Epigenetics, the glory and the hype

Epigenetics is real. But it doesn’t change everything. That needs to be said, because people seem to get the impression that everything is changed. In Trends in Genetics, Serving Epigenetics Before Its Time:

Society prizes the rapid translation of basic biological science into ways to prevent human illness. However, the premature rush to take murine epigenetic findings in these directions makes impossible demands on prospective parents and triggers serious social and ethical questions.

In their efforts to anticipate the eventual human applications of emerging areas of science, scholars of the ethical, legal, and social implications of genetics and genomics sometimes become too speculative to engage the immediate concerns of active scientists and policymakers. However, although evidence-based applications of human epigenetics may emerge in the future, premature epigenetic risk messaging is already here and its content and impact must be understood. The messages in circulation raise ethical and social concerns regardless of whether human epigenetic studies eventually confirm the murine results. Because the prospect for any successful human translation of epigenetic research depends as much on the management of these issues as on further human studies, they deserve close attention by all involved in their design, dissemination, and public consumption.

(the link is ungated)

Dissenting from American liberalism & conservatism

854270_w185I had a long discussion yesterday with an individual who has been reading me since 2003. We talked about lots of things. One issue which perhaps I need to reiterate because it’s implicit is that I dissent to a great extent from the premises which underlay both American conservatism and liberalism. Like American liberals I think the life outcomes of many Americans are not due to their choices simply understood. Rather they are the outcome of chance events, whether it be through social background, or, simple happenstance. Years ago I recall Nassim Taleb complaining that people would read The Millionaire Next Door, and believe that by doing everything those individuals did they too could become millionaires, as if there was no random component to such outcomes. The reality is that some people are in the right place and right time. And, some people are born in the right social positions.

Where I dissent from American liberals is the idea that all of the outcomes in our society, in particular inequality, are due to chance or inherited social position (e.g., race or class privilege). In The Son Also Rises Greg Clark reports on intriguing results which indicate that social competence in heritable. To some extent this is common sense. Personal dispositions are heritable, and some dispositions are more congenial to remunerative activities than others. Though many on the Left (though not all) are willing to acknowledge the arguments in Steve Pinker’s The Blank Slate in the abstract, in the concrete they get very little weight when it comes to social policy. To give an example, for many on the Left we can talk about differences between groups (whether it be cultural or biological) only when all social inequality is abolished. The catch in this though is that any persistent differences may also result in persistent social inequality or difference in outcome.

The_Blank_SlateWhen it comes to the American Right there are two distinct strands. The first is the child of classical liberalism, to some extent in a more thorough fashion than the American Left. For this element the pidea that capitalism is efficient in allocating resources, and that people receive their just desserts due to hard work, becomes such an all-encompassing narrative that other variables are neglected. This was clearly evident in 2008 when some conservative libertarians kept harping on the “free market” mantra because they literally had no other playbook. I recall specifically someone from the American Enterprise Institute on the radio arguing that bankers should keep their bonuses because that’s how capitalism works, even after the bailouts. When confronted by this he really had no response. He was literally dumbfounded. It is as if the market was the ends of the American political system, and all wealth is the product of the market. Though not as constitutionally hostile to the idea of heritable differences this sort of free market conservatism is not comfortable with the idea that not everyone is born with the same opportunities. The reality is that the liberal Left critique of the nature of the outcomes of a free market is correct in some deep sense, even deeper than American liberals may wish to acknowledge. Some people are born with the genetic deck stacked against them, not just the social one (and of course, as noted above there is a lot of random noise). That undermines some of the moral case for the virtue of the market, since it is not blindly arbitrating the outcomes of our choices, as opposed as sifting based on the accumulated weight of inherited history, some of which is due to the genetic lottery.

