Razib Khan One-stop-shopping for all of my content

March 31, 2010

When sickliness is manliness

Filed under: Behavior,Disease,Evolution,Evolutionary Genetics,Genetics,Immunity,Sex — Razib Khan @ 2:25 am

ResearchBlogging.orgBelow I note that sex matters when it comes to evolution, specifically in the case of how sexual reproduction forces the bits of the genome to be passed back and forth across sexes. In fact, the origin of sex is arguably the most important evolutionary question after the origin of species, and it remains one of the most active areas of research in evolutionary genetics. More specifically the existence of males, who do not bear offspring themselves but seem to be transient gene carriers is a major conundrum. But that’s not the main issue in this post. Let’s take the existence of males as a given. How do sex differences play out in evolutionary terms shaping other phenotypes? Consider Bateman’s principle:

Bateman’s principle is the theory that females almost always invest more energy into producing offspring than males, and therefore in most species females are a limiting resource over which the other sex will compete.

Female ova are energetically more expensive, and scarcer, than male sperm. Additionally, in mammals and other live-bearing species the female invests more time and energy after the point of fertilization but before the young exhibit any modicum of organismic independence (the seahorse being the exception). And, often the female is the “primary caregiver” in the case of species where the offspring require more care after birth. The logic of Bateman’s principle is so obvious when its premises are stated that it easily leads to a proliferation of numerous inferences, and many data are “explained” by its operation (in Mother Nature: Maternal Instincts and How They Shape the Human Species the biological anthroplogist Sarah Hrdy moots the complaint that the principle is applied rather too generously in the context of an important operationally monogamous primate, humans).

But the general behavioral point is rooted in realities of anatomy and life-history; in many dioecious species males and females exhibit a great deal of biological and behavioral dimorphism. But the direction and nature of dimorphism varies. Male gorillas and elephant seals are far larger than females of their kind, but among raptors females are larger. If evolution operated like Newtonian mechanics I assume we wouldn’t be theorizing about why species or sex existed at all, we’d all long ago have evolved toward perfectly adapted spherical cows floating in our own effluvium, a species which is a biosphere.

Going beyond what is skin deep, in humans it is often stated that males are less immunologically robust than females. Some argue that this is due to higher testosterone levels, which produce a weakened immune system. Amtoz Zahavi might argue that this is an illustration of the ‘handicap principle’. Only very robust males who are genetically superior can ‘afford’ the weakened immune system which high testosterone produces, in addition to the various secondary sexual characteristics beloved of film goers. Others would naturally suggest that male behavior is to blame. For example, perhaps males forage or wander about more, all the better to catch bugs, and they pay less attention to cleanliness.

But could there be a deeper evolutionary dynamic rooted in the differential behaviors implied from Bateman’s principle? A new paper in The Proceedings of the Royal Society explores this question with a mathematical model, The evolution of sex-specific immune defences:

Why do males and females often differ in their ability to cope with infection? Beyond physiological mechanisms, it has recently been proposed that life-history theory could explain immune differences from an adaptive point of view in relation to sex-specific reproductive strategies. However, a point often overlooked is that the benefits of immunity, and possibly the costs, depend not only on the host genotype but also on the presence and the phenotype of pathogens. To address this issue we developed an adaptive dynamic model that includes host–pathogen population dynamics and host sexual reproduction. Our model predicts that, although different reproductive strategies, following Bateman’s principle, are not enough to select for different levels of immunity, males and females respond differently to further changes in the characteristics of either sex. For example, if males are more exposed to infection than females (e.g. for behavioural reasons), it is possible to see them evolve lower immunocompetence than females. This and other counterintuitive results highlight the importance of ecological feedbacks in the evolution of immune defences. While this study focuses on sex-specific natural selection, it could easily be extended to include sexual selection and thus help to understand the interplay between the two processes.

The paper is Open Access, so you can read it for yourself. The formalism is heavy going, and the text makes it clear that they stuffed a lot of it into the supplements. You can basically “hum” through the formalism, but I thought I’d lay it out real quick, or at least major aspects.

This shows the birth rate of a given genotype contingent upon population density & proportions of males & females infected with a pathogen


These equations takes the first and nests them into an epidemiological framework which illustrates pathogen transmission (look at the first right hand term in the first two)


And these are the three models that they ran computations with


There are many symbols in those equations which aren’t obvious, and very difficult to keep track of. Here’s the table which shows what the symbols mean….


If you really want to understand the methods and derivations, as well how the details of how they computae evolutionarily stable strategies, you’ll have to go into the supplements. Let’s just assume that their findings are valid based on their premises.


- They assume no sexual selection
- They assume unlimited male gametes, so total reproductive skew where one male fertilizes all females is possible
- Fecundity is inversely correlated with population density
- Total population growth is ultimately dependent on females, they are the “rate limiting” sex
- Total population growth is proportional to density
- There is no acquired immunity
- There is no evolution of the pathogen in this model

Basically the model is exploring a quantitative trait which exhibits characteristics in relation to resistance of acquiring the pathogen and tolerance of it once the pathogen is acquired. In terms of the “three models,” the first is one where there is resistance to the pathogen, individuals recover from infection and decrease pathogen fitness. The second is one of tolerance, individuals are infected, but may still reproduce while infected. Note that the ability to resist or tolerate infection has a trade off, reduced lifespan (consider some forms of malaria resistance). The third model shows the trade off of tolerance and resistance.

The “pay off” of the paper is that they show that the male evolutionarily stable strategy (ESS), that is, a morph which can not be “invaded” by a mutation, may be one of reduced immune resistance in certain circumstances of high rates of infection. There is an exploration of varying rates of virulence, but there was no counterintuitive finding so I won’t cover that. In any case, here’s the figure:


The text is small, so to clarify:

1) The two panels on the top left are for model 1, and show variation in male and female recovery from infection left to right (resistance)

2) The two panels on the bottom left are for model 2, and show variation in male and female fecundity when infected left to right (tolerance)

3) The four panels on the right are for model 3, and show variation in recovery in the top two panels and fecundity in the bottom two, with male parameters varied on the left and female on the right

The vertical axis on all of the panels are male infection rate, the horizontal the female infection rate. Circled crosses (⊕) indicate regions (delimited by solid lines) where females evolve higher immunocompetence than males. The lighter shading indicates a higher value of the trait at ESS (recovery or fecundity). Note that the two top left panels show a peculiar pattern for males, the sort of counterintuitive finding which the model promises: when infection rates among males are very high their resistance levels drop. Why? The model is constructed so that resistance has a cost, and if they keep getting infected the cost is constant and there’s no benefit as they keep getting sick. In short it is better to breed actively for a short time and die than attempt to fight a losing battle against infection (I can think of possible explanations of behavior and biological resistance in high disease human societies right now). It is at medium levels of infection rates that males develop strong immune systems so that they recover. The bottom right portion of panel which shows variation in male resistance illustrates a trend where high female infection results in reduced immune state in males. Why? The argument is simple; female population drops due to disease result in a massive overall population drop and the epidemiological model is such that lower densities hinder pathogen transmission. So the cost for resistance becomes higher than the upside toward short-term promiscuous breeding in hopes of not catching the disease. Another point that is notable from the panels is that males seem to be more sensitive to variation in infection rates. This makes sense insofar as males exhibit a higher potential variance in reproductive outcomes because of the difference in behavior baked into the model (males have higher intrasexual competition).

One can say much more, as is said in the paper. Since you can read it yourself, I commend you to do so if you are curious. Rather, I would like a step back and ask: what does this “prove?” It does not prove anything, rather, this is a model with many assumptions which still manages to be quite gnarly on a first run through. It is though suggestive in joint consideration with empirical trends which have long been observed. Those empirical trends emerge out of particular dynamics and background parameters, and models can help us formalize and project abstractly around real concrete biological problems. The authors admit their model is simple, but they also assert that they’ve added layers of complexity which is necessary to understand the dynamics in the real world with any level of clarity. In the future they promise to add sexual selection, which I suspect will make a much bigger splash than this.

