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Yesterday I tweeted out Obesity Rate for Young Children Plummets 43% in a Decade. This is a big deal, and many people retweeted it. Here’s the summary in The New York Times:

But the figures on Tuesday showed a sharp fall in obesity rates among all 2- to 5-year-olds, offering the first clear evidence that America’s youngest children have turned a corner in the obesity epidemic. About 8 percent of 2- to 5-year-olds were obese in 2012, down from 14 percent in 2004.

They helpfully link to the paper in The Journal of the American Medical Association, Prevalence of Childhood and Adult Obesity in the United States, 2011-2012. And actually, if you read the paper the authors themselves seem very unsure about the robustness of this specific result. I quote from the paper:

…Tests for differences by age in children were evaluated with the following comparisons: aged 2 to 5 vs 6 to 11 years, 2 to 5 vs 12 to 19 years, and 6 to 11 vs 12 to 19 years. Similarly, in adults comparisons were made between aged 20 to 39 and 40 to 59 years, 20 to 39 and 60 years or older, and 40 to 59 and 60 years or older. P values for test results are shown in the text but not the tables. Adjustments were not made for multiple comparisons.

…Similarly, there was no significant change in obesity prevalence among adults between 2003-2004 and 2011-2012. In subgroup analyses, the prevalence of obesity among children aged 2 to 5 years decreased from 14% in 2003-2004 to just over 8% in 2011-2012, and the prevalence increased in women aged 60 years and older, from 31.5% to more than 38%. Because these age subgroup analyses and tests for significance did not adjust for multiple comparisons, these results should be interpreted with caution.

In the current analysis, trend tests were conducted on different age groups. When multiple statistical tests are undertaken, by chance some tests will be statistically significant (eg, 5% of the time using α of .05). In some cases, adjustments are made to account for these multiple comparisons, and a P value lower than .05 is used to determine statistical significance. In the current analysis, adjustments were not made for multiple comparisons, but the P value is presented.

The p-value here is 0.03 for the difference in question. That passes the conventional threshold of significance (0.05), but it is close enough to the border that I’m quite suspicious. Here is the full conclusion of the paper:

Overall, there have been no significant changes in obesity prevalence in youth or adults between 2003-2004 and 2011-2012. Obesity prevalence remains high and thus it is important to continue surveillance.

Granted, these may turn out to be real true results. And the age class that showed a decline in obesity is definitely one we should focus on. But public health is a serious matter, and therefore we shouldn’t get ahead of ourselves.

One hypothesis that presents itself in regards to this paper is that a reviewer asked explicitly about the multiple comparisons problem. The authors acknowledged the problem, without actually checking to see if the results hold after a correction, and then the editor let the paper through. Of course this is just a model. I haven’t tested it, so can’t even offer up a p-value, even if I was a frequentist.

Note: The raw data is here.

• Category: Science • Tags: Health, Medicine, Obesity 
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If you have not read Julia Ioffe’s story about getting whooping cough at the age of 31 (also see follow up), you might want to. Here’s some further context, Vaccine Refusals Fueled California’s Whooping Cough Epidemic. This topic has been covered and dissected in great detail by many writers and scientists, so I won’t repeat what you already know in regards to herd immunity. There’s no point in preaching to the choir.

Rather, I want to offer a personal perspective. Over the past few years I’ve become much more aware of cultural streams in public health, and the public’s reaction to that health advice, because I have become a father. More specifically, when my wife was pregnant with my daughter, and after she was born, we encountered major pressure from peer networks to not vaccinate. In the social circles in which we were embedded, “progressive,” “crunchy,” and “alternative,” vaccinating one’s child was the heterodox decision. It was rather obvious to us that one of the major reasons that many people do not vaccinate their children is that many of their friends, and vocal people whom they trust, do not vaccinate their children. We were able to resist and rebuff any peer pressure rather easily because we have a much stronger scientific background than most Americans, but it isn’t hard to imagine being ignorant and trusting those in whom you normally put your trust.

In some ways I am not totally unsympathetic to the skepticism that some in the public have toward the medical establishment. Modern scientific medicine is a genuine miracle, but most of its gains arguably occurred in the first half of the 20th century through public health campaigns, vaccination and antiobiotics. Though the decline in heart disease is a major result which we should celebrate, it is arguably less significant than the sharp reduction in deaths of the young due to numerous infections (heart disease tends to effect the old). Additionally, diseases such as cancer are subject to the problem of what Jim Manzi terms “high causal density”. Cancers, like many diseases of late life, can have many triggers and factors impacting their likelihood, so solving the problem at the root may not be so simple. In reaction to this complexity and uncertainty I do believe that on occasion the medical profession and the public health establishment have unduly emphasized their certainty.

Like the reality that the variegated public health concerns we have today, such as type 2 diabetes and cancer, are probably better problems than endemic smallpox, tuberculosis, or scarlet fever, the downsides of having a medical establishment which on occasion oversteps the bounds of its reasonable confidence are overridden by the upsides. We have empirical evidence of this, because there are nations without medical establishments, and they are not flourishing. But that does not change the reality that a population shielded from the brutal knife of infectious disease and plague is somewhat befuddled by the mysteries of the slow and subtle ailments which are the afflictions of modernity.

One response is the liberal individualist one. Though we may bemoan Steve Jobs’ experimentation with alternative therapies for his cancer, it was his individual choice. It gets more complicated what you have children, who are under the control of their parents. Again, I’m not going to go over the controversies over groups like Christian Scientists, whose children have died due to withholding medical treatment. The cultural consensus seems to be that parents have a right to impose all sorts of crazy beliefs and practices upon their children, but not those which may result in death. Then you move to the issue that when it comes to vaccination one can’t seal off individual choice from consequences to the public. It seems entirely likely that for the next decade we may be seeing a conflagration of preventable diseases among certain segments of the American demographic, and those who they live among, because of cultural fashion. The collective choices of parents opting out from vaccination is subject to negative feedback dynamics. Early dissenters can “free-ride” on herd immunity, and indulge their quackery, but beyond a particular threshold disease and death will come back to the fore. But human beliefs are often rather well insulated against falsification for a great deal of time. The AIDS denialst community is a testament to this phenomenon; it persists despite mysteriously (to them) high mortality rates among its most vocal proponents.

So is there a solution? Conscience is a value which Americans pride, even unto death. I do not see the powers that be intervening in these cases. Rather, this groundswell of denialism must be countered by public opprobrium, and yes, shaming. Peer pressure kills, but it can also save lives. As a matter of safety people with small children should investigate rates of vaccination in their community (young infants are not vaccinated, and so are particularly vulnerable to infections which are dampened by herd immunity). They should move when a dangerous critical mass is present. If people ask, those who leave should explain their rationale. Actions can speak louder than words. Where Authorité falls on deaf ears, the judgment of the populace might be heeded.

• Category: Science • Tags: Medicine, Public Health, Vaccination 
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A quick personal story. I have a treatable autosomal dominant condition. For the non-geneticists, that means any of my children have a 50% chance of exhibiting the trait. Even aggressive treatment is not usually initiated until one is in elementary school. But we want to know now, just so we can know (we plan to have more children soon, so we want to anticipate medical expenses or lack thereof, and well, just to know). When my wife went to the doctor today for a routine checkup for my daughter she asked for a blood test to confirm that my daughter exhibited, or did not, exhibit the symptoms (this is not a common SNP for what it’s worth).

Though the doctor was skeptical of the effectiveness of the test at this age, she also (according to my wife) decided to give my wife a lecture on the appropriateness of testing. Here’s what my wife emailed me:

“she then spent a lot of time educating me about how you (read SHE) wouldn’t ever want to know the status on something like that that you knew was a distinct genetic possibility up until right at the moment when you were going to take a therapeutic or preventative step if the status was positive.”

God knows how the doctor would treat someone who was from a less socially advantaged group, or who was not college educated (and wasn’t married to someone who knows a bit about medical genetics).

Addendum: To be clear, there was going to be a blood draw for another reason, and so she just wanted this extra test added to the panel. It’s a pretty standard test for adults, so I know it’s doable.

• Category: Science • Tags: Medicine 
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Here’s a caption from a Time article, What Your Doctor Isn’t Telling You About Your DNA:

Nice to know that two physicians in Philadelphia not only have medical degrees, but specialize in mind-reading the parents of this nation! Above the caption is a photo of the two concerned and worried looking professionals in question. Let me quote the first two paragraphs of the article:

The test results were crystal clear, and still the doctors didn’t know what to do. A sick baby whose genome was analyzed at the Children’s Hospital of Philadelphia turned out to possess a genetic mutation that indicated dementia would likely take root around age 40. But that lab result was completely unrelated to the reason the baby’s DNA was being tested, leaving the doctors to debate: Should they share the bad news?

When it comes to scanning DNA or sequencing the genome — reading the entire genetic code — what to do with unanticipated results is one of the thorniest issues confronting the medical community. Many conflicted discussions followed the dementia discovery at the Children’s Hospital of Philadelphia (CHOP) before a decision was reached: the parents would not be told that this fatal memory-sapping disease likely lurks in their child’s future. Given the hopelessness of the situation, with no treatment and no cure, the doctors said forwarding such information along felt pointless. We came around to the realization that we could not divulge that information,” says Nancy Spinner, who directs the hospital laboratory that tested the infant. “One of the basic principles of medicine is to do no harm.”

