Functions oh so random

adaptivelandscape150 years after Charles Darwin’s The Origin of Species there are many open questions in evolutionary biology. For example I have been wavering between the possibility that on the molecular genomic scale evolutionary process is predominantly neutral and stochastic, and a new possibility that selection is pervasive (a new possibility that is actually old). The nice aspect of this area of study today is that empirical data can be brought to bear upon ancient arguments. Previously the dialogues were fruitless in terms of actually resolving opposing viewpoints, as interlocutors dug into their presuppositions, and the same theoretical paradigms flew through data free debates.

One area where this was clear was in relation to the of whether evolutionary process is deterministic or stochastic on the most general level. More prosaically, is evolution an experiment which one can broadly reproduce genetic and functional outcomes over and over? Stephen Jay Gould was the most famous proponent of the position that evolution is not a reproducible experiment. Rather, it is a contingent historical process. You can’t rewind the clock and expect the result to resemble what came before. In contrast Richard Dawkins has tended to defend the stance that there are broad inevitabilities as evolution explores the adaptive space of possibilities (see The Ancestor’s Tale for his detailed position). Over the past few years Joe Thornton’s lab has been looking at this issue by examining the evolutionary genetic trajectory of steroid receptors. This may seem abstruse, but obviously these are functionally significant, and, they’ve been able to utilize ingenious biophysical methods to “rerun” evolution. The general conclusion seems to be that steroid receptors as we understand them are subject to path dependence in a fashion where the outcome is sensitive to unlikely sequences of mutations.

The group now has a paper in Nature, Historical contingency and its biophysical basis in glucocorticoid receptor evolution (ungated). Let me jump straight to the conclusion:

If evolutionary history could be replayed from the ancestral starting point, the same kind of permissive substitutions would be unlikely to occur. The transition to GR’s present form and function would probably be inaccessible, and different outcomes would almost certainly ensue. Cortisol-specific signalling might evolve by a different mechanism in the GR, or by an entirely different protein, or not at all; in each case, GR—or the vertebrate endocrine system more generally—would be substantially different. Because GR is the only ancestral protein for which alternative evolutionary trajectories to historically derived functions have been explored, the generality of our findings is unknown. The specific biophysical constraints, and in turn the degree and nature of contingency, that shape the evolution of other proteins are likely to depend on the particular architecture of each protein and the unique historical mechanisms by which its functions evolved.

170px-Type_C_OrcasThe issue about generality is important. Read the whole paper and you’ll be struck by the level of experimental detail that went into making the inferences they arrive at. There’s a reason that these papers get into glamour journals. But is this just a story about a particular class of proteins, or the story of evolution writ large? When molecular evolutionary neutralism became ascendant in the 1980s some responded that though stochasticity might dominate on the sequence level of A, C, G, and T, there was no such randomness when it came to morphology. The power of this argument seems most evident when it comes to the body plans of some metazoans which are clearly dictated by the laws of physics. Marine mammals have evolved toward a morphology which has clear parallels with that of species of the fish lineage which occupy the same niche. Similarly, the elephantine legs of ancient sauropods were no coincidence. As land animals become large their massive bulk becomes unwieldy for more gracile body plans, and there is a tendency toward stout builds, as the cross-section of bone and muscle attempts to race up to the massively increased volume and mass.

The same tension seems to be at play in these sorts of results, which focus on the contingencies of a specific piece of biological machinery. Is there only one way to construct a particular a component due to biophysical constraints? Perhaps. But what does this tell us about the construction of the whole organism, which is the stitching together of innumerable biomolecular parts? In science fiction is not peculiar to imagine worlds where gross morphology is broadly recognizable, but none of the organisms are edible to humans because of divergences in biochemistry. Ultimately as implied in the paper above other groups have to reproduce this sort of work on other families of proteins to see how ubiquitous contingency really is.

The New York Times needs to hire geography bee contestants

dysm

The above map accompanies an article titled Imagining a Remapped Middle East. Do you notice something off? I do. Here’s a list of the provinces of Iraq. Do you notice any that end in -stans? No. Here’s why, -stan:

The suffix -stan (Persian: ـستان‎ -stān) is Persian for “place of”[1] or “country”.[2]

The suffix also appears in the names of many regions, especially in Central and South Asia, but also in the Caucasus and Russia; areas where significant amounts of Persian culture were spread or adopted. The suffix is also used more generally, as in Persian and Urdu rigestân (ریگستان) “place of sand, desert”, Pakistan “land of the pure” and golestan (گلستان) “place of flowers, garden”, Hindi devasthan (“place of devas, temple”), etc.