51RtznSRTALThe second strand in American conservatism is that of the Religious Right. The problem that it has is most clearly illustrated by the issue of gay rights. Though logically toleration of homosexual behavior and its innate or non-innate nature are not related, the Religious Right prefers that homosexuality be a choice for the purposes of moral censure. That is because though these Christians believe in original sin, they seem to espouse a sort of moral perfectionism where all men are equally endowed with the same sentiments and preferences (those sentiments being debased by Satan or the Satanic influence of culture). As opposed to Homo economicus, these Christians believe in Homo christianus. Though I personally espouse the bourgeois virtues of the Religious Right, their neglect of human diversity in disposition and sentiment leads us down the path of great disappointment, as many will miss the mark. A Religious Right which focused more on social cohesion in a general and collective sense, rather than personal and individual moral perfectionism, probably could produce better results (yes, it does take a village!). But the American radical Protestant model is fundamentally individualistic, and treats each human as equal and similar before Christ. And there I believe is the folly with moral crusades which attempt to turn every American family into the same American family. Such a world never was, and such a world will never be.

The Left looks to the perfect future which could be. The Right looks to the perfect past which was, and could be.

Against contingency (in yeast traits)

Quanta Magazine has a piece up audaciously titled Evolution’s Random Paths Lead to One Place. It’s basically a review of the research published in the paper Global epistasis makes adaptation predictable despite sequence-level stochasticity. There’s a lot packed into the title. Here’s the important bit from Quanta:

Many biologists argue that it would not, that chance mutations early in the evolutionary journey of a species will profoundly influence its fate. “If you replay the tape of life, you might have one initial mutation that takes you in a totally different direction,” Desai said, paraphrasing an idea first put forth by the biologist Stephen Jay Gould in the 1980s.

The findings also suggest a disconnect between evolution at the genetic level and at the level of the whole organism. Genetic mutations occur mostly at random, yet the sum of these aimless changes somehow creates a predictable pattern. The distinction could prove valuable, as much genetics research has focused on the impact of mutations in individual genes. For example, researchers often ask how a single mutation might affect a microbe’s tolerance for toxins, or a human’s risk for a disease. But if Desai’s findings hold true in other organisms, they could suggest that it’s equally important to examine how large numbers of individual genetic changes work in concert over time.

There’s been a vogue of late for attacking the utility of mouse genetics for medical research. Perhaps studying flies, yeast, and bacteria to understand evolution is also misguided? Interesting research in any case.

The Islamic States

"Chop-chop square" in Riyadh
“Chop-chop square” in Riyadh
Like Joe Young, the Mormon missionary who becomes involved in the porn industry in the late 90s film Orgazmo, our involvement in the Mid-East is probably going to result in the violation of our purity (yes, that’s only in our self-conception as a nation; we’re mostly definitely only born-again virgins, not the real deal). It’s hard to read anything about the Free Syrian Army which portrays it as anything but hapless, disorganized, if often well meaning and milquetoast (well, when they’re not allying with the Nusra Front and being nasty to Alawites and Christians who support the regime which has been nasty to them). And of course this edition of the coalition of the willing involves our stalwart Western-leaning allies, Bahrain, Jordan, Qatar, Saudi Arabia and the United Arab Emirates. Yes, Bahrain, the sectarian regime dominated by a religious minority which suppresses the majority with foreign forces. Qatar, the Islamists’ number one ally in the Muslim world. The UAE, which is home to the dystopian techno-oligarchy that is Dubai, a glittering vision of the apotheosis of slavery coexistent with post-modernity. And of course there is Saudi Arabia, the only nation in the world which regularly decapitates individuals for capital crimes. Well, except of course the Islamic State if you count that as a state!

I won’t belabor the point. Let’s remember that the Saudi monarchy is quite notably medieval in its practices and institutional arrangement (it abolished slavery in the 1962). Our enemies, Iran, and the Syrian regime, are actually much closer to modernity as we’d understand it using the Saudis as the extreme case. As it is we have to ignore this because the Saudis are our bastards, neo-feudal creeps though they may be. And we’re trusting them to help train the Free Syrian Army? Of the 19 9/11 hijackers 15 were Saudi (a further two were from the UAE, our ally). This is not going to end well. We can’t admit that we’re helping the regime of Bashar al-Assad. Yes, he’s a murdering bastard, but he’s not our bastard.