The fourth in a five-part series exploring the promise and pitfalls of sequencing children’s genomes

Around the same time, Spinner’s lab also tested another child — an unusually short 2-year-old referred for kidney disease — and discovered the toddler had a gene linked to a rare form of colon cancer. In some cases, polyps arising from this kind of cancer have been known to develop as early as age 7. This time, the decision to inform the parents was easier: We feel good about that one,” says Spinner. “Proper screening can make a huge difference.”


Please. The high priests of medicine know better than you what you would like to know about your children! Think about this logically, and apply this rationale to non-genetic disease. Would doctors conclude that perhaps parents shouldn’t know that their child has a terminal disease which would cut short their life until the illness is closer to manifesting visibly, to save them worry? Perhaps doctors already do this? I have no idea now. My trust has just gone down with the statements above.

John Haws has post up titled Lying to patients about genetic tests is wrong. I agree with the sentiment. I understand that physicians are in a no-win situation. There are parents like me who want as much information as possible, and others who wish to not know information which might imply an unpleasant destiny for their beloved offspring. I say might because how exactly do the doctors above know that in 40 years this situation would be hopeless? Would medicine make no progress? More prosaically, if someone’s realistic lifespan is 40 years, they might wish to make appropriate preparations to live life to the fullest. Individuals with cystic fibrosis have had to make these calculations for decades, once medicine was such that it allowed them to attain adulthood, but middle age only rarely.

All this sort of story does is make me be convinced that what we need widespread personalized genomics so that we can analyze our own sequences with open source applications, and cut the physicians and institutional testing laboratories out of the equation. I also believe that this sort of fiat paternalism on the part of the medical community is frankly going to make enemies of exactly the sort of engaged high-information patients who can be their allies in staving off public hysteria about vaccination and the like. On the whole physicians do know better about illness than their patients. But they should leave the fine-grained ethics to others, because in that domain they’re capable of quite gross malpractice from where I stand. Be honest and do your best are coarse dumb rules which will serve us well in the future.

• Category: Science • Tags: Genetics, Genomics, Medicine 
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Well, almost no one:

“The unspoken central reason for the societal taboo and the penal ban on incest is the possibility of hereditary defects — a factor that Strasbourg only hinted at. But the intention behind the eugenic argument is one that is indefensible, and not just in Germany with its terrible Nazi past: The increased risk of hereditary defects does not justify a legal ban. Otherwise you would have to legally ban other risk groups, like women over 40 or people with genetic diseases, from having children. Does anyone truly want to prevent predictable disabilities using penal measures and thus deny disabled children the right to life in 2012? That’s absurd. And yet such fears of genetic damage are precisely what shape the punishibility of sexual intercourse between siblings.”

There are a set of arguments against near relation incest which strike me as generally ad hoc. And there’s social science to back that up. Incest is reflexively disgusting to most people (depending on how it is categorized). But disgust alone is not a sufficient grounds for banning a practice in educated circles today, so people create rationales after the fact. David Hume would not be surprised.

Of course on purely genetic grounds there are serious reasons to ban procreation between first degree relatives. For example, of the four children of this particular incestuous couple, two are routinely described as “disabled.” Several of Elisabeth Fritzl’s children have congenital defects. The genetic reason for this is pretty obvious: first degree relatives have a very high likelihood of sharing the same deleterious alleles which express only in a recessive manner. All humans carry a particular mutational load. But near relations tend to carry correlated mutations. So offspring between near relations naturally express these mutations in deleterious or lethal form far more often than any two random pair of individuals would.

But let’s think about this logically. What about a couple where both carry a Tay Sachs allele. The couple is pro-life, and do not wish to make recourse to pre-implantation genetic diagnosis (embryo screening). Genetic counselors tell them there is a one out of four chance that their child will manifest Tay Sachs. They decide to have children anyhow. This case is arguably riskier than the pairing of first degree relatives. Though there is a three out of four chance of a perfectly healthy individual, there is a one out of four chance that the child will die very young, and painfully. Should we ban the marriage of people who carry these genes, exhibit these attitudes, and express the goals of having children?

It is famously well known that the Orthodox Jewish community encourages genetic screening to prevent the tragedy of Tay Sachs children. I would not shed a tear if no Tay Sachs children were born into this world. I am also willing to go on the record that society should intervene to a reasonable extent to make it so that no children with Tay Sachs are born (e.g., genetic screening, subsidized pre-implantation genetic screening for candidate parents). In our age there is a very strong attachment to the idea that parents, and more precisely individuals, have a right to their own reproductive choices. The question always ends: where do we draw the line if we curtail these freedoms? We won’t know where we draw the line until we start actually having the discussion, and move these concerns out of the inchoate shadows. As a society we don’t agree when human life begins. But we agree that an infant is a human. I believe we should begin to consider the potential suffering that these infants may reap from the choices of their parents, and the liberty which we as a society grant them.

• Category: Science • Tags: Genetics, Human Genetics, Medicine 
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A friend pointed me to the following infographic on the concentration of doctors per county. The orange represents “very high need,” and dark blue “very low need.”

Now let’s compare it to life expectancy by county:

• Category: Science • Tags: Medicine 
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I just attended a presentation where a researcher outlined how epigenomics could help patients with various grave illnesses. Normally I don’t focus on human medical genetics too much because it always depresses me. I don’t understand how medical geneticists don’t start wondering what hidden disease everyone around them has. In any case the researcher outlined how epigenomic information allowed for better treatment, so as to extend the lives of patients. All well and good. But then one individual in the audience began asking pointed questions as to the medical ethics of the enterprise, and whether the researcher had cleared some legally sanctioned hurdles. More specifically, there was a question whether exploring someone’s epigenomic profile might expose private information of their relatives! (because relatives share epigenomic and genomic profiles to some extent)

Frankly I began to get enraged at this point. People are suffering from terminal illnesses, and considerations of the genetic privacy of their near relatives are looming large? Seriously? The reality is that manifestation of a disease itself gives one information about the risks of their relatives. In any case, the researcher admitted that further progress in this area is probably going to be due to the investments of wealthy individuals (e.g., people like Steve Jobs who have illnesses) as well as outside of the United States. You’re #1 America!

• Category: Science • Tags: Health, Human Genetics, Human Genomics, Medicine 
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As I observed before, modern medicine is subject to some of the same statistical issues as social science in its tendency to put unwarranted spotlight on preferred false positive results. Trials and Errors – Why Science Is Failing Us:

This doesn’t mean that nothing can be known or that every causal story is equally problematic. Some explanations clearly work better than others, which is why, thanks largely to improvements in public health, the average lifespan in the developed world continues to increase. (According to the Centers for Disease Control and Prevention, things like clean water and improved sanitation—and not necessarily advances in medical technology—accounted for at least 25 of the more than 30 years added to the lifespan of Americans during the 20th century.) Although our reliance on statistical correlations has strict constraints—which limit modern research—those correlations have still managed to identify many essential risk factors, such as smoking and bad diets.

I need to look at the difference between mortality and morbidity here. The two are clearly related, but if modern medicine has decreased morbidity, then it is still worthwhile to a greater extent than simple life expectancy calculations might indicate. But the reality is that the more and more I look at modern medicine the more worried I get that the age old heuristics and biases which allowed medicine to flourish as a form of counterproductive psychotherapy up until the early 20th century are now coming back to the fore. The issue here is less the profession of medicine, as the incentives and impulses which drive the need for a “cure” from the demand side.

All this brings to mind a passage from the book Religion Explained:

E. E. Evans-Pritchard is famous for his classic account of the religious notions and beliefs of the Zande people of Sudan…one day the roof of a mud house collapses in the village…People promptly explain the incident in terms of witchardcraft…Evans-Pritchard points out to this interlocutors that termintes had undermined the mud house and there was nothing particularly mysterious in its collapse. But people are not interested in this aspect of the situation. As they point out…they know perfectly that termites gnaw at the pillars of mud houses and that decrepit structures are bound to cave in at some point. What they want to find out is why the roof collapsed at the precise time when so-and-so was sitting undernearth it rather than before or after that. This is where witchcraft provides a good explanation.

With all due respect to modern scientifically trained physicians, but the demands that their patients are now making upon them in terms of curing diseases whose causal roots are less than clear are transforming them into latter-day shamans. As it was, it will be?

• Category: Science • Tags: Correlation, Culture, Medicine 
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In my post below on selection for the “better” zygote Michelle observes that “This would be relatively easy for the father, not so much for the mother.” I took her to mean either of two things,

1) Extraction of eggs is a major surgical affair. Extraction of sperm is not.

2) Males generally have many more sperm to contribute than females.

The latter issue made me go look for data on human females, by age. The paper A systematic review of tests predicting ovarian reserve and IVF outcome had what I was looking for. First, let’s review the cumulative distribution of fertility curves for women:

The way I read the figure 50% of women are sterile at 41. 50% begin their fertility drop at 31. Note that a small, but significant, minority of women are already sterile by age 35. People talk about fertility curves, but less weight is given to the fact that the curve varies in terms of its chronology!

