Evolutionary pharmacogenomics (Is toxin exposure expected?)

Articles about evolution and medicine are spread so widely over the scientific landscape that no matter how much you read, you know you are missing things. The pleasure on finding them is, however, like finding a diamond in the sand. Such is the case with evolutionary pharmacogenomics (a phrase that turns up not one hit on Goggle!). At our seminar yesterday, Mark Thomas put us onto work by Daniel Nebert. A long-time leaders in pharmacogenomics, he has written several papers offering an evolutionary framework for thinking about genes that influence drug metabolism. Suddenly, all kinds of things make sense. Why 57 genes in the Cytochrome P450 super-gene family? Because they are products of co-evolution between plants trying to defend themselves and herbivores looking for a meal. All the genes can be traced back to a common ancestor about 2 billion years ago, but the fast differentiation, espcecially in the CYP2 family, came about 400 million years ago as animals moved onto land to be come a problem for plants.

The implications are profound:

The entire field of pharmacology and drug development represents the discovery and characterization of naturally occurring plant metabolites, followed by synthesis of analogs that are found to do a better job with fewer side effects (2006, p4)

His perspective gets us away from thinking about drug metabolizing enzymes-they evolved to deal with endogenous and exogenous substances long before there were drugs, and they are active not only in liver, but in every cell in the body. He also notes that we should not ony expect to find major differences between species depending on their diet, we should expect to find that these systems are inducable by exposure, as of course, they are.

The discussion inspired a new idea. Our ancestors routinely ate somewhat toxic plants until just the past 5-10,000 years. Agriculture and plant breeding now allow us to eat mild tasting foods. I wonder if the resulting inadequate stimulation of "drug" metabolising enzymes may be responsible for some diseases of civilization. This should certainly be testable in rats. Probably it has already be done. If you know about such studies, please leave a comment below.

Nebert DW, Dieter MZ (2000) The evolution of drug metabolism. Pharmacology 61: 124-135

Nebert DW (2006) Drug metabolism: Evolution. Encyclopedia of Life Sciences: Wiley Press (online). pp. 1-6.

No genes for schizophrenia--What gives?

Ten years ago, most of us paying attention were exhilarated about the prospects for psychiatric genetics. Heritability is high for many disorders--80% of the variation in vulnerability to bipolar disorder and schizophrenia can be attributed to genetic variations. We thought we would soon find the responsible abnormal genes, and this would quickly reveal the biochemical defects that cause these disorders, and this would quickly lead to ways to cure, or at least dramatically alleviate, these terrible scourges.

Candidate genes were examined by the best researchers using larger and larger samples and sophisticated statistics; a few were identified as prime suspects. Most results could not be replicated, but a few loci were very suspicious based on multiple studies.

Now, in an article by in this month's American Journal of Psychiatry, Saunderset al. report on 433 SNPs associated with 14 candidate genes that were prime suspects for schizophrenia in about 1900 cases and 2000 controls of European ancestry. The results? Not one of the genes was significantly associated with schizophrenia prevalence. Even a 25% increase would have been detected with high probability.

An editorial by Steven Hamilton doi: http://dx.doi.org/10.1176/appi.ajp.2008.08020218 tries to put the best possible face on the results by noting that studies of tens of thousands of subjects were required to find genes that contribute to real but small (<25%) increases in risk for Type II diabetes. But that is not the point. Sanders, et al. deserve commendation for stating their conclusion clearly:

Our results suggest that, taken together, common DNA variants in these 14 genes are unlikely to explain a large proportion of the genetic risk for schizophrenia in populations of European ancestry. More robust findings are likely to be discovered using genome-wide association methods and, as our knowledge of the biology of mental illness continues to improve, focused studies of genes based on more precise mechanistic hypotheses. Nevertheless, although larger samples could possibly detect small genetic effects that were missed in this experiment, our findings suggest it is unlikely that true associations exist at the population level for the alleles that have formed the basis for the large candidate gene literature for these 14 postulated schizophrenia candidate genes.

Now what? Should we just do larger and larger studies with fancier and fancier bioinformatics? We have been looking for abnormal genes--mutations that cause diseases. But what if that is not the right model? That presumes that there is a normal genome and if all is in order all works fine, but when a part breaks, disease results.

A clue comes from Craig Ventner's genome. The human genome project provided sequences for haploid genomes. But the chromosomes from both Ventner's father and mother have now been sequenced. The results are a big surprise. Variation between human individuals is five times higher than we thought: 0.5% instead of 0.1%. Much of the difference is in the number of copies of a gene, and their locations. DOI: 10.1126/science.317.5843.1311

Copy number variations look likely to explain a lot. They are invisible to genetic testing that just looks for the presence of certain sequences. But they are important. Especially for mental disorders.

In this week's Science,Walsh, et al. report big differences in CNVs in people with schizophrenia: "Novel deletionsand duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases" DOI: 10.1126/science.1155174 In previous work they have found similar differences in autism.

This may well explain why we have not been able to find the genes for schizophrenia--schizophrenics don't have different genes from other people, just different numbers of certain genes. This also fits with paternal age effects on schizophrenia -- the risk of schizophrenia increases as the father's --but not the mother's--age increases. (Male gamtes keep dividing throughout out life, increasing the risk of errors, while the eggs of females are all formed by birth)

So, myriads of different genetic variations may contribute to schizophrenia, many involving micro insertions and deletions. This tells us where to look.