The Islamic State is a nasty piece of work. Unlike Saddam Hussein’s late lamented dictatorship it also has the ability and ambitions to spread its tentacles of nastiness across the region right now. I won’t shed any tears over the pounding Raqqa is receiving from American cruise missiles. But let’s be clear that almost certainly this is going to benefit our Iranian enemies, as well as Hezbollah. Additionally, the Saudis and their Gulf allies will probably attempt to reshape the Sunni insurgency in their own image, which is not one which we in the West would term “moderate,” let alone free. Let’s go into this with eyes open, and acknowledge that it’s a choice between a bad option, and a worse option.

Shorter: America is on the side of the less evil guys. Go America! Also see this cri du coeur, The Barbarians Within Our Gates.

The end of the middle class era

51TpAsC5UlL._SY346_FiveThirtyEight and New York magazine have pieces which look at the prosperity which was the norm in the second half of the 1990s with a soft glow. I was not in the labor market back then, but I recall the excitement, and just how easy it was to get a job for those who wanted one. It seems that these articles reinforce the basic thesis of Tyler Cowen’s Average is Over, looking back to the last golden age for the middle class.

But there’s another angle on this. Would you go back to 1999 if you had twice the income you did today? Probably that depends on your income. But imagine going back to the technology of that era. For many of us the world would be a sluggish and gray place. Cowen would point out that this is not the typical person. But it’s a lot of us, and it isn’t as if smartphones and their various features are low penetration technologies in terms of cultural ubiquity. So a simple apples to apples comparison of income is somewhat misleading. Because of rising demand from China I’m not sure that decreasing expenditures on food is sustainable (though perhaps better GMO would help in that domain). But it does seem to me that public policy is what’s keeping housing prices high, in particular in Blue State urban areas. Make the libertarians happy by getting ridding of rent control. Make the conservatives happy by allowing more sprawl. Make the new urbanists happy by allowing more vertical residential housing.

I think the bigger issue here is not economic, but social. Economic productivity is such that a guaranteed minimum income is probably viable for society. A minority may work so that the majority may eat and recreate. But human psychology is such that it seems implausible that a democratic citizenry can be maintained by passive consumption by those who themselves are not economically productive. Many of these discussions about the passing of the middle class society focus on economic well being, or lack thereof. I don’t think that’s the major issue at all, because economic productivity will continue to increase, at least on the margins, and population growth outside Africa has tailed off. Rather, the larger change will be cultural and social. Even in antiquity when societies were highly stratified the great thinkers understood that social well being rested upon the broad shoulders of the free peasantry, who were the ultimate source of most economic activity. This is very different from the model of stratified societies of the future, where both power and productivity will be concentrated nearer the top of the status distribution.

ASHG 2014, Razib’s fun times (hopefully)

10703498_10102824483928421_3532479251264917335_n (1)
In the Big Apple
I’m very excited to be going to ASHG this year. The last time it was great meeting people like Luke Jostins‘ for the first time (and re-meeting people for the second or third time).  Also, the posters and talks gave a preview of things which came out later in the year, so the cost of attendance was certainly worth that. I dig genetics.  This time I’m going to be in San Diego, a city that I’ve never been to. Excited to explore a little if I have time. Though despite what I’ve said on Twitter I am not going to Tijuana. But speaking of fun, if any reader knows of after hours parties, etc., I’d appreciate it if you’d hook me up. I’m actually a kind, gentle, and fun person in real life who is not a bad dancer (people seem to think I’m mean and brusque from my internet persona; this has been brought up to me by several people after they’ve met me).

Below are the sessions, etc. I’ll be going to if anyone wants to try and assassinate me in broad daylight (that’s a joke, not an invitation).

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The future is coming despite the hype

Credit: A friend of Razib

I’ve been avoiding focusing too much Oxford Nanopore over the past few years. Privately I do ask people smarter than me/”in the know” if they think that the technology is the real deal. The reason for my skepticism is that I remember people being hoodwinked by Pacific Biosciences in 2008. Part of the issue is that biologists want these technologies to deliver, so there’s a bias in terms of how they’re going to be received.