Second, let’s look at the number and quality of ovarian follicles over time (they correspond to number of incipient eggs):

This figure is not easy to read. But you can see that at age 20 there are ~100,000 follicles. That number seems to drop by a little less than half by 30, and is at 20,000 by 40. But by this point 25 percent are of “poor quality.”

• Category: Science • Tags: Fertility, Medicine 
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It’s a fun fact that there are an order of magnitude more bacterial cells in your body than your own cells. Not only that, it’s well known that we wouldn’t flourish, let alone survive, without our gut “flora,” which digest material which would otherwise pass through out system. Not only are microbes good for us, but they’re also bad for us. The evolutionary flexibility of microbial pathogens is one of the major arguments for why sex exists among multiceullar species: it allows them to adapt to rapidly fluctuating disease pressures. Therefore, obviously the ecology of multicellular organisms’ microbial flora is essential to properly characterize. One element of the project involves genomics. This is not so easy for microbes because we don’t have the reference sequences of most of these organisms. We rely mostly on species which are easy to culture, and that does not include most lineages in the wild. That being said, there are workarounds, such as looking at the 16S rNA sequence, which is strongly constrained in bacterial lineages (i.e., it can serve as a “clock” to measure divergence of very deeply separated lineages).

With that, a new paper, Promiscuity in mice is associated with increased vaginal bacterial diversity:

Differences in the number of sexual partners (i.e., mating system) have the potential to exert a strong influence on the bacterial communities present in reproductive structures like the vagina. Because this structure serves as a conduit for gametes, bacteria present there may have a pronounced, direct effect on host reproductive success. As a first step towards the identification of the relationship between sexual behavior and potentially pathogenic bacterial communities inhabiting vital reproductive structures, as well as their potential effects on fitness, I sought to quantify differences in bacterial diversity in a promiscuous and monogamous mammal species . To accomplish this, I used two sympatric species of Peromyscus rodents—Peromyscus californicus and Peromyscus maniculatus that differ with regard to the number of sexual partners per individual to test the hypothesis that bacterial diversity should be greater in the promiscuous P. maniculatus relative to the monogamous P. californicus. As predicted, phylogenetically controlled and operational taxonomic unit-based indices of bacterial diversity indicated that diversity is greater in the promiscuous species. These results provide important new insights into the effects of mating system on bacterial diversity in free-living vertebrates, and may suggest a potential cost of promiscuity.

These two species are sympatric and exhibit very different behaviors. Sympatric means that they aren’t geographically separated, so they are subject to the same environmental conditions. Rather, their distinctions on the species level seem to be due to behavior, in this case, the number of sexual partners of females. This then is a nice test for assessing the relationship of microbial diversity in the vagina as a function of partners. I suspect a priori you’d expect a positive relationship. And that’s what the author found. He presented a diversity index, but the results are rather intelligible visually. You can see clearly that the promiscuous species is characterized by a greater range of species richness than the monogamous one.

There are some studies of metagenomics of bacterial communities in humans. But to my knowledge it doesn’t look like there are any which have attempted to correlate number of sexual partners to diversity of vaginal flora. This is possible very important as a long term issue. The evolutionary biologist Paul Ewald has been reporting that there is a connection between history of infection and many late in life diseases, such as cancers. Mike Snyder had Stanford has been tracking his own biomarkers in extensive detail for several years, and has indicated that his own onset of Type II Diabetes was probably triggered by an earlier infection. These inferences were only possible because of his extremely rich personal data set, part of a broader project in his laboratory. But, it might give us a window into the more precise individual etiologies of diseases.

Citation: Naturwissenschaften. 2011 Nov;98(11):951-60. Epub 2011 Oct 1

Image Credit: Wikipedia, Wikipedia.

• Category: Science • Tags: Anthropology, Genomics, Medicine, Sex 
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In light of growing health care costs and the demographic reality of an aging profession stories like this one in The New York Times are both depressing and hopeful. Calling the Nurse ‘Doctor,’ a Title Physicians Oppose:

But while all physician organizations support the idea of teamwork, not all physicians are willing to surrender the traditional understanding that they should be the ones to lead the team. Their training is so extensive, physicians argue, that they alone should diagnose illnesses. Nurses respond that they are perfectly capable of recognizing a vast majority of patient problems, and they have the studies to prove it. The battle over the title “doctor” is in many ways a proxy for this larger struggle.

Six to eight years of collegiate and graduate education generally earn pharmacists, physical therapists and nurses the right to call themselves “doctors,” compared with nearly twice that many years of training for most physicians. For decades, a bachelor’s degree was all that was required to become a pharmacist. That changed in 2004 when a doctorate replaced the bachelor’s degree as the minimum needed to practice. Physical therapists once needed only bachelor’s degrees, too, but the profession will require doctorates of all students by 2015 — the same year that nursing leaders intend to require doctorates of all those becoming nurse practitioners.

Nursing is filled with multiple specialties requiring varying levels of education, from a high school equivalency degree for nursing assistants to a master’s degree for nurse practitioners. Those wishing to become nurse anesthetists will soon be required to earn doctorates, but otherwise there are presently no practical or clinical differences between nurses who earn master’s degrees and those who get doctorates.

I applaud the wider distribution of medical services outside of the licensing monopoly of M.D.s. As an empirical matter I think there was a practical reason for the professionalization of medicine in the 20th century and the emergence of degree holding as necessary. To be frank about it for most of human history doctors were frauds or butchers. Modern medicine in the 20th century was a major revolution in that sense (though doctors are only part of it, the rise of an effective pharmaceutical industry is probably just as important if not more so). But the arrow of history does not always move in one direction, and we live in an “information age.” Doctors are human, and therefore fallible. They need the aid of both their patients and various other medical professionals to optimize health outcomes. The paternalistic model is just not viable in the long run, especially as the median educational qualifications of their patients keeps rising.

But notice that in this case we’re seeing greater and greater credentialism in fields which were traditionally perceived to be auxiliary to medical doctors. This is not a good sign. Instead of challenging the unquestioned prominence of medical doctors in domains where nurses are sufficient and more cost effective, the nursing profession is “fighting fire with fire.” This is not going to end well. Having to pile on education removes productive years in the work force. This is justifiable when education results in gains in productivity, but just as in education, I suspect that all the extra years for physical therapists and nurses is not doing anything but signalling, and further tightening up labor supply as the number of patients keeps on increasing because of the aging of the population.

• Category: Science • Tags: Medicine 
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The British newspapers have been reporting on a bizarre story about a Dutch sperm donor who hid a history of mental problems from recipients. I didn’t pay much attention to it because of the British tabloid media’s tendency to sensationalize. But Radio Netherlands also reported the outlines of the story, and there seems to be validity to the broad facts at hand. A Dutch man with a history of mental illness did father many children by offering his services online, and hiding various conditions from potential mothers. Now several of the children have developed the same problems (e.g., autism).

But the specific case here highlights some constraints on sperm donation which seem to have resulted in a “gray market” which allowed this man to “slip through” the safeguards. And yet I wonder why there is so much regulation of sperm banks in the first place? It reminds me of a story from a few years back about panic in Turkey over the importation of “foreign sperm.” Is there is a strong public policy reason why we should have a sperm donor shortage? In an ideal world children should know their parents, but there are far greater social ills than anonymous sperm donors. Rather than regulations which distort the behavior of individuals (both single women and infertile couples) there should be encouragement of a robust market, which will allow for better vetting and cataloging as the supply increases.

• Category: Science • Tags: Genetics, Medicine 
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The Pith: Natural selection is a quick & dirty operator. When subject to novel environments it can react rapidly, bringing both the good and the bad. The key toward successful adaptation is not perfection, but being better than the alternatives. This may mean that many contemporary diseases are side effects of past evolutionary genetic compromises.

The above is a figure from a recent paper which just came out in Molecular Biology and Evolution, Crohn’s disease and genetic hitchhiking at IBD5. You probably have heard about Crohn’s disease before, there are hundreds of thousands of Americans afflicted with it. It’s an inflammatory bowel ailment, and it can be debilitating even to very young people. The prevalence also varies quite a bit by population. Why? It could be something in the environment (e.g., different diet) or genetic predisposition, or some combination. What the figure above purports to illustrate is the correlation between Crohn’s disease and the expansion of the agricultural lifestyle.

But don’t get overexcited Paleos! There are many moving parts to this story, and I need to back up to the beginning. The tens of thousands of genes which you inherited from your parents are embedded within the genome and aligned in a set of sequences, one after the other. On the one hand for the purposes of conceptualizing evolutionary dynamics, such as natural selection or random genetic drift, focusing on a single gene is useful. It has power to illustrate some basic and elementary principles. But sometimes you need to take a more synoptic view, and look at genes in their broader context. In this post I’ll avoid molecular or statistical epistasis, gene-gene interaction. Rather, let’s just consider the static landscape of the genome, where genes are physical concrete entities which are embedded in a particular spatial relationship to other genes, upstream or downstream in the genetic code. These physical or statistical associations of genes can form a de facto supergene through linkage, and their variants combine to form haplotypes, sequences of markers across small stretches of the genome. But recall that these associations are counter-balanced by genetic recombination, which tears apart physical sequences and sows them to the opposite DNA strand.

