(here’s the context)

There’s been a recent uptick in interest in the genetic architecture of complex traits (by which I mean the allele frequencies and effect sizes of the relevant loci), some of which has been driven by a much-hyped recent paper from David Goldstein’s group pointing out using simulations that, as one commenter put it, “LD exists”. Though the main point of that paper, that “[associations caused by rare variants] are likely to account for or contribute to many of the recently identified signals reported in genome-wide association studies”, is almost certainly wrong (depending on what you mean by “likely” or “contribute to” or “many”), what is true is that there are alleles at low frequency in the population that contribute to disease risk for just about any disease. Another thing that’s true is that there are alleles that are common in the population that contribute slightly to disease risk, as shown recently in schizophrenia.

The way to go about identifying these loci is straightforward, and I’m pretty sure all geneticists would agree on this: with an infinite budget, you would sequence the genomes of every individual with the disease and every individual without the disease, and do a truly genome-wide association study–identify all the polymorphisms that differ in frequency between people who have the disease and the people who don’t.

The problem, and this is where tempers start to flare, is that obviously the budget isn’t infinite. So, there’s the choice between collecting a sample of N individuals and typing them on a SNP chip (which are currently very skewed towards assaying common variation, though the next generation of chips is somewhat reducing that skew), or collecting a sample of N/10 (or probably fewer, but let’s go with an order of magnitude for argument’s sake) and performing full-genome sequencing. Which do you choose? If you think the rarer variation is more “important”, you choose the latter, while if you think the common variation is more “important”, you choose the former. If we define importance as the proportion of variance in a trait explained, this choice is based on your prior beliefs about what the relevant parameters are for the genetic architecture of your trait of interest. Once the price of sequencing drops sufficiently, this question becomes moot, but for the moment there’s a choice, and we find ourselves in this situation: people have heated, vehement arguments about prior beliefs that seem to outsiders like real, heady scientific debate, but are really about getting funding for your preferred study design. In 20 years this debate will be of interest only to historians (and maybe the people that had to suffer through it); there’s no real contentious scientific question [1]

Personally, I lean slightly towards the common variation crowd, though not because I have a particularly strong feeling about it–bigger sample sizes are always better (or at least nice to have), and chips are covering rarer and rarer variation at a more-or-less fixed cost. But will cool things be found in the initial sequencing studies in smaller samples? Of course. It’s also important to note that sequencing studies are not a radical re-thinking of how to do disease genetics; they’re simply a more comprehensive way to do the exact same genome-wide association studies that people are doing now.

[1] There are some interesting scientific questions that could be answered by simply describing the genetic architecture of a trait (or perhaps more interestingly, comparing this across traits), but the volume of debate is probably not due to them.

On the basis of recent Genome-wide association research, a review by Plomin et al. (2009) predicts that, in line with R.A. Fisher’s reconciliation of Mendelian inheritance and quantitative genetics, investigations “on polygenic liabilities will eventually lead to a focus on quantitative dimensions rather than qualitative disorders”. Basically, they are proposing a shift in thinking: moving from medical diagnoses and towards a broader level of analysis using quantitative traits.

By doing this, we should begin to get a better understanding of pleiotropic relationships and quantitative traits. As the authors highlight using an example of fat mass and obesity (FTO):

Although medical diagnoses (such as obesity) provide a convenient pragmatic framework for the initial discovery of genetic variants, in scientific terms there are no real ‘genes for disorders’. On the contrary, the genetic variants that are implicated in complex traits are associated with quantitative traits at every level of analysis. Thinking and researching quantitatively will provide a much richer picture of the complex biological pathways that lead from genes to disorders and will help us to generate biologically meaningful models of disease aetiology.