That being said I saw some Nanopore machines recently. I knew they were small. In fact, rationally I knew how small they were. But when they were just there on the counter, like large USB drives, it was hard to take it in. The new Illumina machines aren’t very large. They’re mini-fridge scale. But to see a sequencing machine which you might actually step on by mistake was a bit mind-blowing. It’s as if we’re going from 1970s mainframe technology, where it took up a whole room, to the smartphone era, where a computer fit in your back pocket.

I don’t know if Oxford Nanopore will succeed. But it seems obvious, viscerally so, that someone will, and that we’ll have small portable sequencers which are quite accurate and will generate long reads by 2020. That’s a revolution, but by then we’ll probably take it for granted. Then we can forget about the technology, and focus on the biology and what to do with all the data.

Standing variation, polygenic traits, & soft selection

Brawand, David, et al. "The genomic substrate for adaptive radiation in African cichlid fish." Nature (2014).
Brawand, David, et al. “The genomic substrate for adaptive radiation in African cichlid fish.” Nature (2014).

A new paper on cichlid evolutionary genetics in Nature is pretty interesting. It’s open access, so everyone can read it, The genomic substrate for adaptive radiation in African cichlid fish:

Cichlid fishes are famous for large, diverse and replicated adaptive radiations in the Great Lakes of East Africa. To understand the molecular mechanisms underlying cichlid phenotypic diversity, we sequenced the genomes and transcriptomes of five lineages of African cichlids: the Nile tilapia (Oreochromis niloticus), an ancestral lineage with low diversity; and four members of the East African lineage: Neolamprologus brichardi/pulcher (older radiation, Lake Tanganyika), Metriaclima zebra (recent radiation, Lake Malawi), Pundamilia nyererei (very recent radiation, Lake Victoria), and Astatotilapia burtoni (riverine species around Lake Tanganyika). We found an excess of gene duplications in the East African lineage compared to tilapia and other teleosts, an abundance of non-coding element divergence, accelerated coding sequence evolution, expression divergence associated with transposable element insertions, and regulation by novel microRNAs. In addition, we analysed sequence data from sixty individuals representing six closely related species from Lake Victoria, and show genome-wide diversifying selection on coding and regulatory variants, some of which were recruited from ancient polymorphisms. We conclude that a number of molecular mechanisms shaped East African cichlid genomes, and that amassing of standing variation during periods of relaxed purifying selection may have been important in facilitating subsequent evolutionary diversification.

Reading a paper like this makes it very clear to me why organismic information is very critical in trying to understand evolutionary processes. R. A. Fisher was a great scientist, but his attempt to create very general rules for evolutionary processes as outlined in The Genetical Theory of Natural Selection seems quixotic in hindsight. As a professor of mine once said “biology is the science of exceptions.” This is probably one reason that the old 19th century vogue for creating “laws” went into decline; laws are useful only when the exceptions to them are very few. The diversity and specificity of evolutionary biological processes is why I think arguments in the form of dichotomies are in vain. For example, “selectionists vs. neutralists” or those who argue for the primacy of contingency in evolutionary outcomes, or those who favor convergence toward deterministic outcomes. It strikes me that the answer to all these questions must be predicated by the phrase “it depends….”

electr10The story of African cichlids is relatively well known. You have a huge range of phenotypic outcomes which seem to be the result of relatively recent diversification. Not only that, but cichlids look cool. The question though is what can this tell us about evolution? The paper does a lot of genomic slicing and dicing of a few select lineages. Before we knew about genes the nature of transmission in evolution was something of a black-box. With DNA that changed, and now with genomics we can look at how various features differ across lineages and over time. For example copy number variation, coding regions, regulatory elements, and characters more abstruse to those outside of genomics, such as LINEs. Sequencing a bunch of cichlids gets you a publication in Nature, but that’s not the point of it all. The point is what does it tell you about evolution, at least in this case?