The big picture that the above highlights is the fact that evolutionary dynamics operate not just on the gene, but also upon the local genetic neighborhood. Therefore, when we talk about selection upon a gene, we need to recall that this has consequences for that gene’s neighbors. Let’s use a concrete and real example. Northern Europeans tend to have very long haplotypes around the LCT gene, which encodes the production of lactase. Functionally this haplotype has embedded within it a variant which allows for continued production of lactase as an adult, and therefore the ability to extract all the calories from milk beyond childhood in the form of lactose sugar. The molecular genetic details of how this happens does not concern us. Instead, let’s consider why LCT is characterized by a very long haplotype.

This is what we think happened. Between 5 and 10 thousand years before the present there lived an individual who carried a dominant genetic mutation which allowed for the persistent production of lactase into adulthood. Only one copy of the lactase persistent allele is needed for lactose tolerance. That’s why populations such as in Denmark where the persistent allele is present in proportions of 80-90% have nearly universal tolerance. As per the Hardy-Weinberg equilibrium a recessive trait would express at frequencies of 1-4% (square the frequency of the minor allele). Going back to the individual with the mutant copy, if one considers a scenario where lactase persistence would be highly beneficial (this is not hard to imagine) then the frequency of that mutant would rapidly rise. It would “sweep” through the population. As it has a dominant mode of expression half of the children of the original mutant would express the trait and carry the allele, while half would not. Over the generations that one original copy could replicate rapidly within a population due to positive selection and intermarriage.

But it’s not just the functionally relevant genetic variant which would proliferate. The lactase persistent allele would be embedded within the context of a host of other genetic variants across the sequence of the DNA strand in which it was located. As the lactase persistent allele rose rapidly in frequency in a selective sweep its neighbors would hitchhike along. The extent of the hitchhiking would be conditional upon distance from the positively selected variant and the speed of the sweep, which itself would presumably depend upon the strength of selection. All of this together explains the very long haplotype around LCT in Northern Europeans: 5 to 10 thousand years ago a relatively large genomic segment of an individual who carried a lactase persistent allele was driven up in frequency very rapidly because of adaption to new conditions. Not only did that particular individual’s functionally relevant variant, the target of selection, sweep nearly to fixation in some Northern European populations, but many adjacent variants also rose in frequency, in direct proportion from distance from the focal variant. In other words, natural selection in this case was about one specific functional unit within LCT, but as a side effect it also reorganized a whole swath of the total population genome structure of Northern Europeans.

What does that have to do with Crohn’s disease and agriculture? Crohn’s disease may be a modification of the LCT story in a genomic sense, and the trigger of that modification may have been agriculture. Before I go any further, let me post the paper’s abstract:

IBD5 (inflammatory bowel disease 5) is a 250 kb haplotype on chromosome 5 that is associated with an increased risk of Crohn’s disease in Europeans. The OCTN1 gene is centrally located on IBD5 and encodes a transporter of the antioxidant ergothioneine (ET). The 503F variant of OCTN1 is strongly associated with IBD5 and is a gain-of-function mutation that increases absorption of ET. Although 503F has been implicated as the variant potentially responsible for Crohn’s disease susceptibility at IBD5, there is little evidence beyond statistical association to support its role in disease causation. We hypothesize that 503F is a recent adaptation in Europeans that swept to relatively high frequency, and that disease association at IBD5 results not from 503F itself, but from one or more nearby hitchhiking variants, in the genes IRF1 or IL5. To test for evidence of recent positive selection on the 503F allele, we employed the iHS statistic, which was significant in the European…populations…To evaluate the hypothesis of disease-variant hitchhiking, we performed haplotype association tests on high-density microarray data in a sample of 1868 Crohn’s disease cases and 5550 controls. We found that 503F haplotypes with recombination breakpoints between OCTN1 and IRF1 or IL5 were not associated with disease…In contrast, we observed strong disease association for 503F haplotypes with no recombination between these three gene…as expected if the sweeping haplotype harbored one or more disease-causing mutations in IRF1 or IL5. To further evaluate these disease-gene candidates, we obtained expression data from lower gastrointestinal biopsies of healthy individuals and Crohn’s disease patients. We observed a 72% increase in gene expression of IRF1 among Crohn’s disease patients (p=0.0006) and no significant difference in expression of OCTN1….

It’s all a mouthful. But let’s review here. IBD5 is a 250 kilobase haplotype implicated in Crohn’s disease. A long segment of associated markers which also seem to correlate with individuals with the illness. This does not imply that the whole segment is causally connected with Crohn’s disease. But, there are two genes which have been pegged as likely candidates, IRF1 and IL5. Finally, there’s another gene, OCTN1, which is statistically associated with Crohn’s disease, but lacks a biologically plausible connection. Rather, it seems to have a role in absorption of the amino acid ergothioneine, with the 503F allele of OCTN1 resulting in gain of function in regards to this process. Interestingly the authors observe that OCTN1 is positioned exactly in the middle of the haplotype. In other words, you can think of the genome upstream and downstream of OCTN1 extending out across the haplotype as two wings or fringes of this gene.

The IBD5 haplotype is the broader landscape. IRF1, IL5, and OCTN1 are general features embedded within this landscape. 503F is a specific feature, in that it is a flavor of OCTN1. Crohn’s disease is another phenomenon which has an association with this genomic landscape, but is of a different class or category. It is correlated in particular with IBD5 haplotypes with 503F allele. The main aim of this paper is to tease apart all these multitudinous associations. What the authors found is that in terms of biochemistry the symptoms of Crohn’s disease are not correlated with the 503F allele if that allele is not associated with known risk variants of IRF1 and IL5. These are instances where genetic recombination has broken apart the association which couples 503F with the risk alleles of those two genes. The architecture of the genomic landscape then in this case has obscured the more specific causal chain which leads to an increased risk for Crohn’s disease.

So what happened? The authors posit that the 503F allele was selectively favored at some point in the past, and flanking it were the Crohn’s disease risk elevating variants of IRF1 and IL5. All things equal it is best not to have a risk for this disease, but all things are not equal. If there was a strong enough selective pressure on the target, 503F, then the downsides of the fact that it came as a “total package” with some deleterious alleles would be irrelevant. Over a long enough evolutionary time the deleterious alleles would be purified through negative selection because recombination does break apart associations, but there’s a lot of reality which consists of being between beginnings and ends.

To infer that 503F was the target of natural selection the authors used a haplotype based test for detecting such this phenomeon, iHS. This test tends to detect selective sweeps in midstream, or those which do not shift to fixation because of balancing dynamics. One implication of this is that the allele which was the target of selection will tend to have modest frequencies at best, and that is so. From the supplements here are a list of populations with the percentage of the selected allele (some duplicates because they sampled different data sets):

Population N = 503f alleles N = 503L alleles % of 503f
Sardinian 40 16 71%
Tuscan 9 7 56%
Turku 11 9 55%
Basque 23 23 50%
Adygei 15 17 47%
Orcadian 15 17 47%
Italian 12 16 43%
Utah 40 56 42%
French 24 34 41%
Kuopio 8 12 40%
Tuscan 23 35 40%
Pole 7 13 35%
Druze 27 67 29%
Russian 13 35 27%
Uygur 5 15 25%
Terekli-Mektab (Daghestani) 13 43 23%
Makrani 11 39 22%
Balochi 10 40 20%
Mozabite 12 48 20%
Palestinian 19 83 19%
Kalash 8 42 16%
Pathan 8 42 16%
Kubachi (Daghestani) 7 39 15%
Brahmin Niyogi 4 26 13%
Brahmin 5 33 13%
Hazara 6 42 13%
Burusho 6 44 12%
Brahmin Vydika 5 41 11%
Sindhi 5 43 10%
Bedouin 10 88 10%
Brahui 5 45 10%
BantuSouthAfrica 1 15 6%
Yakut 3 47 6%
Xibo 1 17 6%
Daur 1 19 5%
Lahu 1 19 5%
Tu 1 19 5%
Yi 1 19 5%
Cambodian 1 21 5%
Mbuti Pygmy 2 74 3%
Mbuti Pygmy 2 74 3%
Mbuti Pygmy 2 74 3%
Mbuti Pygmy 2 74 3%
Mandenka 1 47 2%
Khonda Dora 1 51 2%
Irula 1 59 2%
BiakaPygmy 1 69 1%
!Kung (San) 0 22 0%
Alur 0 16 0%
BantuKenya 0 22 0%
Biaka Pygmy 0 10 0%
Cambodian 0 10 0%
Chinese 0 16 0%
Dai 0 20 0%
Han 0 70 0%
Han-NChina 0 18 0%
Hema 0 42 0%
Hezhen 0 20 0%
Japanese 0 62 0%
Japanese 0 38 0%
Khmer Cambodian 0 8 0%
Malasian 0 12 0%
MbutiPygmy 0 30 0%
Melanesian 0 44 0%
Miao 0 18 0%
Mongola 0 20 0%
Nande 0 36 0%
Naxi 0 20 0%
Oroqen 0 20 0%
Papuan 0 34 0%
Pedi (northern Sotho) 0 22 0%
San 0 14 0%
She 0 20 0%
Sotho 0 10 0%
Southern Chinese 0 8 0%
Taiwan 0 6 0%
Tsonga 0 12 0%
Tswana 0 14 0%
Tujia 0 20 0%
Vietnamese 0 18 0%
Xhosa 0 4 0%
Yoruba 0 50 0%
Zulu (Nguni) 0 18 0%

From these data the authors make the inference that the 503F allele was selected for its enhanced transport of ergothioneine, which is lacking in many plant foodstuffs which became prominent with the Neolithic Revolution. In other words, Crohn’s disease is a byproduct of an adaptation to nutrient deficiencies brought on by agricultural monocultures. The main problem this thesis seems to have is that many Middle Eastern populations which have long been agricultural don’t have a high frequency of the 503F allele. This doesn’t mean that the selective model proposed here is impossible, but, it does indicate that if this was a plausible adaptation then Middle Eastern populations must have their own distinctive variants.