It’s obviously Indo-Iranian; note Rajasthan. Therefore it is bizarre to label a region as “Wahhabistan“. To make it clear for readers “Wahhabistan” is in Saudi Arabia, which is an Arab land, and Arabs don’t use any such suffix. The usage of that suffix connotes areas of Persianate cultural hegemony, which has often included non-Persian regions such as Turkestan and Hindustan (i.e., the Turkic and Indian cultural domains). But not Arab ones. There is a term “Arabistan”, but it means “land of the Arabs” in Persian. Wahhabistan, Shiitestan, and Sunnistan might make sense if the cartographer was Iranian. But that seems strange in an American publication, to be presenting an Iranian-centric worldview. Then again, mainstream publications have a problem with remembering that Iran is not an Arab country, so perhaps they tasked an Iranian with coming up with the labels.

The main reason I point this out is not to catch people in picayune details, but observe how shallow and superficial a grasp of facts is in much of the media establishment which is attempting to inform and enlighten the public. The reality is that the establishment is full of bullshit artists. Beware. If these people can’t even best 12 year old contestants for the geography bee, do you think they can inform you reasonably about world affairs?

(of course to be fair to The New York Times 99% of people who talk about foreign policy seem to be bullshit artists with a tenuous grasp of history and geography)

On “anonymous” comments, etc.

Just a minor administrative note. I now have some power to have pre-approved comments. That means if you don’t change your name/email/IP your comments are going to go through even if I don’t approve them. The only catch is that it works via a script which runs only every hour, so there’s some latency. Second, I am going to ask people to use pseudonyms rather than just “anonymous.” It makes it hard to keep track of who is saying what. From now on I’m just not going to publish anonymous comments.

Update: OK, heard from the top that the auto-approval script will be set to run every time the page loads soon. So there won’t be a latency.

Living in a world that is, not as it ought to be

Future-of-Freedom-ZakariaAbout ten years ago Fareed Zakaria wrote The Future of Freedom: Illiberal Democracy at Home and Abroad. Zakaria has been dismissed as many things, in particular being a sort of middlebrow establishmentarian voice who can be relied upon to package the latest safest conventional wisdom in stylish erudition, and still remain palatable to a non-scholarly audience. But he does deserve credit for putting the concept of “illiberal democracy” in front of the reading American public. Those with any sort of historical perspective won’t be surprised by the basic definition of illiberal democracy, because it is an ancient idea which simply been given a catchy name. Tyrannical majoritarianism manipulated by demagogues is one of the reasons that Greek democracy generally had a bad reputation until the past few centuries. The republican form of government enacted by Rome differed starkly from the populist direct democracy of Athens, integrating aspects of representation of the majority over time, at least symbolically*, balanced with customary protections of the individual liberty of citizens, in particular those of high standing.** American representative democracy in its populist guise itself is not something which characterized the founding, but crystallized as the conclusion of decades of faction during the “Age of Jackson” in the 1830s. Though in practice periods of populism have alternated with domination by elites since that era, the rhetoric remained explicitly democratic. Legitimacy only comes from the will of the people, broadly understood.

Read More

MIT Technology Review on my son’s whole genome sequencing

Recently MIT Technology Review contacted me to talk about my son’s whole genome sequencing. After some digging it turned out that it is possible that my son could be “the first healthy person ever born with his entire genetic makeup deciphered in advance.” You can read the whole story, For One Baby, Life Begins with Genome Revealed. Though I do agree with Jay Shendure, “My guess is that a few people may have done this privately already.” Hopefully this story will prompt these individuals to come out of the shadows. There’s nothing to hide.

