the association might be caused because they tag rare mutations."

    Could you please explain how these common genes associated with autism "tag rare mutations"?

    And I'd also like to know the details of the studies that you refer to in which thse findings were not replicated.

    "The most probable explanation for why autism persists at a high rate is that new mutations arise quite frequently and that so many genes are required to build a human brain."

    I've read that the human species is characterised by a high rate of mutations in genes that code for brain function. Think about this for a few moments and it doesn't seem like a mistake of nature. Given the clear association between the autistic spectrum and high intellectual achievement and possibly specific intellectual strengths I think your speculation that all autism genes are destined to be selected against swiftly is questionable.

    Regarding the late Stephen Jay Gould, his credibility is shot as far as I'm concerned. Anyone can make a mistake, but that level of bias... I'd love to know what Richard Dawkins thinks about that PLoS Biology paper.

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  10. Hi Lili,

    The common variant studies did not replicate each other's results. The sample sizes might still be too low to give enough statistical power to expect that, or they original observations might have been false positives - it is probably still too early to say.

    A common variant can look like it is associated with a disease in a population either because it really affects the likelihood of developing the disease itself, because it is near some other common variant that affects disease or because there are rare mutations in the population that are linked to the common variant. The original association you get from genome-wide association studies does not distinguish these possibilities.

    Regarding the human mutation rate, there is some evidence that in the evolution of humans, genes involved in neural development underwent more positive selection than the average. The idea is that some changes in those genes were selected for and may be involved in specifying our human brain. This does not mean that there is a higher mutation rate in those genes however. nor does it mean that ongoing variation in those genes is selected for. (Once we got the variants that helped give us a big brain, they would rapidly have become fixed in the human population, in fact - i.e., not variable any more).

    When I say that mutations that result in autism will be rapidly selected against, this is based on the observed very large decrease in average numbers of offspring associated with the condition.

    P.S. If you send me an email I will forward you some relevant articles.

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  11. I think the relevant thing that you need to consider is the numbers and probable success of the total number of offspring that carry the gene, not just considering the numbers of offspring from those diagnosed as having an associated behavioural condition, when speculating about whether a gene is likely to be selected against.

    The few offspring of conscientious wealthy parents might be more likely to keep the family name going than a larger set of offspring of impoverished and bad parents, in theory at least.

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  12. Lili, you are right again. However, people have looked at the numbers of offspring of siblings or other relatives of patients with psychiatric disorders (who might be expected to carry the same single mutation or a subset of the same set of mutations) and found no increase that would counterbalance the decrease in offspring of the patients.

    On this topic, a new paper show direct evidence of very strong negative selection on schizophrenia-causing mutations:

    http://www.ncbi.nlm.nih.gov/pubmed/21855053

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  13. But weren't we specifically discussing autism?

    I'm not the least surprised that schizophrenia might be nothing more than a non-adaptive breakdown of a system. I know that plenty of researchers believe that there is a link between SZ and creativity, but I do wonder about the populations of SZ patients who have been used for such research, considering how lax and over-inclusive schizophrenia diagnosis has been in the not-so distant past.

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  14. I am new to the whole "GENE" thing. I am pretty much uneducated and have 3 boys with autism. I am now forcing myself to sit down and research about autism. I feel perplexed when I read that the sun (UV rays) can cause genetic mutations. That is a real wide spread of the knife and pen for that matter. It appears to take skin cancer and throws it in the bushel with autism at the same time. Unless I am wrong here and the sun does cause autism.
    Why is it that no one in the federal level will come out and state that the environment is killing us? It appears to me; being ignorant folk as I am...that the environmental issues is truly what is killing us. I am no tree hugger but maybe I should have been one. What else could cause autism to rise so rampantly? In the 1970's the autism ratio was 1 in 10,000. Last week the CDC released new data....1 in 88! 1 in 88??? Excuse me but what the hell is going on here? Did neanderthals have autism? Wait, maybe this is what killed the dinosaurs! Sarcasm...mmmm, yes I am a little pissed and frustrated that scientists are in the governments pockets. Yes, I understand that we cannot and should not jump to conclusions but for goodness sakes the sun? Why don't we just say that it was the one armed man on that grassy knoll or better yet, how about the freaking Easter Bunny? Ok, I have acted and typed like a maniac and I feel a smudge better. Wait, my kids still have autism and the sun is at fault. Maybe we can send a spaceship and Armageddon it! Where is Bruce Willis when I need him...

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    1. struck down..., I can understand your frustration. It is true that UV rays can cause mutations, but only in skin cells - these can lead to skin cancer, but they are not passed on the next generation. The type of mutations that are believed to cause conditions like autism happen in the "germ cells" in the testicles or ovaries - the cells that generate sperm or eggs. These can arise due to errors in copying the DNA when cells are dividing - the entire genome (the total content of DNA in all your chromosomes) is about 3 billion letters long - each time it is copied, some small number of those is not copied correctly. Sometimes, such mutations affect genes that control processes like the development of the brain. It is thought that some cases of autism are caused by new mutations that happened when the sperm or egg was being generated. Others are caused by an older mutation - one that happened several generations ago and has been passed on in the family.

      For what it's worth, I think the increase in rates of autism diagnoses is largely caused by increasing recognition of the disorder by parents and doctors. There are data to show that a substantial proportion of the increase can definitely be ascribed to that cause - the rest may or may not be. At present, we have no good reason to label it an "epidemic" or to think there is some new environmental factor causing it.

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    2. I certainly hope you do not think this is the only cause.

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  15. Hi Kevin,

    First of all, I would like to say I like your blog ! -- it certainly seems to bring cold-dry issues in science to the life. You expose and explore fundamental assumptions made in genetics and neuroscience. In line with this, I am wondering whether or not you have thought about the information construct used in molecular biology. Scientists (including yourself), describe genes as storing or conveying "information" and use terms such as reading, transcribing, translating, signalling which all feed into this mode of thinking. However, amidst all of this, information is never defined and (from my knowledge) never used in unique way to elucidate new paths for research. One could say that sure, genes are information -- when something goes wrong, it's because the information is erroneous (i.e. a mutation). Hence, let's go in and "correct" this "information" (i.e., gene therapy). However, this in itself is not a unique use of the informational construct. One could just as easily explained this research and approach in biochemical ways.

    I am wondering what your opinion is on this mode of thinking. Do molecular biologists actually believe that information is some sort of commodity represented by and transferred through genes?

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