I think this is a great paper, though I’m not confident about the conclusion. Agriculture was obviously one of the major selective pressures on the human genome. Even if some of the preliminary tests of natural selection from the mid-2000s don’t hold up because they tend to confuse genuine natural selective targets from spurious positives I’m rather confident that genes which are associated in some way with agriculture are going to be enriched in terms of functional constraint and adaptive sculpting.

Citation: Chad D. Huff, David Witherspoon, Yuhua Zhang, Chandler Gatenbee, Lee A. Denson, Subra Kugathasan, Hakon Hakonarson, April Whiting, Chad Davis, Wilfred Wu, Jinchuan Xing, W. Scott Watkins, Mike Bamshad, Jonathan P. Bradfield, Kazima Bulayeva, Tatum S. Simonson, Lynn B. Jorde, and Stephen L. Guthery Crohn’s disease and genetic hitchhiking at IBD5, Mol Biol Evol, doi:10.1093/molbev/msr151.

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A story in The Los Angeles Times seems to point medical implications of being a sickle cell carrier, Sickle cell trait: The silent killer:

At least 17 high school and college athletes’ deaths have been tied to sickle cell trait during the past 11 years. The group includes Olivier Louis, a player at Wekiva High School near Orlando, who died on Sept. 7, 2010, following his first football practice.

You have surely heard about sickle cell anemia. It is a recessive disease which expresses in those who carry two sickle cell alleles. T-boz of TLC has the disease for example due to her homozygosity. But the allele also famously confers some resistance against malaria, which explains its concentration in regions which have historically been malarial. Sickle cell is arguable the classic case of heterozygote advantage driving the emergence of a recessive disease. The frequency of the allele is balanced at the equipoise between the proportion of people who are more susceptible to malaria if its proportion is too low and those who express sickle cell anemia if its proportion is too high. This advantage is obviously context sensitive. The standard assumption is that in a non-malarial environment selection pressure against anemia will drive the frequency of the allele down over time as heterozygotes don’t impose a floor in the proportion of the mutant allele. This seems to have occurred among African Americans, they’re ~80% West African, but their frequency of the sickle cell anemia allele is less than {0.80*(the West African proportion)} from what I know (remember that the median number of generations which an African American’s black ancestors have been in the USA is probably ~10).

But this ignores the reality that there’s more to heterozygote advantage than just advantage. When talking about the genetics of recessive diseases as a first approximation it makes good sense to focus on the dominance-recessive dichotomy. You’re fixated upon the disease which expresses in the homozygotes. But quite often the heterozygote also exhibits some phenotypic deviation from the “wild type” homozygote. Just not enough to pass the threshold of notice for a medical geneticist. The stories above were all in abnormal situations, as the body was pushed toward its physiological limits. Heterozygote carriers of sickle cell may start deviating from the phenotype of wild type homozygote only at the tail of the range of likely environments, but it still goes to show that “dominance” of the wild type is contextual. It’s convenient terminology which has an obvious meaning and allows us to model the world efficiently with a minimum of cognitive overhead, but it’s a construct of our making mapped onto the distribution of reality.

Another issue is that the same locus may have dominant and recessive effects on different traits. Most genes have many effects, so in some dimensions it will be dominant and in others it will be recessive. Additionally in many it will be additive. There is some evidence for example that the genes which are implicated in the recessive expression of blue eyes in Europeans may have an additive effect on skin color toward lightening, with a slight dominance bias perhaps. In other words, the expression levels of melanin controlled by these loci in the eye manifest recessively in terms of down-regulation, but express somewhat dominantly in relation to down-regulation! So very similar phenotypic consequences in the same trait value direction have different dominance deviations in different tissues.

This brings me to the broader issue: dominance can be an artifact of the social construction of the trait. For example, eye color is generally “binned” into distinct categories. That’s because that’s how human perception seems to work on a cognitive level. This is also true for skin color, but there is more texture and nuance in description, likely because of the larger perceptual target of the trait. Therefore it’s not surprising that scientists have developed methods for measuring lightness or darkness of skin on a quantitative scale using reflectometers. Whether you bin traits into categories or measure them on a continuous scale may change our understanding of genetic inheritance.

Skin color is an easy character to illustrate this because as humans we’re cued toward it, and, its genetic architecture has been well elucidated. Two genes have variants which explain most of the between population difference between Africans and Europeans in pigmentation, SLC24A5 and KITLG. To the left you see charts which show the effect of the variants on the distribution of complexion in sets of African Americans. The researchers used a quantitative index of complexion, where lower values represent lighter skin color. Since African Americans are ~20% European in ancestry they have skin lightening alleles segregating within their population, and so are an ideal population to test the effects of these variants. The top panels show individuals who carry two copies of the European/light allele, the bottom panel individuals who carry two copies of the African/dark allele, and the middle panel heterozygotes. Observe that the heterozygote seems to exhibit a value closer to the European/light homozygote than the the African/dark homozygote! This finding is replicated on both of these genes.

There need to be proper caveats in not over extrapolating from one particular context (the effect size may be influenced by genetic background, so substituting the same genotypes into a European-Asian admixed population may lead to differing results). But, is there a general perception that light skin is dominant to dark in inheritance? In the West of course not. That’s because social paradigms shape our perceptions. In the United States Salma Hayek, Thandie Newton, and Gabrielle Union are all “actresses of color,” despite their objective difference in complexion. That’s due to a social norm where everyone is first binned into white vs. non-white (before non-whites are further subdivided), with a high threshold for what counts as white. When you reframe the argument in this way then the fact that Thandie Newton’s complexion on a reflectometer may be closer to her English father than her African mother has less weight than the fact that she is not white-skinned, period. Dark is dominant to light purely as an artifact of social norms which sharply constrain what counts as light.

This cognitive and cultural filter looms large in sciences which require a layer of abstraction between raw description and explanatory models. To a great extent this applies to all sciences. We need models and approximations to make sense of the data mess. In the case above with sickle cell trait confusions engendered by this human “middle-ware layer” can be deadly, giving the false perception that heterozygotes who carry a disease allele are functionally equivalent to homozogytes. For all practical purposes they probably are. Most humans aren’t going to engage in sporting activities to such an extent that the differences between wild type and carrier are going to manifest on the margins of the environmental distribution of exposure. But on an individual level awareness of carrier status and its possible functional relevance may be important in the era of personalized medicine.

The medical relevance of this discussion also illustrates that just because something is socially constructed doesn’t mean that it doesn’t have concrete consequences and utility. Dominance is to a great extent a coarse category which we map onto reality for the sake of our own comprehension. It has great upsides, in terms of differentiating between carriers and non-carriers, and highlighting the risk of recessive Mendelian diseases expressing when two carries come together (e.g., cystic fibrosis). Just because it’s a construct doesn’t mean we should discard dominance, we just need to keep it in perspective, and understand that it’s not “real” in a deep fundamental sense. Then again, I don’t think mathematics is “real” either. But it’s awful useful, isn’t it? You’ll probably accede to that if you’re not a Platonist.

Image credit: Mutuwandi

• Category: Science • Tags: Dominance, Genetics, Health, Medicine 
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The Pith: the genetic relationships between bacteria in our stomach can tell us a lot about the relationships between various groups of people. Additionally, the distribution of different strains of bacteria may have significant public health implications.

The above image is from a paper which was pushed online yesterday in PLoS ONE: Evolutionary History of Helicobacter pylori Sequences Reflect Past Human Migrations in Southeast Asia. It’s a paper which caught my attention for several reasons. First, I’ve exhibited some curiosity about the history and prehistory of Southeast Asia of late. Elucidating this region’s historical dynamics may bear upon more general questions of human evolutionary and cultural process. Second, H. pylori is a fascinating organism whose connection to specific human populations is tight enough that it can shed light on past interactions of different groups. In short, just like humans H. pylori exhibits regional specificity and local history. But additionally, H. pylori is also subject to natural selection after introduction into a new population, and so can serve as a window upon cultural contacts which might otherwise leave a light demographic footprint. In other words, the spread of H. pylori across human populations may be compared to the spread of Buddhism. This religion came to China and Japan with some Buddhists of South and Central Asian origin, but by and large its spread was memetic rather than through natural increase of a Buddhist population.