A big piece of the puzzle remains missing, however. Why can so many different genetic variations all cause schizophrenia? Part of the answer is heterogeneity of the phenotypes--we should talk about the schizophrenias, in the plural. Nonetheless, it is remarkably that the brain fails so often in the same general ways. Why are bipolar disorder and schizophrenia so common compared to any number of other disorders, and the myriads of disorders that could exist but don't? The answer will come, I think, when we quit thinking of the body as a machine designed by engineers in which problems are caused by broken single parts. Bodies are fundamentally different from machines. Genes that make traits that on average tend to Darwinian fitness become more common. They form networks and modules, but in ways that often do not correspond to anything a sensible engineer would do. They create robust networks that are resistant to damage, until, that is, some slight variation wrecks the whole system. This may be why certain cognitive system are so vulnerable.

My best guess is that a cliff-edge effect is involved. Some trait has given such a large advantage that it has been pushed rapidly by selection to a value that is close to a cliff-edge, where the system is prone to fail catastrophically. Levels of uric acid in humans are a good example. Uric acid levels have increased in humans relative to other primates, probably because the antioxidant effects of uric acid are selected for in a a species with a long life span, despite the risk of gout. The strong correlation between uric acid levels and life span in primates is supportive evidence. For schizophrenia, Crespi summarize relevant evidence for signals of positive selection on candidate genes.

There are many other ideas out there. Bernie Crespi's work on the possibility that autism and schizophrenia are flip sides of conditions resulting from imprinted genes that advance maternal and paternal genetic interests is particularly intriguing.

We are getting there. But it is increasingly clear that it is a serious mitake to think of the brain as a machine with parts that break. The brain is, instead, an organ in an evolved soma whose information code is nothing like anything a any human programmer would write. It is not irreducibly complex, but it may well be incomprehensibly complex at the molecular level. Deeper evolutionary thinking about genomics may prove essential to understanding schizophrenia and autism.

Balancing selection--no answer for schizophrenia

Many have asked why genes that cause such a serious disease persist, and a number of evolutionary hypotheses have been inspired by the kind of balancing selection that explains the persistence of genes that cause sickle cell disease. A new article by Adriaens debunks such hypotheses. He offers a nice review of studies about the reproductive success of people with schizophrenia, although I think he discounts excessively the evolutionary significance of a 50% fitness decrease for male schizophrenics.

It seems to me that he is absolutely right, however, to point out data that undermine hypotheses based on covert benefits of schizophrenia genes. He generalizes about evolutionary psychiatrists as if they are not only all in one category, but as if they all think the same things. This is especially surprizing given his emphasis on the mistake of assuming that schizophrenia is a natural category. It is so important to criticize hypotheses, not people or groups.

There is much additional useful in his paper, especially his outline of evolutionary reasons why the genetic factors in schizophrenia will be much more complex than we have imagined. This all fits very nicely with other reports this week about the genetics of schizophrenia I do think, however, that we do need to ask why such a highly heritable devastating disorder persists. Balancing selection is not likely. It could be just that new mutations happen. But I think that the high heritability has kept attention focused on the level of the gene, when the problem may well be in constraints and trade-offs at a higher level. See a previous post for more on this.

Why are humans such lousy dog trainers?

Training Lucy has taught me so much. Mostly it has taught me what a lousy dog trainer I am. I started off confident that my knowledge of psychology and learning theory would make me a superior dog trainer. Besides, humans have been training dogs for thousands of years, and, we have had a few hundred thousand years to learn how to influence each other. So, it shouldn't be hard to train an eager, smart, poodle puppy.

Not so! Over and over again, I discover that my innate dog training inclinations are exactly wrong.

I say, Lucy, Come! She runs away. Annoyed, I call her name in a harsh commanding tone: LUCY! She looks toward me, then runs further away.

I come in the door at home. Lucy jumps up on me eagerly. I say firmly, NO! Down!, all the while looking at her and touching her to try to get her to sit down. Every time I come home, she jumps a bit more wildly.

STAY! I say, giving the hand signal as well. Lucy sits, and looks at me. Wonderful! I give a reward. Immediately, she jumps up and runs ahead. No, Lucy, stay staying, please!

We are at the dog park, and it is time to go home. COME! Lucy, I yell. She immediately runs to the far corner of the dog park. I chase her. She runs faster. Much faster than I can.

Thanks to help from several experienced dog trainers, I have gradually overcome the worst of my natural dog as training habits, but only very gradually and with constant inhibition of my natural impulses. Gradually, I learn that her name must only be used in a positive setting. I discipline myself to completely ignore her jumping behavior. I gradually figured out for myself, that to get her to stay, I need to give her not just one, but a series of treats at random times during the stay. And, at the dog park, I began calling her every few minutes, leash in one hand, treat in the other, until COME! at the dog park no longer signals that she will soon be separated from her happy pack.

If natural selection is so great, why aren't we better dog trainers? It seems that we humans are lousy at using rewards and punishments to influence the behavior of all others, not just dogs, but people as well. In my work as a psychiatrist, I am constantly amazed at spouses who angrily demand love from a partner. Then there are parents who fear a daughter will be promiscuous, so they make wild angry accusations whenever she stays out too late; they are not surprised when she fulfills their expectations. Neither am I, but for different reasons. Then, there are parents who yell at their infants, telling them to stop crying; when the baby does not obey, they get enraged. How can we are so poor at the most basic skill of influencing others?

Another possibility to explain our specific deficit in dog training abilities is that we use strategies that tend to work to influence adult humans. Anger and commands can influence others, especially if they’re dependent or lower and social rank. In the long run it creates enemies looking for opportunities for revenge, but in the short run it works. Words work to influence humans. For dogs, hand signals are far better, words are far less influential and the tone is as important as the phonemes.

Why don’t we all have better innate dog (and person) training skills? This is worth more thought.