I’ll let them finish. From their conclusion:

We assessed the selective pressures on a subset of sex-specific traits (recovery rate, reproductive success during infection and lifespan) caused by arbitrary differences between males and females in infection rate or virulence (i.e. disease-induced death rate). In so doing, we covered a range of scenarios whereby sex-specific reproductive traits such as hormones and behaviour could plausibly affect the exposure to infection…r the severity of disease…First, we showed that changes in the traits of either sex affect the selective pressures on both sexes, either in the same or in opposite directions, depending on the ecological feedbacks. For example, an increase in male susceptibility (or exposure) to infection favours the spread of the pathogen in the whole population and therefore tends to select for higher resistance or tolerance in both sexes if the cost of immunity is constitutive. However, above a certain level of exposure, the benefit of rapid recovery in males decreases owing to constant reinfection (we assume no acquired immunity). This selects for lower resistance in males, ultimately leading to the counterintuitive situation where males with higher susceptibility or exposure to infection than females evolve lower immunocompetence…A similar pattern arises if the cost of immunity is facultative, in the form of a trade-off between rate of recovery and relative fecundity during infection (model (iii)): if males happen to be more susceptible (or exposed) to infection than females, they are predicted to evolve a longer infectious period balanced by higher sexual activity during infection than females.

Restif, O., & Amos, W. (2010). The evolution of sex-specific immune defences Proceedings of the Royal Society B: Biological Sciences DOI: 10.1098/rspb.2010.0188

March 30, 2010

The ways of the forefathers & foremothers

Filed under: Anthroplogy,Cultural Evolution,Culture,phylogenetics — Razib Khan @ 6:17 pm

Fascinating post by Bayes, Phylogenetics, cultural evolution and horizontal transmission:

For some time now, evolutionary biologists have used phylogenetics. It is a well-established, powerful set of tools that allow us to test evolutionary hypotheses. More recently, however, these methods are being imported to analyse linguistic and cultural phenomena. For instance, the use of phylogenetics has led to observations that languages evolve in punctuational bursts, explored the role of population movements, and investigated the descent of Acheulean handaxes. I’ve followed the developments in linguistics with particular interest; after all, tracing the ephemeral nature of language is a daunting task. The first obvious road block is that prior to the invention of writing, the uptake of which is limited in geography and history, language leaves no archaeological record for linguists to examine. One particular note I’d like to make is that when Charles Darwin first formulated his theory of natural selection, he took inspiration from linguistic family trees as the basis for his sketch on the evolutionary tree of life. So it seems rather appropriate that phylogenetic approaches are now being used to inform our knowledge regarding linguistic evolution.

Like many other attempts applying evolutionary thinking in culture, phylogenetic approaches are, at times, met with contempt. This stems from assertions that cultural evolution and biological evolution differ greatly in regards to the relative importance of horizontal transmission….

I guess the general points to take away from this post are: 1) Do not necessarily assume horizontal transmission is dominant in shaping culture; and, 2) Even with certain levels of reticulation, it does not necessarily invalidate a phylogenetic approach in investigating cultural and linguistic evolution.

I think the point that horizontal transmission may be less important relative to vertical transmission than we’d previously thought in regards to the spread and diffusion of cultures may explain some of the recent findings from DNA extractions which suggest that hunter-gatherers were replaced in Europe by farmers. The standard model before the recent wave of extractions was that farming spread through cultural diffusion, with a minority view championed by L. L. Cavalli-Sforza of “demic diffusion” whereby demographic growth from the point of origination spread a culture, though the initial distinctive genetic signal became progressively weaker through dilution via admixture. But if cultural practices such as agriculture were much more vertically transmitted, from parent to child, rather than horizontally across societies, the genetic pattern of replacement becomes more comprehensible.

Of course, the main caveat is that intermarriage has been very common between neighboring groups. The rape of the Sabine women may reflect a common practice on the part of migratory males; the Greek colonization of the western Mediterranean was almost all male, so the subsequent generations were biologically the products of Greek men and native women (though culturally they were fully Greek, as evidenced by the term “Magna Graecia” to refer to Sicily and southern Italy). It is not atypical for vertical transmission of culture to occur from one parent, and in particular one sex. More recently the descendants of the pairings of Iberian men and indigenous women in Latin America tend to speak Spanish and avow the Christian faith. Though aspects of local identity, such as cuisine and clothing, may retain an indigenous stamp it is no coincidence that these populations are labelled “Latin American” despite their mixed genetic provenance.

Note: In the United States children have traditionally been more often raised in the denomination of their mother than father, so there isn’t always a male-bias in vertical transmission when the parents are not concordant for a cultural trait.

The sexual straightjacket

Filed under: Biology,Evolution,Evolutionary Genetics,Genetics,Sex,Sex Differences — Razib Khan @ 5:21 pm

Earlier I pointed to the possibility of biophysical constraints and parameters in terms of inheritance shaping the local trajectory of evolution. Today Olivia Judson has a nice post [link fixed] on how the existence of two sexes in many species results in a strange metastable tug-of-war in terms of phenotypic evolution:

In sum, the traits that make a “good” male are often different from those that make a “good” female. (Note: I’m only talking about “good” in evolutionary terms. That means a trait that improves your chance of having surviving offspring.) Since many of these traits have a genetic underpinning, male and female genes are thus being sculpted by different forces.

But — and this is the source of the tension I mentioned — males and females are formed from the same underlying set of genes. After all, in humans, whether you’re a boy or a girl comes down to whether you have a Y chromosome or not: boys do, girls don’t. The rest of the genes occur in both sexes.

The X choromosome in mammals spends about 2/3 of its time in females and 1/3 in males.* And obviously the Y is found only in males. But the rest of the genome is found in both males and females. Judson notes that traits which may be attractive in males may not in females, and which may be attractive in females may not in males. There’s a fair amount of evolutionary psychological work in humans in this vein in regards to the heritability of testosterone and estrogen levels in females and males and how it effects the same and opposite sex (in short, there is suggestive data that “sexy” individuals of one sex, those who exhibit strong secondary sexual characteristics, may be prone to having less sexy offspring of the opposite sex).

Of course you can overcome the balancing tug of war; that’s why you have sexual dimorphism in things like size or facial proportion. But these sorts of traits emerge very slowly because of the equilibrium described above, modifier genes and sex-specific gene expression have to slowly engineer around the overwhelming problem that males and females are genetically no different on a sequence level aside from the Y chromosome. Some estimates put the rate of evolutionary change of sexual dimorphism, that is, trait differences between sexes, between 1 and 2 orders of magnitude slower than conventional population level evolution. Ergo, one would expect that sexual dimorphism differences varying across populations have great time depth, and are probably more interspecific than intraspecific (for example, gorillas vs. humans).

There is naturally a whole field devoted to the study of the origin of sex. But whatever its ultimate rationale and utility an evolutionary context, its existence as a background condition in many taxa may result in a constraint of the exploration of phenotype space, as species divided into two sexes characterized by strong phenotypic differences dance between two sex-specific phenotypic optima.

* Sex determination varies by taxon.

The brothers Emanuel as behavior geneticists

Filed under: Behavior Genetics,Genetics,Rahm Emanuel — Razib Khan @ 4:21 am

I stumbled onto this New York Times Magazine The Brothers Emanuel, from 1997. Zeke, Rahm and Ari Emanuel have all become even more accomplished over the past 13 years. But I was surprised to discover that they had a younger sister, and that her life prompted the brothers to reflect on the influence of genetics and environment on life outcomes. Here’s the relevant portion:

Today, the brothers argue just as passionately about the role that environment and genetics played in the life of their sister, who in recent years has been on and off the welfare rolls that Rahm worked so hard to cut. Benjamin Emanuel met his daughter when he gave her a well-baby checkup and discovered that she had suffered a brain hemorrhage at delivery. The baby’s future was unclear; Shoshana’s birth mother, a young woman of Polish Catholic background, asked Dr. Emanuel if he knew someone who wanted her child. ”But I couldn’t find placement,” Benjamin Emanuel says. After a week of debate between both parents and sons – Marsha Emanuel had always wanted a girl – the Emanuels themselves took Shoshana in. ”What are you going to do?” Benjamin Emanuel says philosophically.