They also discuss the possibility of using weighted sets of variants to predict the polygenic risk score, which refers “to the set of multiple DNA variants that are associated with a disorder”. From here, a particularly salient point is raised about the inherent limitations of traditional case-control studies: that the control subjects are normally chosen on the basis of them not having the disorder in question, even though their phenotypic score may be near to the actual cases. By this, they mean that if we characterise disorders in terms of quantitative traits, then on a normal distribution some members of the control group fall very close to the low-end tail. To enhance the statistical power of these studies, the authors propose two alternative risk distributions: either contrast both ends of the distribution (the actual cases versus what they dub as super controls) or assign each participant their own phenotypic score and then study the entire distribution (what I dub as ambitious).

Still, there are limitations to this approach, namely: “for most disorders, we do not know what the relevant quantitative traits are”.

Here’s the abstract:

After drifting apart for 100 years, the two worlds of genetics – quantitative genetics and molecular genetics – are finally coming together in genome-wide association (GWA) research, which shows that the heritability of complex traits and common disorders is due to multiple genes of small effect size. We highlight a polygenic framework, supported by recent GWA research, in which qualitative disorders can be interpreted simply as being the extremes of quantitative dimensions. Research that focuses on quantitative traits – including the low and high ends of normal distributions – could have far-reaching implications for the diagnosis, treatment and prevention of the problematic extremes of these traits.

Citation: Plomin, Haworth & Davis. Common disorders are quantitative traits. Nature Reviews Genetics, 2009; 10, 872–878. DOI: 10.1038/nrg2670.

Hat-tip F1000.

We’ll never have utopia. A world in which in many nations it is normal for the poor to be fat is, is a utopia by any measure from the perspective of someone who lived in 1900. Prompted to think about this after listening to part of this diavlog between a transhumanist and Massimo Pigluicci. Sometimes I think the ideal futurist wold be someone with a background in evolutionary biology, economics/economic history and engineering.

Heartthrob’s Barbed Blog Challenges China’s Leaders:

Since he began blogging in 2006, Mr. Han has been delivering increasingly caustic attacks on China’s leadership and the policies he contends are creating misery for those unlucky enough to lack a powerful government post. With more than 300 million hits to his blog, he may be the most popular living writer in the world.

In a recent interview at his office in Shanghai, he described party officials as “useless” and prone to spouting nonsense, although he used more delicate language to dismiss their relevance. “Their lives are nothing like ours,” he said. “The only thing they have in common with young people is that like us, they too have girlfriends in their 20s, although theirs are on the side.”

It looks like internet usage in China may be reaching 400 million soon. This may seem a bit of a stretch, but I wonder if someone such as Han Han might be viewed as an heir to the long tradition of Confucian scholars who serve as outsider critics against Imperial regimes they deemed morally unfit.

Did not know this:

Still, these platonic tickle sessions appear to be rare. Based on a survey he conducted for his fascinating book Laughter, neuroscientist Robert Provine notes that adults and adolescents are seven times more likely to be tickled by members of the opposite sex. When asked whom they would most like to be tickled by, there was a fifteenfold disparity. Provine also notes that “the Dutch word for clitoris is kittelaar, ‘the organ of being tickled or titillated.’ ” The Internet is littered with tickle fetish sites.

…

Nevertheless, Robert Provine notes that history and mythology tell tales of death by tickle. The Leshii, a Russian fairy-tale monster, abducted peasants and tickled them to death. The Rusalka, drowned maidens of Ukrainian lore who populate inland waterways, tempted bypassing bachelors and delivered fatal tickle attacks. Real-life Prince Vlad—yes, that Vlad—of Transylvania may have tortured victims by dripping salty water onto their feet and letting goats lick it off. English rebel Simon de Montfort reportedly tickled opponents to death with a feather, and an Anabaptist sect uncomfortable with bloodshed is also alleged to have used the method. Provine suggests one possible mechanism for death-by-tickle: “The sustained, uncontrollable laughter and struggling of the victim may cause cardiac arrest or cerebral hemorrhage.”

There’s a lot more to tickling than I thought!