Basically it seems that cichlid radiation has occurred due to selection on the natural genetic variation across many loci that already existed in the ancestral lineage. It was easy enough to type, but in some ways this reality is a bit difficult, in that classical models of selection were often predicated on new mutations emerging in the genetic substrate, and rapid sweeps to fixation from the original mutant form. A human illustration of this is lactase persistence, which seems to be due to a change in gene regulation via a new mutation that arose ~5,000 years ago, and quick swept to near fixation across many diverse human lineages. This sort of phenomenon is like striking a hammer at the genome; it leaves a big mark which is easy to detect. In contrast to hard selection, soft selection on standing variation operates across many loci, and rather than a novel genotype in a singular sense produces a change in underlying allele frequencies. In some ways this is more classical Darwinian, but it also generates more work and is not as elegant as a simple model of a hard sweep from a new mutation. But that’s just how it is. At least in the cichlid lineage.

41SWwcvSm6L._SX258_BO1,204,203,200_Actually, I suspect that’s how it is in many complex organisms. For a human illustration, see The Genetics of Human Adaptation: Hard Sweeps, Soft Sweeps, and Polygenic Adaptation. I’m betting that it’s also the norm among our many domestic animals. For example rabbits. A few years ago at a conference Claire Wade reported that the focus on traits and genes with disjoint distributions across dog breeds had obscured the reality that much of the variation in this lineage is still shared, and there is probably a lot of soft selection on polygenic traits going on.

So the near future is in quantitative traits, and natural selection reshaping the variation which is already present in lineages. Perhaps people should start re-reading Genetics and Analysis of Quantitative Traits. And as a weird side effect, if I was interested in such things I bet that the emphasis on selection from standing variation probably supports philosophical monism. All is one. Or something.

More than bread & water

As you all know by now the eligible electorate of Scotland has voted “No”, against independence. At least 55 percent has. I think that the fact that this has occurred relatively peacefully and in a civilized manner should be edifying to all. Though I do not have great passion on this subject, I am broadly sympathetic to separatist movements within the European Union, as it strikes me that the existence of the European Union itself obviates many arguments for the gains of being part of a larger nation. Scotland though differs from the Catalans in that the United Kingdom is not part of the Euro, and the claims by the Scottish independence camp as to their ability to remain with the pound did strike me as disingenuous. In fact, I found the “Yes” camp ludicrous in terms of their economic arguments, and the “No” camp quite sensible and conservative in the literal sense. I am not particularly sympathetic to social democracy, and much of the pro-independence elite seems to have been arguing that their goal was to transform Scotland into a Nordic welfare state. But economists more sympathetic to the welfare state are also confused as to the cost vs. benefit calculation.

The issue here is that sometimes a cost vs. benefit calculation is not the point. The global elite, high earning cosmopolitans extracting incredible gains from free flow of capital, goods & services, and people, feel the modern nation-state to be simply a device which exists to enact and execute laws which can serve as a framework for the free market. In other words, the nation is a means toward economic welfare. From that perspective Scottish independence seems irrational. But the average Scot is not a part of the global elite. Of course the pensioners and much of the middle class seems to have voted against independence, so one can’t assert that resistance to separatism is just a feature of the wealthy elites. But it does seem likely that a larger proportion of those who voted “No” were voting to keep what they have, rather than looking toward future gains. It wasn’t passion or enthusiasm, but prudence. A bourgeois virtue, which has its points.

But a nation is more than the sum of utils. Would anyone ask that soldiers should sacrifice their lives for productivity gains? Should Britain have yielded to Germany in 1940 because of rational calculations? Or more to the point should the Scots have bowed down before bourgeois, when it seems clear that the odds beforehand were against them? What the global elite seems to not comprehend when facing ‘irrational’ nationalism is that their opponents do not share their premises. In the developed nations of the West there is a sense of ennui due to the lack of motivating spirit. The goal of economic well-being above and beyond basic needs has long been met. Now it is on to the bigger house, the bigger car, and so forth. This rush toward competitive consumption results in short term happiness, but it is often ultimately empty. The cosmopolitan elites may be wealthy in money, but they are also often wealthy in life satisfaction because of the nature of their careers, and the experiences which they can indulge in. They do not comprehend the vacuousness of the lives of the middle to lower classes, because they live lives with verve and excitement. But at some point they will have to face the reality that the 90 percent do not exist purely as means to the ends of the 10 percent. If a system is not sustainable, it will not be sustained.