Intellectually, Shoshana developed normally – like her brothers, she graduated from New Trier, one of the most competitive high schools in the country – but she needed four operations and years of physical therapy to give her 85 percent use of her left side. She had a difficult adolescence, and today Marsha Emanuel, at the age of 63, is raising Shoshana’s two illegitimate children. (None of the Emanuels will talk about Shoshana in detail, and she declined to be interviewed for this article.)

The conversation the brothers continue to have about Shoshana is also, of course, a conversation about themselves. Were Zeke, Rahm and Ari simply successful products of Jewish middle-class parents who valued education and hammered them with expectations? How much of their drive came from their immigrant father? Certainly each Emanuel brother derives a large part of his identity that of the others. No one else, it seemed, mattered as much. ”The pressure is that you were judged by the family,” Ari says. ”Our family never cared about the kid down the block.”

Ari Emanuel also seems to have some opinions about I.Q.:

”Ari can carry on a conversation!” Rahm says at one point, noticing that his younger brother is talking with me about Los Angeles. ”What an accomplishment! A complete sentence!”

Ari retaliates when the conversation turns to money. ”I.Q. brings down – I’m not going to go into it,” Ari says impishly.

”Income?” shouts Zeke. ”Is that what you were going to say? I.Q. and income are correlated?”

”They should be!” counters Ari, who says he made between $1 million and $2 million last year.

”Inversely, that’s the thing,” says Zeke.

”This is all off the record,” says Rahm.

The discussion about genetics and environment apparently continues down to the present day. Here’s a profile from the spring of 2008:

Shoshana, who now has two children of her own—one of whom lives with Benjamin and Marsha—has not had the sterling success of her brothers. Zeke says all three, who were like older uncles to Shoshana when she was growing up, now have an “episodic” relationship with her, and he wonders about the genesis of her life’s troubles: “It’s a good question as to how much is environment, following three such brothers, and how much is genetic. It’s hard to know.” Marsha Emanuel says her daughter is extremely proud of her brothers “but keeps her distance.”

RSS feed

Filed under: Administration — Razib Khan @ 1:31 am

I notice that not too many people seem to have switched from the old feed to the new. Part of the issue is that many people have subscriptions which they never check or have forgotten. But in case you’re reading this on the old feed, that’s because the techs are currently pointing the old feed to the new. But at some point this will not occur, and you’ll need the new feed. So if you haven’t, please switch to:



(thanks to Edmund for reminding me)

Again, Malthus was right (in the past)

Filed under: Anthroplogy,Economics,History — Razib Khan @ 12:15 am

Ed reviews a new paper on the fall of the Angkor civilization. He concludes:

Of course, a changing environment was far from the only reason behind the fall of Angkor. By the time the droughts kicked in, the city was already weakened by social, economic and political strife. Buckley simply thinks that the climate simply sealed the city’s demise. In fact, others have suggested that some force may have pushed the local people to move from inland agriculture to maritime trade. Buckley says that this transition coincides neatly with the aftermath of the first drought.

An economic historian might term the droughts which Angkor was subjected to an “exogenous shock.” Basically an outside factor which slams into an equilibrium system periodically (I assume that super-droughts would exhibit a poisson distribution but readers more climatically savvy can correct me). On the other hand, there are parameters which are endogenous to the system; consider the institutional frameworks which regulate social relations and distribute economic surplus.

Pre-modern societies often live on the Malthusian margin on a per capita basis. In other words, the average Chinese peasant was no more wealthy than the barbarian nomad to the north (in fact, a peasant may be less wealthy on a median basis than a nomad for a variety of reasons). Despite the greater sum total of wealth of pre-modern China, and so the greater surplus which the rentier elites could tax or steal, most of that wealth vis-a-vis Mongolia or Central Asia was realized in the form of people. That wealth was fundamentally based on primary production, agriculture, and when the environmental conditions for agriculture were less favorable then the wealth would decrease. Naturally you would then see a major contraction in the primary manifestation of that wealth, census size. If that environment once more became favorable toward primary production then there might be a transient where individual per capita wealth increased before census size “caught up” (e.g., the average English peasant in the century after the Black Death was healthier and wealthier than before because the population was so much smaller).

Grand per-modern polities such the the Khmer confederacy of which Angkor was the apex rely on massive numbers of primary producers from which they can skim and squeeze just short of destitution. In other words the elites who produced high culture were parasites. Civilization was located for most of history in cities, and all cities before 1900 were demographic sinks due to the pervasiveness of morbidity and mortality. Environmental catastrophe which forces the primary producers to look to themselves and evade or dodge taxation or theft by the elites results in the collapse of civilization. This environmentally induced collapse was not limited to the Khmer confederacy in Southeast Asia, in Strange Parallels: Volume 1, Integration on the Mainland: Southeast Asia in Global Context, c. 800-1830 the author shows that the same dynamic of disruption and destabilization was evident to the west and east, from Myanmar to Vietnam, correlated with climatic variation in the region.

But things are never always the same. Similar environmental catastrophes did not result in total dissolution of the political order after 1500 in mainland Southeast Asia, the institutional framework which generated some sort of equilibrium managed to withstand exogenous shocks because they had become more robust. The same is evident on a global scale in The Human Web: A Bird’s-Eye View of World History and After Tamerlane: The Global History of Empire Since 1405; political institutions over the past 2,500 years are much more robust than they were in the first 2,500 years of civilization. And they have been much more robust over the past 500 years than the previous 2,000 years. There are long term institutional changes which occurred through which we must view the predicted impact of environmental catastrophe. I am not here even touching upon the rapid rise in economic growth which allowed much of humanity to break out of the Malthusian trap after 1850 (see A Farewell to Alms).

The main caution from history would be supplied by Brian Fagan in The Long Summer: How Climate Changed Civilization. He admits that political institutions during the Holocene have become more robust, dampening the impact of local famines or disruptions. But, he observes that when collapse does happen it is all the more catastrophic as enormous interlocking social, political and technological systems may now unwind. In other words, we’re trading short term small risks for longer term large risks. The analogy that seems appropriate here is that of earthquakes, whereby small quakes tend to release energy which might otherwise pour out in a super-quake. This is why I like to suggest that only technology will save us.

March 29, 2010

Please change your links

Filed under: Admin — Razib @ 11:36 pm

If you have a blog, and you link to http://scienceblogs.com/gnxp/, I would appreciate it if you switched to http://blogs.discovermagazine.com/gnxp/. I know most people don’t use blogrolls much, but it matters for PageRank, and the archives have been copied so I’d rather have search engine traffic go to the active weblog ASAP. Thanks.


Thomas Malthus was right. Mostly

pleistocene_brain_sizeJohn Hawks has an excellent post rebutting some misinformation and confusion on the part of Colin Blakemore, an Oxford neurobiologist. Blakemore asserts that:

* There was a sharp spike in cranial capacity ~200,000 years ago, on the order of 30%

* And, that the large brain was not deleterious despite its large caloric footprint (25% of our calories service the brain) because the “environment of early humans was so clement and rich in resources”

Hawks refutes the first by simply reposting the chart the above (x axis = years before present, y axis = cranial capacity). It’s rather straightforward, I don’t know the paleoanthropology with any great depth, but the gradual rise in hominin cranial capacity has always been a “mystery” waiting to be solved (see Grooming, Gossip, and the Evolution of Language and The Mating Mind: How Sexual Choice Shaped the Evolution of Human Nature). Blakemore may have new data, but as they say, “bring it.” Until then the consensus is what it is (the hominins with the greatest cranial capacities for what it’s worth were Neandertals, and even anatomically modern humans have tended toward smaller cranial capacities since the end of the last Ice Age along with a general trend toward smaller size).

But the second issue is particularly confusing, as Blakemore should have taken an ecology course at some point in his eduction if he’s a biologist (though perhaps not). One of the problems that I often have with biologists is that they are exceedingly Malthusian in their thinking, and so have a difficult time internalizing  the contemporary realities of post-Malthusian economics (see Knowledge and the Wealth of Nations: A Story of Economic Discovery).Innovation and economic growth combined with declining population growth have changed the game in fundamental ways. And yet still the biological predisposition to think in Malthusian terms is correct for our species for almost its whole history.*

A “tropical paradise” is only a tropical paradise if you have a modicum of affluence, leisure, and, modern medicine. Easter Island is to a great extent a reductio ad absurdum of pre-modern man and gifted with a clement regime. Easter Island’s weather is mild, the monthly low is 18/65 °C/°F and the monthly high is 28/82 °C/°F. The rainfall is 1,118/44 mm/in. But constrained on an island the original Polynesians famously transformed it into a Malthusian case-study. We literally breed up to the limits of growth, squeezing ourselves against the margins of subsistence.