I’ve already linked to this blog on ScienceBlogs, but I thought I might as well point to it from here. Check out The Oscillator, every entry is dense with science. The focus in synthetic biology. I wanted to see if there’d been a mention of Craig Venter’s synthetic bacteria project, but the the search box doesn’t yield anything. Perhaps that’s information in and of itself. One can’t put this in the ALH84001 category since Venter’s produced some real science out of the project already, but it has a Friedman Unit feel. Though I assume that there wouldn’t be hype around the synthesis if they didn’t perceive themselves really close, I have noted that Venter said “by the end of the year” in the summer of 2009. And to be fair, the quote is from a British periodical, and they’re not always reliable (no offense Brits).

Update: Carl Zimmer asks:

And he performed the first genome transplant and figured out how to make yeast churn out entire genomes of bacteria If this is limbo, it’s a pretty productive place to be. If Venter does manage to pull this project off in 2014, will history really care much that he was off by 5 years?

My response: No. But if he keeps saying it’ll happen “this year” until he gets it done in 2014, that should reduce our confidence that he can get it done between this date and that date. In fact, it should reduce his own confidence too I would think if he’s being sincere, since it indicates that his model at any given moment of what’s going on has serious holes which he can’t account for.

Though to make a fully informed guess on this sort of thing we should probably look at historical precedents for paradigm shifting science & engineering like this. Getting to the moon. Nuclear power. Economically viable nuclear fusion. The human genome project.

One of the major shifts in thinking about language came in 1990, when Steven Pinker and Paul Bloom published their groundbreaking paper: Natural language and natural selection. In it, they argue natural selection was the central process in shaping the biological structures underpinning language. Since then, the field of language evolution has blossomed into a truly multidisciplinary subject. Yet now, I believe we are in the process of undergoing another paradigm shift: incorporating cultural evolution.

For some features, particularly the physical capacity to produce and receive multiple vocalizations, there is ample evidence for specialisation: a descended larynx, thoracic breathing, and several distinct hearing organs. Given that these features are firmly in the domain of biology, it makes intuitive sense to apply the theory of natural selection to solve the problem: humans are specially adapted to the production and reception of multiple vocalizations. Yet Pinker and Bloom’s argument is found somewhat wanting when extended to incorporate the notion that natural selection shaped specialised mental organs, or modules, for acquiring language. First and foremost, the notion of a putative language acquisition device (commonly referred to as LAD) is not an established fact: rather, it’s derived from Noam Chomsky’s arguments from the poverty of the stimulus (POTS) and assumptions that all languages are essentially the same in structure, but differ in their sound systems and vocabularies.

As such, under the stewardship of Pinker, Chomsky and others, the origin, evolution and acquisition of language is primarily seen as a biological question to be answered. Whilst it is certain that biology plays a role in the evolution of language, its exact purpose is still contentious in light of new research emerging from theories into cultural evolution. A notable instance came at the 2009 CogSci conference, where some of the leading researchers into the cultural evolution of language met up at a symposium, namely: Nick Chater (philosophy), Thomas L. Griffiths (Bayesian analyses), Simon Kirby (evolutionary psycholinguistics) and Morten H. Christiansen (molecular genetics). Each of these individuals are key influences on my own thinking in regards to language evolution (Simon Kirby was formerly my course supervisor at Edinburgh), and I think it is worthwhile to dedicate a few paragraphs discussing their ideas.

Read more…

Given this is my first post on GNXP I guess the first place to start is with a brief background: my main areas of study are focused on language, evolution and anything else unfortunate enough to find itself in between. Over the last year much of my time was spent at Edinburgh University, where I graduated with an MSc in the Evolution of Language and Cognition. More recently, however, I’ve found myself focusing on gene-culture co-evolution, cumulative culture and demography. So I suppose my role at GNXP will largely involve me expounding upon all these areas of research – something I’ll begin fairly soon. Until then, here’s an abstract of a very interesting paper I read this morning on nonhuman vocal learning in Bengalese Finch:

Humans learn to speak by a process of vocal imitation that requires the availability of auditory feedback. Similarly, young birds rely on auditory feedback when learning to imitate the songs of adult birds, providing one of the few examples of nonhuman vocal learning. However, although humans continue to use auditory feedback to correct vocal errors in adulthood, the mechanisms underlying the stability of adult birdsong are unknown. We found that, similar to human speech, adult birdsong is maintained by error correction. We perturbed the pitch (fundamental frequency) of auditory feedback in adult Bengalese finches using custom-designed headphones. Birds compensated for the imposed auditory error by adjusting the pitch of song. When the perturbation was removed, pitch returned to baseline. Our results indicate that adult birds correct vocal errors by comparing auditory feedback to a sensory target and suggest that lifelong error correction is a general principle of learned vocal behavior.