First, let’s hit the abstract:

The human population history in Southeast Asia was shaped by numerous migrations and population expansions. Their reconstruction based on archaeological, linguistic or human genetic data is often hampered by the limited number of informative polymorphisms in classical human genetic markers, such as the hypervariable regions of the mitochondrial DNA. Here, we analyse housekeeping gene sequences of the human stomach bacterium Helicobacter pylori from various countries in Southeast Asia and we provide evidence that H. pylori accompanied at least three ancient human migrations into this area: i) a migration from India introducing hpEurope bacteria into Thailand, Cambodia and Malaysia; ii) a migration of the ancestors of Austro-Asiatic speaking people into Vietnam and Cambodia carrying hspEAsia bacteria; and iii) a migration of the ancestors of the Thai people from Southern China into Thailand carrying H. pylori of population hpAsia2. Moreover, the H. pylori sequences reflect iv) the migrations of Chinese to Thailand and Malaysia within the last 200 years spreading hspEasia strains, and v) migrations of Indians to Malaysia within the last 200 years distributing both hpAsia2 and hpEurope bacteria. The distribution of the bacterial populations seems to strongly influence the incidence of gastric cancer as countries with predominantly hspEAsia isolates exhibit a high incidence of gastric cancer while the incidence is low in countries with a high proportion of hpAsia2 or hpEurope strains. In the future, the host range expansion of hpEurope strains among Asian populations, combined with human motility, may have a significant impact on gastric cancer incidence in Asia.

H. pylori can be separated into very distinctive lineages of geographically limited scope, despite some horizontal gene flow. One clade seems generally restricted to western Eurasia, another to eastern Eurasia, and there are some Africa specific lineages as well. But within these particular clades one can drill-down to a finer-grain. For example, there are Indian lineages within the broader west Eurasian family of strains. As mutation over time results in the build up of distinctive variants in localized populations, a simple assessment of mutational steps between lineages can allow one to infer a tree of descent from a common ancestor.

Let’s tack for a moment to some history without microbial goodness. To some extent Southeast Asia can be considered part of “Greater India,” more or less. This is most evident in Thailand and Cambodia, two nations which are cultural heirs to the Khmer civilization which produced Angor Wat. The religious and artistic sensibilities of both these modern societies are deeply imprinted by South Asian norms through that precursor polity. The Theravada Buddhism of these societies still has a vital connection to South Asia (especially Sri Lanka) and is more obviously Indian in its sensibility than for example the Zen sect of Japan (which derives from Chinese Chan). In Vietnam there remains a small group of Malay Cham Saivite Hindus, the remnants of the Champa Empire.

The affinities in maritime Southeast Asia are a bit clouded because of the interposition of Islam between moderns and the Dharmic past. Only the Balinese remain as a vital living heir to the Indian-influenced polities of early Indonesia, Srivijaya and Majapahit. Despite this notional reality the Indian influence remains discernible even among Muslim Indonesians, in particular in East Java, where shadow puppet shows of the Ramayana remain popular. Like Angor Wat, Borobudur in Java is a testament to the monumental Indian past. But even the avowed Islamic flavor of modern maritime Southeast Asia may have some Indian connection, insofar as there is the possibility that South Asian Muslims were critical players in the eastern Indian ocean trade network which slowly Islamicized over the course of the second millennium.

We are then presented with the question: if the Indian influence in Southeast Asia was so strong in the past, where are the genes of Indians? The authors note that mitochondrial DNA analyses, the maternal lineage, show no South Asian specific lineages in appreciable frequencies among native populations. A fixation on mtDNA seemed rather strange to me for two reasons. First, with the PanAsian SNP data set there’s some autosomal data. Second, there are strong reasons to suppose that Indian migrants would be male. The myths and sketchy historical references of this period don’t seem to envisage mass folk migrations, where Indian men bring their women and children and recreate their homelands. Rather, often these men are portrayed as religious specialists or military leaders of genius. The authors note that there is evidence of Indian artisans in Thailand ~2,000 years ago. This is eminently plausible, there are references to towns of Indian merchants in Sumeria ~4,000 years ago! But again, there is no reason that these artisans necessarily brought their wives. Rather, if they were purchased for their skills they may simply have been the human property which was the object of capitalist transactions between two autocrats.

The nature of cultural transfer, and the relatively high fidelity of that transfer, implies to me that some Indians did migrate to Southeast Asia. But they were few, and their genetic impact was minimal. Rather, what we see is the power of memes to operate very differently from genes. The Indian memes rapidly swallowed up the cultural commanding heights, and became normative from Java to northern Thailand (northern Vietnam is the exception to this rule, as it was influenced by China).

H. pylori shares many of the same tendencies as memes, despite its more concrete biological character. As bacteria it can spread rapidly within a population, and decouple itself from the endogenous natural increase of its original hosts. That spread can be driven by natural selection which means that it isn’t a good representation of the ancestry of its hosts. But even natural selection can’t erase the inferences one can make about original contacts between distinct groups.

In this paper the authors present evidence from the nature of H. pylori in Southeast Asia that there was tangible physical contact between Indians and Southeast Asians in the antique past. More precisely, below is a figure which shows the nature of relationships of west Eurasian H. pylori lineages in India and Southeast Asia, with European and other west Eurasian samples as a control.

What you see here is that Indian H. pylori is basal to the Southeast Asian branches, though within the same clade against the European lineages. This tells you that there’s an affinity between Indian and Southeast Asian lineages under consideration here, but that that affinity is diminished by a period of separation. This matters because some regions of Southeast Asia, such as Malaysia, have a large Indian population which arrived in the past few centuries. The fact that there is a distinct Southeast Asia specific lineage suggests that there has been a long period of separation between the two populations, and one can’t attribute the frequency of the west Eurasian Indian H. pylori simply to recent contacts. At least in most of Southeast Asia. It turns out that in the Philippines the west Eurasian H. pylori cluster with Spanish populations. This has to be the outcome of hundreds of years of colonialism.

There’s also this fascinating historical and geographical tidbit:

A study on the distribution of H. pylori virulence factor cagA among Vietnamese identified 84% of the strains harbouring the type II of the cag-right motif…which is characteristic for East Asian strains (hpEastAsia), ranging from 76% in Ho Chi Minh city in South Vietnam to 93% in Hanoi in North Vietnam. However, there was a remarkable difference in the frequency of cag-right motif of type I which is predominant in European (hpEurope) strains. While the type I motif was absent from North Vietnam, it was found in 8/49 (16%) of the samples from Ho Chi Minh city near the Mekong delta. Interestingly, prior to annexation by the Vietnamese in the 17th century, this city was an important Khmer sea port known as Prey Nokor…Thus, hpEurope strains also seem to be frequent among Vietnamese in the Mekong delta, and thus the Annamite mountain range that originates in the Tibetan and Yunnan regions of southwest China and forms Vietnam’s border with Laos and Cambodia seem to have shaped an effective natural barrier for the containment of Indian influence in the Mekong basin, explaining the low prevalence of hpEurope strains elsewhere in Vietnam.

The geographic contours of the nation-state of Vietnam as we understand it today are a relatively new phenomenon. The Vietnamese people, the Kinh, are an ancient nation. But for most of the past ~2,000 years what we know as Vietnam was divided between the Kinh in the north, and the Khmers and later Austronesian Chams in the center and south. Unlike the other peoples of Southeast Asia the Kinh looked to the north, to China, as their cultural model. While India’s influence in Southeast Asia (excepting the Chola adventures) has been through “soft power,” the Chinese have periodically ruled Vietnam directly, and otherwise placed it into the category of tributary state.

There needn’t be any geographical determinism here. Projection of cultural or military power declines in proportion to distance. In relation to culture that projection does not decline linearly, but often exhibits a sharp break. The Vietnamese did not move the Annamite range south when they defeated Champa and began to swallow the eastern flank of the Khmer kingdom. Rather, they shifted populations and cultural identities of populations, and therefore the civilizational boundaries. The line which separated Indic and Sinic moved south with the spread of the Kinh and the retreat of the Khmer. This did not eliminate in totality the Indic influence. Hindu Cham remain in Vietnam, while forms of Therevada Buddhism have some purchase in the Mekong delta, unlike in the rest of country where Chinese derived Mahayana reigns supreme. And so it is that Indic H. pylori also remains as a residual in the southern regions of Vietnam, evidence of the trade and cultural networks which bound it to Greater India as some point in the past.

Next let’s look at the distribution of East Asia specific H. pylori:

The figure is hard to read, but here’s the short of it: there are Amerindian, Taiwan-Oceanian, Chinese, and Southeast Asia specific lineages. More specifically the authors attempt to infer the origin of one particular Southeast Asia specific lineage which exhibits some overlap in southern China. This is because they believe that it can trace the migration of the Austro-Asiatics, likely the first agriculturalists in Southeast Asia. The H. pylori strain in question spans southern China to Malaysia. The geographic zone encompasses regions now inhabited by Thai or Malay speakers, but it seems likely that at one point the whole zone was dominated by Austro-Asiatics. The clincher would be to see if Munda from northeast India carry this same H. pylori strain. In fact an analysis of the phylogenetic tree of strains of H. pylori found in Austro-Asiatic populations or their descendants might be able to move the needle on whether they’re exogenous to India or not (the “older” lineages should be basal).