I can think of only one way in which Blakemore’s thesis that the environment of early humans was rich in resources might hold, at least on a per capita basis: the anatomically modern humans of Africa exhibited bourgeois values and had low time preference. In other words, their population was always kept below ecological carrying capacity through forethought and social planning, since there is no evidence for much technological innovation which would have resulted in economic growth to generate surplus. My main qualm with this thesis is that it seems to put the cart before the horse, since one presupposes that a robust modern cognitive capacity is usually necessary for this sort of behavior.

* Malthus’ biggest mistake was probably that he did not anticipate the demographic transition, whereby gains in economic growth were not absorbed by gains in population.

Hari Seldon and the liberal punditocracy

Filed under: Culture,Isaac Asimov,Pundits,science fiction — Razib Khan @ 11:59 am

Matt Yglesias muses on the possible influence of Isaac Asimove’s Foundation series on the way he looks at the world. Interestingly, Paul Krugman admits his debt to this series as well in getting him interested in economics. Unlike Robert Heinlein or mentor John W. Campbell Asimov was a political liberal. It is not uncommon for nerdy males, who are disproportionately represented in the pundit-class, to go through a science fiction phase in their youth. It would be interesting to see how interests in various authors tracked their current political positioning (I’d bet money that Poul Anderson is more popular with people who work at the Cato Institute).

Note: William Sims Bainbridge’s Dimensions of Science Fiction explores the various demographic trends which characterize the science fiction subculture. Politically there’s a bimodal distribution between liberals and libertarians, with more traditional conservatives such as Jerry Pournelle being the exception.

A splice of evolution?

Filed under: Biology,Genetics,Genomics,Uncategorized — Razib Khan @ 12:50 am

It is famously noted that when Charles Darwin published The Origin of Species he had no plausible theory of inheritance to drive his hypothesis. Specifically, one of the major issues of the “blending” model whereby the phenotypes of the parents average out in the subsequent generation is that such mixing eliminates the variation which is a necessary precondition for natural selection. At the same time that Darwin was revolutionizing our conceptualization of how the tree of life came to be, Gregor Mendel was preforming the experiments which solidified his eponymous theory of inheritance. Though ignored in his own day by ~1900 Mendelism reemerged and offered a relatively parsimonious abstraction which could explain why variation was not eliminated through the fusion of sexual reproduction. The discrete genes themselves were simply rearranged every generation in a digital manner, a genotype was translated into a phenotype, rather than the more analog model of phenotypic mixing which underpins a blending theory.* The fusion of genetics and quantitative evolutionary biology resulted in population genetics (see The Origins of Theoretical Population Genetics), while the cross-fertilization with ecology, natural history and paleontology eventually crystallized into what we would term the ‘Neo-Darwinian Synthesis’ by the middle of the 20th century.

And it was then that Francis Crick and James Watson elucidated specifically the biophysical substrate, DNA, through which Mendelian inheritance occurred. It was then that Crick also outlined his famous and infamous ‘central dogma,’ whereby information was transmitted unidirectionally from DNA to protein via RNA. While molecular biology was flowering the theorists who relied on the older abstractions were relatively unperturbed (see The Narrow Roads of Gene Land 1 by W. D. Hamilton). In Darwin’s Dangerous Idea the philosopher Daniel Dennett asserted that evolution was fundamentally substrate neutral; that is, how genetic information is transmitted biophysically is of less relevance than the abstract parameter of natural selection which operates upon the character of that information through the mediation of fitness and phenotype. In a broad philosophical sense this may be true. Assuming infinite population sizes and time this is indubitably so. But there is much that transpires from the beginning to the end, and more recent work has suggested that the physical realities and constraints of molecular function can not simply be abstracted away on a realistic time scale. It is I think somewhat peculiar to push the abstraction too far when speaking of biology in particular, because biological processes often operate under physical constraint or scarcity as a matter of course.

To understand evolution today in any non-trivial sense, that is, to understand evolution as a process which operates on scales shorter than the heat-death of the universe, it seems that one must consider the details of the substrate. In other words the great wall between molecular biology and evolutionary science must be buried once and for all. We have come far from the isolated alleles operating in a statistical sea of random variation which R. A. Fisher conceived of when he attempted to reformulate Darwin’s theories so that they were as precise and crisp as the laws of thermodynamics (see The Genetical Theory of Natural Selection). The recent debates between Sean Carroll and Michael Lynch (or Sean Carroll and Jerry Coyne) put into sharp relief the relevance of substrate, the importance of gene regulation and particularly cis-regulatory elements.**

Gene regulation entails the modulation of the expression of some genes by other genes, by any means possible. A new letter to Nature gives us a possible taste of the future, using the familiar HapMap data set to explore variation in gene expression, Understanding mechanisms underlying human gene expression variation with RNA sequencing:

Understanding the genetic mechanisms underlying natural variation in gene expression is a central goal of both medical and evolutionary genetics, and studies of expression quantitative trait loci (eQTLs) have become an important tool for achieving this goal1. Although all eQTL studies so far have assayed messenger RNA levels using expression microarrays, recent advances in RNA sequencing enable the analysis of transcript variation at unprecedented resolution. We sequenced RNA from 69 lymphoblastoid cell lines derived from unrelated Nigerian individuals that have been extensively genotyped by the International HapMap Project…By pooling data from all individuals, we generated a map of the transcriptional landscape of these cells, identifying extensive use of unannotated untranslated regions and more than 100 new putative protein-coding exons. Using the genotypes from the HapMap project, we identified more than a thousand genes at which genetic variation influences overall expression levels or splicing. We demonstrate that eQTLs near genes generally act by a mechanism involving allele-specific expression, and that variation that influences the inclusion of an exon is enriched within and near the consensus splice sites. Our results illustrate the power of high-throughput sequencing for the joint analysis of variation in transcription, splicing and allele-specific expression across individuals.

The mapping of a genotype to a phenotype through the production of proteins is complex. All the cells in your body have the same set of genes, but they obviously express differently. If you have a background in biology you will be probably recall examples of this issue in the case of the liver, whose fine tune balance is essential toward our health. But think of something more prosaic, some haplotypes around the HERC2-OCA2 locus seem to correlate with somewhat lighter skin color, and also result in blue eyes. Pigmentation genes seem to vary in how they express (or don’t express) in various tissues, primarily the eyes, skin and hair.

Add to this the tangle that is RNA splicing in eukaryotes, and it gets very complicated indeed. The appeal of Fisherian abstraction is very strong, but after nearly one century of abstracting away the concrete I suspect to genuinely understand how the tree of life came to be we may have to understand its physical accidents in more depth. The paper finishes with an observation on the importances of SNPs around splice site:

We proposed that, as in the example described earlier, the mechanism of many of these associations acts through disruption of the splicing machinery. To test this, we extended a Bayesian hierarchical model used previously to include exon-specific effects…This model allows us to estimate the odds ratio for different types of SNPs to affect splicing. First, we considered the binding sites for the U1 small nuclear ribonucleoprotein (snRNP) and U2AF splice factor (of which the canonical splice sites are a part25); we found that SNPs throughout these binding sites are highly enriched among sQTLs relative to non-splice site intronic SNPs…We considered whether SNPs within the canonical 2 bp of the splice site alone are enriched for sQTLs; we find that they are…in contrast to previous studies using exon microarrays…Furthermore, SNPs within the spliced exon itself are also significantly enriched among sQTLs and, as expected, non-genic SNPs are markedly under-represented among sQTLs….

Not too surprising that the QTLs of note are near locations which we know to be importance in a molecular genetic context. Obviously we’ll have to get much further in understanding variation on this level of complexity before we can talk much about evolution. But if we want to understand something like height with any greater depth than Francis Galton I suspect that the long climb is just beginning….

