When sickliness is manliness

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

The ways of the forefathers & foremothers

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

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

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

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)

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.

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

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?

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.