So far I’ve been focused on issues of phylogeny. How populations of humans and bacteria relate to each other. But there are functional and adaptive implications and dynamics at work. In terms of adaptation it seems that some strains of H. pylori are simply more fit than others in some environments. The Spanish presence in the Philippines was very light demographically over the centuries of their colonial rule. There was considerable residential segregation of the Spanish away from the natives, and the Chinese, who outnumbered the Spaniards often by two orders of magnitude. And yet you have a situation where H. pylori of Spanish provenance seems to be dominant. Why? The authors report that there’s a fair amount of evidence that European H. pylori strains are generalists who outcompete the specialist East Asian and Amerindian lineages. I think one can’t ignore the reality that the “European” strains are endemic to a huge swath of western Eurasia, from Europe to India. Because of their large population sizes these lineages probably have more diversity than the other populations, and so can adapt to a wide range of conditions.

A functional and public health concern is that East Asia H. pylori may be the cause of the much higher stomach cancer rates in that region of the world. You probably know that H. pylori is a critical player in ulcers, so its impact in this region shouldn’t be a surprise. Prior to reading this paper I’ve heard that East Asian stomach cancer rates were due to condiments used. This goes to show the difficulty of much of medical science which relies on correlations and rough guesses about causality.

Obviously I’m interested in what markers such as the distribution of pathogens which are reliant on humans can tell us about history. But over the long term the complex interplay between these pathogens, disease risk, and other phenotypic characteristics, is where the real action is going to be.

Citation: Breurec S, Guillard B, Hem S, Brisse S, Dieye FB, & et al. (2011). Evolutionary History of Helicobacter pylori Sequences Reflect Past Human Migrations in Southeast Asia PLoS ONE : 10.1371/journal.pone.0022058

Image credit: Mark Alexander

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The Pith: You are expected to have 30 new mutations which differentiate you from your parents. But, there is wiggle room around this number, and you may have more or less. This number may vary across siblings, and explain differences across siblings. Additionally, previously used estimates of mutation rates which may have been too high by a factor of 2. This may push the “last common ancestor” of many human and human-related lineages back by a factor of 2 in terms of time.

There’s a new letter in Nature Genetics on de novo mutations in humans which is sending the headline writers in the press into a natural frenzy trying to “hook” the results into the X-Men franchise. I implicitly assume most people understand that they all have new genetic mutations specific and identifiable to them. The important issue in relation to “mutants” as commonly understood is that they have salient identifiable phenotypes, not that they have subtle genetic variants which are invisible to us. Another implicit aspect is that phenotypes are an accurate signal or representation of high underlying mutational load. In other words, if you can see that someone is weird in their traits, presumably they are rather strange in their underlying genetics. This is the logic behind models which assume that mutational load has correlates with intelligence or beauty, and these naturally tie back into evolutionary rationales for human aesthetic preferences (e.g., “good genes” models of sexual selection).

Variation in genome-wide mutation rates within and between human families:

J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline…Diverse studies have supported Haldane’s contention of a higher average mutation rate in the male germline in a variety of mammals, including humans…Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell lines from which the DNA was derived. Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families.

From what I gather there’s a straightforward reason why the male germline, the genetic information which is transmitted by sperm to a male’s offspring, is more mutagenetic: sperm are produced throughout your whole life, and over time replication errors creep in. This is in contrast to a female’s eggs, where the full complement are present at birth. The fact that mutations creep in through sperm is just a boundary condition of how mutations creep in to the germline in the first place, errors in the DNA repair process. This is good on rare occasions (in that mutations may actually be fitness enhancing), more often this is bad (in that mutations are fitness detracting), and, oftentimes it is neutral. Remember that in terms of function and fitness a large class of mutations don’t have any effect. Consider the fact that 1 out of 25 people of European descent carry a mutation which can cause cystic fibrosis in the general population if it manifests in a homozygote genotype. But the vast majority of cystic fibrosis mutations are present in people who are heterozygote, and have a conventional functional gene which “masks” the deleterious allele.* And there are many mutations which are silent even in homozogyote form (e.g., if there is a change in a base at a synonymous position).

As noted in the letter above until recently estimating mutation rates was a matter of inference. On the broadest canvas one simply looked at differences between two related lineages which had been long separated (e.g., chimpanzee vs. human), and so accumulated many differential mutations, and assayed the differences. It may have been a fine-grained inference in the case of individuals who manifested a disease which exhibited a dominant expression pattern, so that one de novo mutation in the offspring could change the phenotype. For most humans this is thankfully not a major issue, and mutations remain cryptic for most of our lives. But no longer. With cheaper sequencing at some point in the near future most of us will have accurate and precise copies of our genomes available to us, and we will be able to see exactly where we have unique mutations which differentiate us from our parents and our siblings.

In this paper the authors took two “trios,” parent-child triplets, and compared their patterns of genetic variation at the scale of the full genome to a very high level of accuracy. Accuracy obviously matters a great deal when you might be looking for de novo mutations which are going to be counted on the scale of hundreds when base pairs are counted in billions. In the future when we have billions and billions of genomes on file and omnipotent computational tools I suspect there will be all sorts of ways to ascertain “typicality” of regions of your genome, but in this paper the authors naturally compared the parents to the children. If a mutation is de novo it should be underivable from the genetic patterns of the parent. But, sequencing technologies are not perfect, so there’s going to be a high risk for false positives when you are looking for the de novo mutations “in the haystack” (e.g., an error in the read of the offspring can be picked up as a mutation).

So they started with ~3,000 candidate de novo mutations (DNMs) for each family trio after comparing the genomes of the trios, but narrowed it down further experimentally as they filtered out the false positives. You can read the gory details in the supplements, but it seems that they focused on the identified candidates to see if they were: germline DNMs, non-germline DNMs, variant inherited from the parents, or a false positive call. So it turns out that half of the preliminary DNMs were somatic and about 1% turned out to be germline. Remember that the difference is that the germline mutations are going to be passed on to one’s offspring, while the somatic mutations only have impact on one’s physiological fitness over one’s life history. For the purposes of evolution germline mutations are much more important, though over your lifetime somatic mutations are going to be very important as you age.

After the methodological heavy-lifting the results themselves are interesting, albeit of somewhat limited generalizability because you are focusing on two trios only. Before we examine the results here’s a figure which illustrates the study design:

From what I can gather there are two primary findings in this paper:

1) Variance in the sex-mediated nature of DNMs across trios. One of the pairs was much closer to expectation. The male germline contribution was responsible for the vast majority of DNMs.

2) A more precise estimate of human mutational rates which might have implications for “molecular clock” estimates used in evolutionary phylogenetics.

Here are the findings in a figure which shows the 95% confidence intervals around estimated mutation rates:

CEU refers to the sample of white Utah Mormons commonly used in medical genetics, while YRI refers to Yoruba from Nigerians. Remember, these are two families only. That severely limits the power of the insights which you can draw, but already you see that while the CEU trio shows the expected imbalance between male and female contribution to DNMs, the YRI trio does not. But, both of the trios do suggest a lower mutation rate than found in previous studies which inferred the value from species divergence. Here is the portion which is relevant for human evolution: “These apparently discordant estimates can be largely reconciled if the age of the human-chimpanzee divergence is pushed back to 7 million years, as suggested by some interpretations of recent fossil finds.” I wouldn’t put my money on this quite yet, going by just this one study, but I’ve been hearing that this paper doesn’t come to this number in a scientific vacuum. Other researchers are converging upon a similar recalibration of mutational rates which might push back the time until the last common ancestor of many divergent hominoid and hominin lineages (including modern humans).

Moving the lens back to the present and of more personal genomic relevance:

Mutation is a random process and, as a result, considerable variation in the numbers of mutations is to be expected between contemporaneous gametes within an individual. If modeled as a Poisson process, the 95% confidence intervals on a mean of ~30 DNMs per gamete (as expected from a mutation rate of ~1 × 10−8) ranges from 20 to 41, which is a twofold difference. Truncating selection might act to remove the most mutated gametes and thus reduce this variation among gametes that successfully reproduce, however, any additional heterogeneity in stem-cell ancestry or environment (for example, variation in the number of cell divisions leading to contemporaneous gametes) would likely increase inter-gamete variation in the number of mutations.

Using the much smaller marker set obtained from 23andMe I found that two of my siblings are nearly 3 standard deviations apart in in identity-by-descent when it comes to the distribution of full-siblings. In the near future we might be able to ascertain the realized, not just theoretical, extent of mutational load across a family. As noted by the authors much of this might be a function of paternal age. Rupert Murdoch has children who are younger than many of his grandchildren, so there are many, many, “natural experiments” out there, as males are having offspring over 40 years apart.

On a societal level we may be able to estimate the exact cost in terms of public health costs of rising mean age of fathers. Personally we may also be able to note the correlations within families between high levels of DNMs and traits of interest such as intelligence and beauty. Compared to more fine-grained tools of ancestry inference I presume this is going to be dynamite. But it isn’t as if we didn’t know siblings varied before.