Citation: Pickrell, JK et al., Understanding mechanisms underlying human gene expression variation with RNA sequencing, doi:10.1038/nature08872

* I am aware that there were many theories of inheritance between Darwin and Mendelism.

** Not the Sean Carroll, but this Sean Carroll.

March 28, 2010

Intelligent Design & idiocy

Filed under: creationism,Intelligent Design — Razib Khan @ 11:57 am

idiotsguidIDI am consciously aware that the “Idiot’s Guide” series are not parodies. But when Josh Roseneau introduced me to The Complete Idiot’s Guide to Understanding Intelligent Design I simply assumed that this was a parody or gag-gift. This illustrates the lack of unity of cognitive process. On the one hand as I note above I was aware of the reality that this was a well-known brand of introductory books, but my prejudice against Creationists and Intelligent Design folk, and my perception that they’re stupid, led to me infer reflexively that this was an ironic parody. After all, it seemed mean to point out that those looking to understand Intelligent Design may be somewhat duller, on average, than those who would find the enterprise laughable.

For your information, here are the mean WORDSUM scores for various evolution related questions on the General Social Survey (WORDSUM is a vocabulary test, with scores from 0 to 10).

“Human beings developed from animals”

True = 6.36
False = 5.87

“View about origin & development of man”

God created = 6.02
Evolved, god guided = 6.36
Evolved = 6.71

“Humans evolved from animals”

Definitely true = 7.02
Probably true = 6.11
Probably not true = 5.59
Definitely not true = 5.84

“Human beings developed from an earlier species of animal”

Definitely true = 6.91
Probably true = 6.33
Probably not true = 6.14
Definitely not true = 5.92

Photo Dave Munger

More on recombination & natural selection

A follow up to the post below, see John Hawks, Selection’s genome-wide effect on population differentiation and p-ter’s Natural selection and recombination. As I said, it’s a dense paper, and I didn’t touch on many issues.

America the Catholic, t + 40 years

Filed under: Projection,Religion — Razib @ 12:25 am

Bryan Caplan points to a quote from Will Durant’s The Lessons of History:

In the United States the lower birth rate of the Anglo-Saxons has lessened their economic and political power; and the higher birth rate of Roman Catholic families suggest that by the year 2000 the Roman Catholic Church will be the dominant force in national as well as in municipal or state governments. A similar process is helping restore Catholicism in France, Switzerland, and Germany; the lands of Voltaire, Calvin, and Luther may soon return to the papal fold.

Caplan observes that I would not be surprised. Well as I was reading the first sentence I did think, “yes, this is what I talk about all the time….” I remember in 1994 telling a Roman Catholic friend that his church was projected to surpass Protestantism sometime around 2020-2030. Fifteen years later that seems to have been another false prophecy, and data show that Roman Catholicism has had a very hard time hanging onto those raised Catholic in the United States over he past generation. As for France, well:

A poll published in Le Monde des Religions yesterday showed the number of self-declared French Catholics had dropped from 80 per cent in the early 1990s and 67 per cent in 2000 and to 51 per cent today.

The data for Switzerland and Germany are easy to get because church-state separation is not an issue as it is in France (or the USA). Here are some trends (keep in mind Durant wrote in the the late 1960s):

In Switzerland Protestantism seems to be correlated with urbanism and higher SES (though the latter may simply spring from the correlation between Protestantism and urbanism) whether the canton is French or German speaking (recall that Geneva was once the “Rome of French Protestantism”). In Germany the unification in 1990 buttressed the proportion of Protestants because the Lander of the former East Germany were historically Protestant, and their residual religious population remained so. But the big story since Will Durant’s time has been the shift from nominal Christianity toward outright irreligiosity; the proportion of those avowing no religion or being confessionless has rocketed upward across the Western world. In relation to what is happening with the Protestant vs. Catholic dynamic, I think what Durant was witnessing or observing was what had occurred earlier in the Netherlands, the more thorough evisceration of establishment Protestantism as opposed to Roman Catholicism. What he did not anticipate, and was not quite as advanced in the 1960s, was the total rollback of the influence and power of the Catholic Church across much of its historic range of domination, from Quebec in North America, in much of Latin America, as well as Spain and other regions of Europe. This rollback seems to have exhibited time lag with Vatican II, as well as the collapse of the Iberian and Latin American autocracies, as well as the fall of Communism (which made Catholic identity less wedded to nationalism in Poland).


March 27, 2010

The Mysterious Other

Last week Nature published a paper which may have found a new ‘branch’ of the hominin evolutionary bush which may have been coexistent which modern humans and Neandertals. I recommend The Atavism, Carl and John Hawks on this story. Interesting times.

The science of human history as written by Herodotus

The following passage is from the epilogue of The Real Eve: Modern Man’s Journey Out of Africa by Stephen Oppenheimer:

In this book I have offered a synthesis of genetic and other evidence. Everything points to a single southern exodus from Eritrea to the Yemen, and to all the non-African male and female gene lines having arisen from their respective single out-of-Africa founder lines in South Asian (or at least near the southern exit). I regard the genetic logic for this synthesis as a solid foundation, and I have based the rest of my reconstruction of the human diaspora upon it. Obviously, the ‘choice’ of starting point (mine or theirs) determined all the subsequent routes our ancestors and cousins took. Tracing the onward trails is only possible as a result of marked specificity in regional distribution of the genetic branches The geographic clarity of both male and female gene trees is a big departure from the fuzzy inter-regional picture shown by older genetic studies. The degree of segregation of lines into different countries and continents is in itself good evidence that once they got to their chosen new homes, the pioneers generally stayed put, at least until the Last Glacial maximum forced some of them to move. This conservative aspect of our genetic prehistory also provides a partial explanation for the fact that when we look at a person, we can usually tell, to the continent, where their immediate ancestors came from, and underlies differences that some of us still call ‘race.’

Oppenheimer wrote the above in the early aughts, as his book was published in 2003. Much of this is generally in line with the ‘orthodoxy’ of the day. I believe that Oppenheimer’s assertion that there was one southern migration out of Africa by anatomically modern humans has gained some advantage over the alternative model of two routes, northern and southern, over the past ten years (Spencer Wells’ The Journey of Man sketches out the two wave model). Other assertions and assumptions have not stood the test of time. In particular, I would contend that generally the ‘conservative aspect of our genetic prehistory’ can no longer be taken for granted. Specifically, it seems likely now that much occurred after the Ice Age and during the Neolithic.

420px-AGMA_HérodoteThe false inferences of the early aughts were due to two primary problems. First, they relied heavily on the powerful new techniques of extraction and analysis of uniparental ineages; the male and female direct line of descent. Concretely, mtDNA and the nonrecombintant portion of the Y chromosome. The lack of recombination allows for relatively easy reconstruction of phylogenies assuming a coalescent model. Second, the inferences attempt to make connections between the patterns of variation in modern populations, and what one may infer about the past from those patterns. Obviously constructing a phylogeny, or plotting haplogroup frequencies as a function of geography, is rather straightforward science. But using these results to generate inferences of the past is often more of an art than a science, and implicit assumptions lurk behind the causal chains. Consider for example the utilization of modern Anatolian (i.e., Turkish) genetic variation as a reference for the expansion into Europe of Neolithic farmers from the Near East. This of course presumes that modern Anatolians are a good proxy for ancient Anatolians. There are various suggestive reasons for why this is a plausible assumption, but assemble enough plausible assumptions, and rely on their joint likelihood, and you construct a very rickety machinery of possibility.

In early 2007 I began to have serious doubts about the orthodoxy of genetic conservatism. The primary trigger was the story of the Etruscans. Here is the crux of the issue: there are two models for the origins of the Etruscans, first, that they were the pre-Indo-European autochthons of Italy, or, that they were the migrants from the eastern Mediterranean, in particular Anatolia. The second may seem an outlandish hypothesis, but there were several tendrils of evidence to support it. But perhaps the ’support’ which weighed most against it is that the fact that the Anatolian model has an ancient source, the Greek historian Herodotus. I should perhaps put historian in quotes as well, because Herodotus is often viewed more as a repeater of myths, and derided by some as the ‘father of lies’ (in this he stands in sharp contrast to contemporary perceptions of the ‘modern’ Thucydides, though revisionists have begun to challenge this narrative). In contrast, the model that Etruscans are indigenous to Italy, and that their ‘exotic’ foreign traits were simply acquired through trade and cultural diffusion, dovetailed well with the post-World War II ‘pots not peoples’ paradigm. That cultural change was ubiquitous, while at the same time populations were immobile. It was boring, prosaic, and conservative, and so an ideal null hypothesis.