If you noticed my highlighted section then, yes, I do have a picture of said headphones, stylishly modelled by Ben Finch:

Besides the picture, the paper’s well worth reading for those of you interested in language-learning and its relationship to song-learning in Finches.

Citation: Sober & Brainard. Adult birdsong is actively maintained by error connection. Nature Neuroscience, 2009; 12 (7): 927-932 DOI: 10.1038/nn.2336.

According to this survey done by Zogby International. The numbers:

42% Muslim
9% Christian
6% Jews
5% Zoroastrian
7% Bahai
31% “Other” (the pollsters presume this is mostly those with “No religion”)

The sample size was small, only around 400. And it seems really strange that there was a religious option for “Other” but not “No Religion,” but perhaps the pollsters simply weren’t expecting that so many people wouldn’t select the religion of their cultural tradition. I was surprised by the low proportion of Jews (several Persian American actors are Jewish), and high proportion of Zoroastrians. Of course Zoroastrians emigrated in large numbers, but their population base in Iran itself wasn’t that huge to begin with, European ethnographers were shocked to “discover” that they were still a living community in the 19th century (part of this was that they isolated themselves in remote areas to escape Muslim persecution). One hypothesis: some Iranian Americans identify as Zoroastrian to reassert their Persian cultural heritage even if they are from traditionally Muslim families (this has happened in Tajikistan somewhat, though only among intellectuals, as secularization during the Soviet period made it psychologically feasible for some to simply “leap-frog” the Muslim period back to their presumed primal identities).

Obviously Iranian Americans are very different from people in Iran. Americans sometimes assume that the anti-clerical attitude of many Iranians indicates a general anti-religious stance, but this is not evident in The World Values Survey. 16% of Iranians consider themselves “not religious” while 84% consider themselves “religious.” 0.1% were convinced atheists, out of a sample size of ~2500 (survey taken in 2005). As a comparison in Turkey 16.9% are “not religious” while in Egypt it is 7.5%. For a Middle Eastern country Iran is actually relatively on the secular side, but only for a Middle Eastern country.

Of course there is no reason that the demographics of an immigrant community would represent well that of the source region. An enormous proportion of people whose ancestors came from the Russian Empire were Jews. Arab Americans in the United States are much more likely to be Christian or other religious minorities (Casey Kasem is Druze). Until recently the rule-of-thumb has been that a majority of Arabs in the United States are Christian, not Muslim, but I suspect that is no longer true. Many people of part Arab heritage (e.g., the 1980s pop singer Tiffany) may no longer identify as Arab (and Christian Arabs seem to have had high outmarriage rates), and the recent immigrant waves have been much more Muslim in composition (this makes some sense since there simply aren’t that many Arab Christians left in the Middle East, though numerically the Copts are still substantial because of Egypt’s large base population).

A final note on Iranian Americans: did the high frequency of those with no religious affiliations emerge in the United States, or was that due to the selection biasing of the Iranian migrants? One can imagine that Iranian Communist intellectual contingent may have been irreligious, but I would assume that educated Iranians would generally have had a nominal religious affiliation to begin with. But with the option to defect in the United States, combined with a secular reaction to make themselves distinctive from the Iranian theocracy, I suspect that the generation born or raised in the United States had less use for adherence to a cultural Islam. In other words, the extent of Iranian American secularity may be as contingent as the prevalence of Latoya face & small-dog ownership among female Tehrangelinos.

(other interesting, if unsurprising, data at thePDF)