Citation: Donald F Conrad, Jonathan E M Keebler, Mark A DePristo, Sarah J Lindsay, Yujun Zhang, Ferran Casals, Youssef Idaghdour, Chris L Hartl, Carlos Torroja, Kiran V Garimella, Martine Zilversmit, Reed Cartwright, Guy A Rouleau, Mark Daly, Eric A Stone, Matthew E Hurles, & Philip Awadalla (2011). Variation in genome-wide mutation rates within and between human families Nature Genetics : 10.1038/ng.862

* In a random mating population the proportions are defined by the Hardy-Weinberg Equilibrium, p2 + 2pq + q2 = 1, so where q = 0.04, q2 = 0.0016 and 2pq = 0.0768. Heterozygote genotypes of CF outnumber homozygote ones 50 to 1.

Bloggy addendum: The first author of this letter is Don Conrad who is a contributor to Genomes Unzipped.

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So I’ve been seeing headlines like this today: Physicians Recommend Different Treatments for Patients Than They Choose for Themselves, Study Finds. Here are the numbers:

A total of 242 physicians returned the colon cancer questionnaire (response rate of 48.4 percent), and when asked to imagine they had received the cancer diagnosis, 37.8 percent of physicians chose the surgical procedure with a higher rate of death, but a lower rate of adverse effects. Conversely, when asked to make a recommendation for a patient, only 24.5 percent of physicians chose this option.

The second scenario asked 1,600 physicians to imagine that a new strain of avian influenza had just arrived in the U.S. One group of physicians were asked to imagine they had been infected, and the other group was asked to imagine that his or her patient was infected. One treatment was available for this strain of influenza: an immunoglobulin treatment, without which persons who contract flu have a 10 percent death rate and a 30 percent hospitalization rate with an average stay of one week. The treatment would reduce the rate of adverse events by half, however it also causes death in 1 percent of patients and permanent neurological paralysis in 4 percent of patients.

The avian influenza scenario was returned by 698 patients (response rate of 43.6 percent), and 62.9 percent of physicians chose to forgo immunoglobulin treatment when imagining they had been infected, to avoid its adverse effects. However, when imagining that a patient had been infected, only 48.5 percent of physicians recommended not getting the treatmen

I actually would have thought that the differences would have been stronger than they ended up being. My needle of trust in physician objectivity just went up! Though perhaps my expectation was a little too pessimistic.

• Category: Science • Tags: Health, Medicine 
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When Michelle mentioned on Twitter that she was going to write about circumcision, I told her to expect some angry people to come out of the wood-work. Today she has a post up at Scientific American, What’s the deal with male circumcision and female cervical cancer? She concludes:

In addition, while it is true that women with circumcised partners are less likely to get cervical cancer, they are not immune. Women with circumcised partners still contract HPV and develop cervical cancer! They just do it at a reduced rate.

There are other methods that are much more likely to reduce a woman’s chance of contracting HPV and developing cervical cancer, such as vaccination and condom use. Therefore, from a public health standpoint in the United States, it may not be necessary to circumcise male babies solely for the purpose of reducing the risk of cervical cancer in his future sexual partners (of course, this doesn’t take into account the possibility that the child might not be heterosexual).

On the whole I think that Michelle’s take is reasonable and fair-minded. But, I think numbers are of the essence here. What is the expected reduction in rate of risk? This was the major bone I had to pick with Jesse Bering’s post on this topic last year at Scientific American. Bering closes on a pro-circumcision note on public health grounds:

I started this piece with an open mind but I’ll close by putting my cards clearly on the table. For me, if one fully appreciates the scientific findings reported by these landmark studies with sub-Saharan African men, circumcision is the more humane decision. Some minor bloodletting today could spare that child unthinkable degrees of suffering tomorrow. Nobody knows where your child will live as an adult (perhaps Africa), or how rampant HIV will be there, or whether he’ll wear a condom every time he has sex with a stranger, or whether an infected, beautiful woman will cross his path on the day he forgets to tuck a condom into his wallet. Admittedly, my own “son” is a border terrier, but this issue is still a no-brainer to me. However, I’m well aware that male circumcision is a contentious topic for many people, some of whom, aghast, will make their opinions known to me in the coming days.

If I’m not being generous, I’d have to say that circumcising your son because he might live in Africa which might still have a rampant HIV epidemic 20-30 years from now, is kind of a stupid decision if grounded on probabilistic logic. After all the probabilities of the various outcomes contingent upon your priors matter. My future children will be raised in the United States of America. If male, they will likely be straight. They will probably middle to upper-middle-class. HIV rates vary a great deal by demographic category. I know I won’t allow my sons to be circumcised as infants. I don’t see the need, and I am familiar with the literature on the efficacy of mass circumcision in preventing the spread of sexually transmitted diseases in some environments.

But, if I lived in South Africa I might make a different decision based on the probabilities of my different environment. This is why I would dissent a bit from Michelle’s note that even women with circumcised partners can develop cervical cancer. Risk assessment, by its nature, should not be viewed dichotomously. To make proper decisions based on probabilities you need to take into account the magnitudes of all the risks.

• Category: Science • Tags: Circumcision, Health, Medicine 
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The figure to the left is a three dimensional representation of principal components 1, 2, and 3, generated from a sample of Gujaratis from Houston, and Chinese from Denver. When these two populations are pooled together the Chinese form a very homogeneous cluster. They don’t vary much across the three top explanatory dimensions of genetic variance. In contrast, the Gujaratis do vary. This is not surprising. In the supplements of Reconstructing Indian population history it was notable that the Gujaratis did tend to shake out into two distinct clusters in the PCAs. This is a finding you see over and over when you manipulate the HapMap Gujarati data set. In reality, there aren’t two equivalent clusters. Rather, there’s one “tight” cluster, which I will label “Gujarati_B” from now on in my data set, and another cluster, “Gujarati_A,” which really just consists of all the individuals who are outside of Gujarati_B cluster. Even when compared to other South Asian populations these two distinct categories persist in the HapMap Gujaratis.

Zack has already identified a major difference between the two clusters: Gujarat_A has some individuals with much more “West Eurasian” ancestry. To be more formal about this in the future I simply assigned individuals in my merged data set to one of the two Gujarati clusters based on their position in the first two PCs. Yesterday night I ran ADMIXTURE K = 2 to 10, with 75,000 SNPs. I also removed the Native American groups, and added more European and East Asian samples from the HapMap. Below are some populations at K = 4:

Let’s drill down to the level of individuals. Here are the Gujarati individuals, along with Sindhis, and my parents (Bengali). I’ve sorted by the “European” and then “South Asian” components (light blue and green respectively, while purple is modal in Papuans and red in East Asians):

The ADMIXTURE plots are in total alignment with the PCA. In the PCA Gujarati_A exhibit a spectrum of distance from the European cluster, and in the ADMIXTURE you see the same. In contrast, Gujarati_B is relatively uniform. So what’s going on? I will be posting something similar over at Sepia Mutiny soon. But my guess is that Gujarati_B are a subset of Patels. In other words, they’re a genetically distinct jati. I suspect that Gujarati_A are a more diverse bunch from a number of different jatis.

Does this matter? I believe it does. If Gujarati_B are a distinct ethno-social group which is a subset of Gujaratis, then they may not be as good a proxy for South Asian medical genetics as Gujarati_A. More concretely, Gujarati_B may have relatively high frequency rare disease alleles because they’re an inbred clan. In contrast, while Gujarati_A may exhibit all the hallmarks of South Asian endogamy, if they’re a larger number of different groups, then they’ll have all sorts of different rare alleles. The ones they have in common may be more generally South Asian.

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Randall Parker asks, Genetic Privacy And Identical Twins:

Suppose you have a right to genetic privacy. You might believe you do. Suppose you have an identical twin. Suppose the identical twin decides to publish his (or her) genetic sequence on the web. Do you have the right to stop this?

People who have identical genetic sequences each can get themselves sequenced and then release their genetic data for all the world to download and study. But when an identical twin does this another person also gets their genetic sequence released to the world.

So should twins be able to legally stop each other from publishing their shared DNA sequence on the web?

This is not a question that just applies to twins. As I noted earlier individuals share ~50% of their distinctive genetic material with their parents and full-siblings. I share ~12.5% with first cousins whom I have never met. If I just released my raw sequence by uploading it somewhere I would implicitly “expose” to a non-trivial degree dozens of people (many without their knowledge).

Of course all these issues were considered by the Genomes Unzipped gang. I think they’re right to judge the risks relatively low. Additionally, there’s nothing magical about genes. Family members can disclose all sorts of phenotypic information, in terms of disease, which would effect those whom they were related to. For example, imagine that an individual gets cancer, and decides to blog about their experience as a form of personal therapy. In theory*, perhaps insurance companies could data-mine the web for these weblogs, and then cross-reference with sites like Intelius and engage in “familial profiling,” assuming that the odds of cancer in the siblings of the blogger was higher than they had assumed prior. Could siblings sue the blogger to not make public their illness in a way that would make it easy for everyone to know of their possible likelihood of cancer? (to make this concrete, imagine we’re talking about breast cancer, and the woman is Jewish, so there’s a non-trivial chance of a BRCA mutation in her relatives) This seems absurd. To many the transparent society is a crazy idea on the face of it. But sometimes I think old ideas of “privacy” in an age of such free-flowing information really need to be revisited.

* In practice my understanding is that insurance companies engage in much coarser profiling, so there really isn’t much to worry about for 99% of people.

Razib Khan
About Razib Khan

"I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. If you want to know more, see the links at"