But here it turns out that Herodotus was right, and archaeologists were wrong. Genetic analysis of modern Tuscans from isolated villages shows that some are surprisingly closely related to extant eastern Mediterranean lineages. Genetic analysis of Tuscan cattle showed that they were surprisingly closely related to extant eastern Mediterranean lineages of cattle. Finally, extraction of ancient Etruscan DNA showed that they were closely related to extant eastern Mediterranean lineages. The overlap was often with Anatolia, and combined with fragmentary linguistic and archaeological data, the evidence clearly points to an exogenous origin for the Etruscans. The boring null hypothesis was wrong. After these genetic stories gained prominence I went and reread recent archaeological texts on the Etruscans, and there were many models which showed exactly how Etruscan cultural uniqueness derived back to prehistoric Italy. It seems in hindsight that the prior assumption served as an interpretative filter, and people saw patterns that they were primed to see based on what they ‘knew’ to be the history of prehistoric and early Iron Age Tuscany.

Of course to refute the primacy of Oppenheimer’s conservative model of genetics one has to offer more examples than that of the Etruscans, and in particular, examples which are of greater scope and weight. I believe those examples exist. In the early aughts based on the mtDNA evidence the likelihood was that South Asian genetic variation is by and large a product of changes wrought upon the basic elements extant in the region around the end of the last Ice Age. The Y chromosomal data was more confused, though it did imply a closer relationship to groups in western Eurasia. But based on the mtDNA Oppenheimer posited a model whereby India was the mother of all non-Africans, that is, all non-African lineages derived from roots within the Indian subcontinent before the Last Glacial Maximum. This is at sharp variance with colonialist narratives of an Aryan invasion of the subcontinent, and the subjugation of the natives by quasi-European overlords, who are the ancestors of the moder upper castes. The charged ideological import of this model is transparently obvious.

Unfortunately the reality is likely more complex. I suspect that some form of Oppenheimer’s model is correct, insofar as South Asia was likely an important way station for modern humans as they left Africa, and pushed into other regions of Eurasia, on to Australasia and the New World. This interpretation does gain support from mtDNA, the direct maternal lineage. But a new analysis of South Asian genetic variation using a substantial proportion of the autosomal genome implies in fact that South Asians are possibly descendants of an ancient hybridization event between a native population with deep roots in the subcontinent, and a quasi-European population which was exogenous to the subcontinent.* Genetically the quasi-European population is quite close to northern Europeans, similar to the genetic distance between modern Finns and Italians, not trivial, but far closer than that between modern South Asians and Europeans. Was this the ancient Aryan invasion? I remain skeptical of this particular detail for various reasons, as I suspect that the history of the Indian subcontinent is in fact even more complex than has been assumed before (I think it is more likely that the quasi-Europeans came before the Indo-Aryans, who arrived late, and had a stronger cultural than genetic influence).

Finally, there is another region of the world where it seems likely that the old orthodoxies of genetic conservatism will be overthrown. That region is Europe. The scientific orthodoxy of deep time continuity is strong enough that it has percolated into the public consciousness, the leader of the British National Party even referred to the deep roots of white British in demarcating who he believed ‘indigenous people’ of the Isles were. But newer data is more supportive of the hypothesis that in fact Neolithic farmers who arrived from elsewhere are the likely ancestors of most Europeans, not the hunter-gatherers who remained after the Ice Age. Extraction of ancient DNA has yielded a set of results which simply are not explicable assuming the older models of genetic continuity, which were based on inferences made from modern population variation. If I had to hazard a guess, I would have some, though not high, confidence in the following story. First, the indigenous hunter-gatherers are assimilated or marginalized by waves of Neolithic farmers pushing out from the eastern Mediterranean. The demographic expansion does not necessarily sweep outward along a southeast-northwest axis, rather, it follows the Mediterranean and Atlantic fringes, as well as along river systems in the interior. Its impact is weakest in the northeast of Europe, where Middle Eastern crops are least suitable, and the natives have the most time to absorb the cultural toolkit of the newcomers so as to resist their advance. Second, and far later, there was another wave pushing out from the region of the Ukraine to the Volga, likely the ancestors of the Indo-Europeans. Tentatively I would contend that these were the carriers of the Kurgan culture, and also brought the allele for lactase persistence. Again, for ecological reasons the populations of the northeast Baltic and into the forests of northern Russia were most insulated from this push (and non-Indo-European languages persisted in Iberia down to Roman times, and specifically in the Basque-country down to modern times, though I suspect this is a function of distance). So modern European populations may be assumed to be tri-hybrid, first a synthesis of Middle Eastern farmers overlain upon the Paleolithic substrate, and second a synthesis of Indo-Europeans from the east overlain upon pre-Indo-European substrate. Unlike the case of India I suspect teasing out these patterns in modern populations is more difficult because the genetic distance between the three ancestral populations is far smaller than between the indigenous peoples of India before the quasi-Europeans arrived.

This leaves much of the world untouched by my speculations, but I believe showing that the genetically conservative null hypothesis is now in serious doubt in South Asia and Europe is sufficient to knock it from being a necessarily default assumption through which we must filter our interpretations. I do not believe that the reordering of human variation and the welter of population movement after the Ice Age was equivalent in effect to the Out of Africa migration, but I do believe that it was important enough to make the world of 2000 BCE very different from that of 15000 BCE in regards to genetic variation. In some cases, such as Central Asia from the Caspian to the Taklamakan the world of 2000 CE is fundamentally different from the world of 0 CE.

I will then end with a prediction, one in which I do not have much confidence, but which may no longer be wrong on the face of it with these new data in mind. Here is a passage from page 7 of Jared Diamond’s Guns, Germs, and Steel:

Initially, archaeologists considered the possibility that the colonization of Australia/New Guinea was achieved accidentally by just a few people swept to sea while fishing on a raft near an Indonesian island. In an extreme scenario the first settlers are pictured as having consisted of a single pregnant young woman carrying a male fetus…..

Let me stipulate that Diamond seems skeptical of the extreme model, but it illustrates the consensus that Australian Aboriginal populations are descended from the first settlers. That is, the modern populations of indigenous Australians are the direct descendants of those who swept Out of Africa along the fringe of the Indian ocean, through Southeast Asia, and arrived in Australia (more specifically, Sahul), on the order of 40 to 60 thousand years ago. From what genetic data I have seen this may be true. But I do not know of any extractions of ancient DNA, and it seems to me that the analysis of the phylogenetics of Australian Aboriginals is relatively sketchy. Therefore, I will suggest that within the last 10,000 years there has been a major new migration of people into Australia, and the modern range of genetic variation of Australian Aboriginals is significantly different from that of the populations of the Ice Age. I suggest this primarily because the dingo arrived within the last 10,000 years, more likely as recently as 4,000 years ago. With the expansion of the utility of ancient DNA extraction and analysis this question may be answered in the near future. I would still bet I’m wrong with the hypothesis I just offered, but I’m far less sure than I would have been 2 years ago.

Note: This post emerged from a conversation I had with Kevin Zelnio and Dave Munger.

* I say ‘quasi-European’ because the population may have origins outside of the boundaries of modern Europe at the Urals. Perhaps in western Siberia. Additionally, the idea of ‘Europe’ is relatively new, and exhibits little ancient cultural coherency.

Image source: Wikipedia

Dr. Pangloss in the house

Filed under: Economics,Finance — Razib Khan @ 3:14 pm

Daniel Gross has a piece out on the rise of the cash economy, Cash Is King I found this section interesting, though not surprising:

…During the go-go years, it was common to hear theorists talk about the “discipline of debt.” On paper, high debt loads force managers (and homeowners) to make tough, swift decisions to stay solvent. Default, and you lose the company (or the house). But in reality, rather than scrimp, overextended borrowers are more likely to walk away from mortgages, or push companies into Chapter 11 bankruptcy protection. Americans are now discovering that cash exerts a superior discipline. The real discipline of cash may be that it causes executives, consumers, and investors to think twice—and to think about the long-term consequences—before spending. The need for instant gratification is part of what created the current mess.