Demographic supernovae ignited by culture

Screenshot - 090614 - 19:56:13

Screenshot - 100614 - 01:23:00David Reich’s talk at SMBE 2014 has come and gone, and it seems like from the reports on Twitter that it was a synthesis of the results in their bioRxiv preprint from last fall, Ancient human genomes suggest three ancestral populations for present-day Europeans, and the ancient DNA samples from Samara in Russia. The major takeaway being that genetically modern Europeans are by and large an admixture between three very distinct population groups, which fused together only during the Holocene (last ~10,000 years). A stylized variant of the model is represented in the figure I’ve taken from the bioRxiv preprint.

But a question that’s nagged me is how realistically to take the proposition that some of these nodes are genuinely distinct populations separated by barriers to gene flow, as opposed to being part of a broader continuum of genetic variation? For example, populations separated by water barriers such as those of Sahul almost certainly exhibited enough attenuated gene flow so that drift could work to shift their allele frequencies away from the populations of Sundaland. On the other hand, it seems reasonable to me that genetic variation on the broad plain from western Europe to the Urals in northern Europe may have been mostly clinal, with each population exchanging genes with the next, from the Atlantic to the fringes of Siberia. Some have argued that the Paleo-Siberian population which has been termed “Ancient North Eurasian” (ANE) is only part of a cline across Eurasia which extends out toward the European hunter-gatherers (to be clear, I’m skeptical of this because the genetic distance seems too great, but who knows how rapidly genetic distance increased as a function of distance in the Pleistocene?). On the other hand one might posit regions of extremely low population density during the Pleistocene due to inclement conditions in many regions so that various ancestral groups may have been isolated enough to drift apart due to more conventional genetic isolation (for example, it seems to me that the ancestors of groups such as the Han Chinese have been isolated from western Eurasians for ~40,000 years, unless you count relatively recent fusions such as the Uygurs and the peoples of Turkestan more broadly).

And yet some discussions I’ve had recently (on Twitter) have made me clarify my thoughts and admit that for some purposes it really doesn’t matter whether ANE was part of a genetic continuum or not in relation to European hunter-gatherers. The reason is that I believe that the human past was characterized by many powerful demographic sweeps which we are beginning to comprehend due to the power of ancient DNA. If the expansions occur from specific narrow geographic zones, and overwhelm a huge area adjacent, then whether the genetic variation is characterized by clines or not is irrelevant, as it will look like a discontinuous replacement in regions far from the core point of origination.

This brings me to a major update in my own personal views on these sorts of dynamics. I recently read Richersen, Boyd, and Heinrich’s Gene-culture coevolution in the age of genomics. It’s a good overview of the intersection of the fields of cultural evolution and genomics, but too often it struck me that the authors were keen on ascertaining how genomics could illuminate problems in cultural evolution, without considering the converse. That is, what can our understanding of cultural evolutionary process tell us as to what patterns of genomic variation we should see around us? Modern human genomics has a surfeit of data, and population genetic theoretical machinery of yore is being drafted to hammer away at the massive rich empirical seams, but in the domain of paleodemography a model of culture is probably more informative in allowing us to gain an expectation of the distribution of dynamics. More concretely cultural and economic factors are clearly critical in understanding why a few nations of western Europe* entered into massive settlement of the New World after 1492, and others did not. Obviously we’ll never have historical records from 50,000 years in the past, but a better understanding of the processes of cultural evolution might allow us to judge whether rapid archaeological transitions signal demographic shifts, or not. And these then might serve as an interpretative framework for genomic results.

* I specify western Europe because the genetic distances here are small, and the major settler nations, the British and Iberians, are not particularly clustered together.

SMBE 2014

The Society For Molecular Biology & Evolution is having its meeting in Puerto Rico right now. Here’s the website. The Twitter hashtag seems to be #SMBE14. With stuff that’s going on in my life no way I’d be able to make it, though I plan on going to ASHG 2014 in San Diego for what it’s worth. Here are some abstracts that I think are interesting (I assume a substantial fraction are going to make it to high profile pubs).

Read More

Open Thread , 6/8/2014

Thinking that understanding the distribution of phenomena which characterize human cultural evolution might be extremely important toward understanding genomic patterns of variation. Also, excited about Peter’s Heather’s The Restoration of Rome: Barbarian Popes and Imperial Pretenders and Jürgen Osterhammel’s The Transformation of the World: A Global History of the Nineteenth Century (America in the World). When I’ll get to read them, who knows?