There’s theory, and then there’s reality. I really don’t know if cash is so much better at enforcing discipline, but I’m sure theorists can invent a new rationale for why it is superior to debt financing in maximizing economic utility. Economic behavior is the most amenable in the social domain to theorizing, but too often it seems to fall prey to false certainty and after the fact rationalization of the status quote as the timeless equilibrium. This of course does not mean that we should not think logically, or deduce inferences from what we know a priori. Rather, in the social domain we should be extremely self-aware of our uncertainty as to the validity of our inferences based on the lessons of history. For example, there’s an obvious straightforward possible social consequence in regards to the spread of cash envelope usage, more break-ins. The greater utilization of relatively concrete paper currency* and its consequent drawbacks will probably make us more cognizant of the benefits of more abstract financial tools such as revolving credit card accounts (e.g., you lose cash, you’re screwed, you lose your credit card, you’re insured).

* Paper currency is itself a relatively new invention over the scope of human history

March 26, 2010


Filed under: Blog,Katz — Razib Khan @ 1:25 pm

Open thread

Filed under: Administration,Open Thread — Razib Khan @ 8:33 am

Since I need to attend to non-internet related activities I thought I would leave this open thread for bugs, questions, etc. Seems like something happened to the feed within the past few hours, though it will be fixed soon. Thanks for understanding!

Natural selection & recombination in the human genome

Filed under: Genetics,Genomics,Human Genetic Variation,Population genetics — Razib Khan @ 8:28 am

If you are like me, and if you are reading this weblog there is a significant probability you are like me, you read L. L. Cavalli-Sforza’s History and Geography of Human Genes in the 1990s, and in the early aughts Spencer Wells’ A Journey of Man. Science has come very far in the last in the last 10-15 years, even Cavalli-Sforza’s magnum opus pales in comparison to the literal tsunami of data and analysis which the “post-genomic era” has ushered in. Instead of a gene here and there, or even the mtDNA and Y chromosome, researchers are now looking at hundreds of thousands of genetic variants, SNPs, across genomes. We’re rapidly approaching the era of whole genome sequencing, even if we’re not quite there yet.

But what’s the purpose of advances in technique and computation? Though the long-term project is to understand human variation and genetic function so as to have biomedical utility, in the short-term there is an enormous wealth of more abstract population genetic insight which can be extracted. Because of the biomedical focus of contemporary genomics we take a somewhat anthropocentric view, which is fine by me as I am an unregenerate speciest. The fish, fowl and crawling things of the earth can come later. And in any case, the beauty of the human focus of modern evolutionary genomics is that there are whole disciplines such as paleoanthropology which can serve as partners in interdisciplinary projects.

Humans are like any other organism, buffeted by conventional evolutionary genetic dynamics, drift, migration, natural selection, as well as processes which are more biophysically rooted such as recombination and mutation. Each of these processes leave their tell-tale marks on the genome. Mutation replenishes variation which drift and selection often eliminate, the former by chance and the latter in the form of negative selection. Migration serves to homogenize across populations through gene flow, while diversifying within populations by introducing novel variants. Finally, recombination breaks up linear associations of genetic variants along a DNA sequence, and has been used to explain sex.

In regards to H. sapiens it seems that our recent evolutionary history is dominated by a few big events. Within the last 100,000 years we underwent an extremely rapid population expansion from a small founding group within Africa, and radiated adaptively across all continents except for Antarctica. We are a then a relatively genetically homogeneous population, with much of the extant variation remaining within Africa, and the non-African groups getting progressively less diverse with distance from that continent. Basically a model whereby our species spread across the world via serial founder events. This simple model suffices in the broad sketch, but there is much more to the story. Over the past few years the older idea that current continental populations are the descendants of the first settlers, that is, the first modern humans who displaced the archaic populations which preceded them, seems unlikely to be to totally correct in all cases. It is likely wrong in Europe and to some extent India, no trivial exceptions.

There is much which can be said about details of demographic history in regards to the possibility of mass migrations, but today I want to focus on another dynamic: the effect of natural selection on the human genome. There are some researchers who are very skeptical of the efficacy of selection in shaping the patterns of variation we see, constraining it to a few loci such as that which confers lactase persistence or resistance to malaria. Others feel that selection’s power in shaping the genome is far more pervasive. Finally, there is a middle path, which emphasizes a diverse and complex portfolio.

A new paper explores the extent and nature of selection in human genomes through combining a rather old population genetic statistic with new expanded data sets and powerful statistical techniques, Human Population Differentiation Is Strongly Correlated with Local Recombination Rate:

Allele frequency differences across populations can provide valuable information both for studying population structure and for identifying loci that have been targets of natural selection. Here, we examine the relationship between recombination rate and population differentiation in humans by analyzing two uniformly-ascertained, whole-genome data sets. We find that population differentiation as assessed by inter-continental FSTshows negative correlation with recombination rate, with FST reduced by 10% in the tenth of the genome with the highest recombination rate compared with the tenth of the genome with the lowest recombination rate (P≪10−12). This pattern cannot be explained by the mutagenic properties of recombination and instead must reflect the impact of selection in the last 100,000 years since human continental populations split. The correlation between recombination rate andFST has a qualitatively different relationship for FST between African and non-African populations and for FST between European and East Asian populations, suggesting varying levels or types of selection in different epochs of human history.

You know of FST, even if you don’t know what FST is. You have heard that 15% of the variation in human genes is between races, and 85% within races. That 15% is an FST of 0.15. In other words,FST is a population genetic statistic which partitions the variance in genes between and within populations. If you have two populations and both have allele frequencies of 0.50 for two alleles, A & B, at one locus, then the FST would naturally be 0 as there is no between population difference, you can swap individuals from either group interchangeably for purposes of comparison. In contrast if the frequencies were disjoint so that all individuals in one population were of allele A and all individuals in the other of B, then naturally the FST would be 1, as all the variance is between populations, and all the information you need is found within population substructure. A perfect opportunity for profiling!

But this varies by gene and genomic region. As you know from above most variance is within races, not between them. But for the gene SLC24A5 almost all the variance is between Europeans and Africans, not within them. Similarly, all the variance on this gene is between Europeans and East Asians. Finally, there is no variance between East Asians and Africans on this gene. Why? Because it looks like that this gene has recently increased in frequency in West Eurasia, to the point where a new mutation has replaced the ancestral variant, which is common in Africa and East Eurasia. Additionally, it is notable that this genetic variant seems to account for 30-40% of the skin tone difference between Africans and Europeans. The point is that total genome variation is not always a good indicator of the evolutionary history of a specific gene. This is a problem especially in the case of those which we might find of interest.

In the paper above they find that areas of high recombination are negatively correlated with FST on a global scale. In other words, genomic regions which recombine more often across DNA strands and so shuffle genetic variation about and break apart linear associations show lower FST values. Reduced between population variation.

It’s rather clear in their first figure. Before we jump to that, let me note that they’re using the Perlegen data set, which has two dozen African Americans, Chinese and Europeans, respectively, and 1 million SNPs. Each panel has the FST values on the Y axis, and the recombination rate on the X axis.


It’s pretty clear what’s going on just through inspection. There’s an average decrease of 4% in FST for every 1 cM increase in recombination rate. The correlation estimates for FST and median recombination rates are for each panel:

A −0.962 (P = 8.9×10−6)
B −0.815 (P = 0.0041)
C −0.931 (P = 0.0001)
D −0.361 (P = 0.306)

The correlation estimates tell you something you can see visually: there’s a big difference in the relationships contingent upon which populations you’re using to calculate FST. In particular, a lot of the linear relationship between FST and recombination rate is actually due to the African vs. non-African difference. This is not a total surprise, Africans have a lot of genetic variation. In terms of genes one can think of non-Africans as simply a branch of Africans in many ways. Additionally, there’s been suggestive data for a decade now that when Africans left Africa they were subject to new selection pressures which seem common to Eurasians as a whole (though to be fair these signatures of selective sweeps in Eurasia may simply be false positives generated by population bottlenecks and the like).

Yes, I will work back to selection from genetic variation; the two are related, though the relation can be subtle. So why the negative correlation between FST and recombination? Consider an SNP, a single DNA base pair, which is subject to positive selection. It can increase rapidly in frequency so that it goes from ~0 to ~1 in proportion with the population. Fair enough, but SNPs do not exist in an abstract universe, they’re physically embedded in DNA, and so are flanked by many other bases. If an SNP is subject to powerful directional selection which drives its frequency upward, then adjacent bases also “hitchhike” along in frequency. In other words, powerful directional selection can reorder the variation of whole genomic regions, depending on how powerful the selection is. It can sweep away the noisy scatter of variants introduced over many generations by mutation and replace them with a long sequence of alleles from an ancestral genome which harbored the selected variant. Over time mutation can mask the homogenization as it replenishes variation, but there is also another dynamic which blocks the long march to genetic uniformity: recombination. Recombination can tear apart blocks of alleles as they sweep up in frequency, and the more recombination, the greater the counterforce to the homogenizing power of selection on the local genome as the block is chopped up evermore.

Now consider the nature of selection in different populations. Let us stipulate that the light skin of East Asians and Europeans are adaptations; we know that they are conferred by different SNPs. In other words, selection operated on different genetic variants to produce the adaptation (though by and large across the same set of genes). Therefore, FST on pigmentation genes is relatively high because of between population difference, and these genes tend to be surrounded by regions of homogenization as they seem to have swept up to high frequency rapidly and dragged along many nearby alleles. Assuming this effect of natural selection equal recombination would naturally tend to work against increased FST by reducing the number of linked alleles being dragged along by breaking apart the genomic blocks along their transient up.

A similar effect occurs in the case of background selection, which is operative around deleterious mutations. When there are alleles which are negatively selected their neighbors are also effected; consider it a sort of population genetic “property value.” Because negative selection tends to reduce effective population size, on a large geographical scale it can result in increased FST (consider the genetic uniqueness of isolated populations which have gone through bottlenecks). Again, recombination can blunt the impact of a deleterious allele on its neighbors. The authors do note that the particular dynamics of positive and background selection differ, the latter is a gentler affair by far, a repetitive tap as opposed to a sledgehammer, but the genomic resolution of their analysis is such that they lack power to explore these differences.

I’ll let the authors describe the peculiarities of the European-Chinese panel:

…The weaker correlation for the FST between European and Chinese populations is driven by a dip in differentiation at very low recombination rate loci…which is not at all what is seen in the comparison of African and non-African populations…This curve shows a qualitatively non-monotonic pattern, which motivated us to perform a quadratic regression fitted within the bootstrapping framework. The regression is concave and includes very significant linear (P = 3.0×10−4) as well as quadratic (P = 1.8×10−5) terms. Conversely, quadratic regression gives a non-significant quadratic term for FST between African Americans and each of the other two populations and if anything is slightly convex. As expected, for single SNP analysis (without binning by recombination rate), linear regression is very significant for FST between African Americans and either non-African population (P≪10−12). For FST between Chinese and Europeans, however, linear regression is not significant (P = 0.81), while a quadratic regression is very significant (P≪10−12)….

Non-monotic is just a way to say that the trend reverses direction. In other words, the linear model isn’t too good a fit on what’s going on with the variation between Europeans and Chinese, and how it relates to recombination rates. They offer two speculative possibilities for the “inverted U-shaped” nature of the relationship between FST and recombination in Europeans and Chinese. First, the smaller effective population sizes of non-African groups results in greater efficacy of background selection. As random genetic drift tends to increase the frequency of deleterious alleles, powerful negative selection is given opportunity work against that region of the genome. This results in more background selection as adjacent genomic regions are impacted. Because of differing population sizes the balance between positive and background selection is different for Africans and non-Africans. A second hypothesis is that gene flow between the two Eurasian groups allowed for selective sweeps to move from one group to the other. In other words, between population variance can be reduced if a favored alleles spreads across all populations from one original group (lactase persistence in much of northern Eurasia may be a case of just this).

Intriguingly they found the linear relationship between FST and recombination to be stronger in genomic regions which are coding (i.e., they have genes which code for proteins), and in particular in the X chromosome. The second aligns with other recent work which indicates that the X chromosome may be subject to stronger selective pressures than the rest of the genome because of its peculiar expression pattern (males have only one copy of the gene, and females express only one copy per cell due to X chromosome inactivation).

Finally, they replicated their results using other data sets. I’ll just show the figure from HapMap3:

I obviously rotated so you could see the labels at higher resolution. Here are the populations:

WAF (“West African”) is a combined sample of YRI (Yoruba in Ibadan, Nigeria) and LWK (Luhya in Webuye, Kenya)

EAS (“East Asia”) is a combined sample of CHB (Han Chinese in Beijing, China), CHD (Chinese in Metropolitan Denver, CO, USA), and JPT (Japanese in Tokyo, Japan)

EUR (“Europe”) is a combined sample of CEU (ancestry from Northern and Western Europe) and TSI (Toscani in Italia)

GIH is a sample of Gujarati Indians in Houston, TX, USA

MKK is a sample of Maasai in Kinyawa, Kenya; and CHI (Chinese) is a combined sample of CHB and CHD.

Their analysis of these findings are cautious:

A striking result is that the relationship between FST and recombination rate is stronger for FST between pairs of closely-related populations, whether within or outside Africa: FST between a West African sample and Maasai (of mixed West African and East African ancestry…decreases by an average of 6% for every 1 cM/Mb…FST between Italians and individuals of North-Western European ancestry decreases by 10% for every cM/Mb …and FST between Japanese and individuals of Chinese ancestry decreases by 4%...In view of the large effective population size in recent human history since each of these pairs of populations have split, these observations support the possibility that the different patterns observed between different pairs of populations are due to natural selection operating more efficiently in the context of larger population sizes. We observed a weak convex relationship with recombination rate for FSTbetween closely-related populations in a quadratic regression analysis …which is intriguingly opposite to what was observed between Europeans and Asians…On the other hand, these observations do not seem to support the possibility that the different patterns are due to selective sweeps being shared to different extent across different pairs of populations since the level of gene flow between HapMap 3 closely-related populations likely have had been higher than that between continents. These results, while interesting, should be viewed with caution due to the confounder of ascertainment bias. It will be possible to test these observations further by analyzing data from the 1000 Genomes Project, where whole-genome sequencing will generate data that is largely free of ascertainment bias for many of the HapMap 3 populations as well as additional populations

The reason that selection would be more powerful at large population sizes is that the noise of random genetic drift is less likely to interfere with its deterministic process. Additionally, one presumes there would be more extant genetic variation in large populations than small ones. But though these results are interesting, they don’t seem to put too much stock in them.

Let me finish with the author’s conclusion:

In conclusion, we have shown that genome-wide human population differentiation in allele frequencies is significantly correlated with recombination rate on a megabase scale, demonstrating that natural selection has had a profound effect on allele frequency distributions averaged over the last hundred thousand years. While these results likely reflect the effects of hitchhiking and background selection, disentangling the strengths of these two forces will require extending the analyses presented in this paper. One important direction is to use genetic maps that have fine spatial resolution, which may shed light on the detailed distribution of selective coefficients that have shaped allele frequency differentiation. A second direction in which these results can be extended is to compare more populations of continentally diverse ancestry. This should facilitate an exploration of the relationship between recombination rate and population differentiation during different epochs of human evolution, and should allow a better understanding of how demographic history has shaped the impact of natural selection on patterns of human genetic variation.

Note: I left a lot out in this treatment. It’s Open Access so you can read the whole thing!

Citation: Keinan A, Reich D, 2010 Human Population Differentiation Is Strongly Correlated with Local Recombination Rate. PLoS Genet 6(3): e1000886. doi:10.1371/journal.pgen.1000886

Nice digs, nice neighbors

Filed under: Administration,Carl Zimmer Wild-Man — Razib Khan @ 7:35 am

Compliments back at you Ms. Kirshenbaum. Short time no see! Now let’s get the party started. I’ll let Carl go first, since he’s a wild-man.

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