Category Archives: journal club

The Genetical Book Review: The Postmortal

So, welcome to the first Genetical Book Review of 2012, where we’re going to talk about The Postmortal, by Drew Magary. As the book starts, Science!™ has developed a cure for aging, so that people can live forever. What follows is an exploration of the psychological and sociological consequences of immortality.

I love this picture. You can almost hear Death going, “D’oh.”

I don’t think I’m giving anything away when I tell you that the book winds up being predominantly dystopian. Basically, if you are the sort of person who frets about the future of humanity, who is prone to think things like, “How could I possibly bring a child into this world,” well, don’t read this book. At least, don’t read it in bed after a spicy take-out meal.

If you do enjoy the occasional sci-fi dystopia, this one is of the variety where you make only a small technological (or, in this case, medical) change, and explore the implications in a world that is otherwise very much like our own. One of the interesting things that the author gets to do with this particular premise is to follow history over many decades through the eyes of a single, first-person narrator. So, the protagonist experiences technological and societal changes that would normally take place over the course of generations.

The book is presented as a series of blog posts, some of which are personal, narrative entries, and some transcripts of news reports, others link roundups, and so on. Magary is a contributing editor at Deadspin, and his reporting / media background shows through in the writing. The whole book is engaging, but the writing really shines in the news bits, which are pitch-perfect.

In the book, the cure for aging is achieved through gene therapy, targeted at a single locus, which seems to be closely linked to MC1R, the gene most commonly responsible for redheadedness. What we’re going to use this as a jumping-off point to talk about different evolutionary theories of aging, and the extent to which each might be consistent with the existence of a single gene serving as a master control over the aging process.

In The Postmortal, the cure for aging is discovered serendipitously as a byproduct of research aimed at changing hair color. In our actual dystopia, it would have gone differently. Benjamin Button would have been indefinitely detained under NDAA and selectively bred with normal humans. A series of backcrosses would have been used to isolate the gene responsible for his aging reversal. 

But first, a couple of quibbles.

Quibble number 1. There are two biologists who feature prominently in the book: father and son Graham and Steven Otto. Now, I’m not going to argue sexism on the basis of a sample of two, since, even in a world with full gender equality, a random sample of two scientists would both be male about 1/4 of the time (p = 0.25). However, Graham Otto’s devoted wife (and Steven Otto’s loving mother) is (apparent) non-scientist Sarah Otto. It just so happens (presumably unbeknownst to Magary) that there is a real-life Sarah Otto, a prominent biologist who was just awarded a Macarthur “genius” grant. So, that’s . . . unfortunate.

Quibble number 2. The “cure for aging” as presented in the book arrests an individual at whatever age they are when they receive the cure, whether it is three or eighty-three. This actually conflates two different processes: development and senescence. My biological intuition is that, even in the simplest conceivable case, there would be at least two distinct master switches controlling these very different processes. (Actually, possibly a third switch as well, controlling puberty and the onset of secondary sexual characteristics, as distinct from growth to adult size and shape.)

In talking about evolutionary theories of “aging,” I will focus on evolutionary theories of senescence, which is really the most important aspect of “aging” with respect to this book.

[Note: none of this should be interpreted as a criticism of the premise or execution of the book, which I loved. The inherent power of science fiction comes from the idea that you build a world that differs from our own. Rather, as always with The Genetical Book Review, the book’s premise serves as an excuse and a specific context for talking about evolution.]

Basically, there are three major classes of ideas about the evolutionary origins of senescence, which have different implications for how much and how easily natural selection or medical intervention might be able to extend our lifespans. As is often the case, these different theories are not necessarily mutually exclusive or incompatible, but rather have different emphases. Most consistent with the premise of the book are theories that propose a positive adaptive value to senescence and mortality. Somewhat less consistent are theories that focus on senescence as a byproduct of the fact that natural selection becomes weaker for traits that are expressed later in life. Least consistent are theories suggesting that senescence and lifespan are profoundly constrained by biological universals. We’ll take each of these in turn.

Just as youth is wasted on the young, discounts are wasted on the elderly.

1) Senescence as an adaptation.

The idea that there could be a single genetic master switch controlling senescence is most plausible under models where aging and death are specifically adaptive. How would that work, you ask. I mean, after all, the whole idea behind natural selection is that is favors surviving and reproducing, right? Well, in some models, you can actually identify conditions where it makes sense beyond a certain age for adults to go ahead and die. One particular model (cited below) describes an adaptive benefit (at the group / inclusive fitness level) to senescence from limiting the spread of disease.

Perhaps somewhat more generally applicable are models in which senescence is selectively favored as part of a trade off. The idea is that it would be possible to construct a human who lived to be, say, 150, but that it could only be achieved through some sort of compensatory change in another trait. Candidate examples would be size or reproductive output. In fact, all else being equal, smaller humans do tend to live longer than larger ones. Similarly, there are a handful of studies purporting to show that abstaining from reproduction extends lifespan.

In this sort of case, it is easy to see how natural selection might actually favor earlier senescence. To first order, what matters to evolution is how many offspring you produce. If you can grow big and have lots of kids, you’re going to win the evolutionary race, even if it means that you drop dead of a heart attack at thirty-five.

Under one of these models, it is easy to imagine the existence of one or a few genes that function as controllers, or strong modifiers, of senescence. Under the strongest version, you can even imagine a gene affecting only senescence. Under the weaker, trade-off version, it might be possible to dramatically extend lifespan, but not without side effects. Maybe the immortals would all weigh eighty pounds and have dramatically – or indefinitely – delayed onset of reproductive capacity.

In a world dominated by evolutionary trade-offs, the immortals will all be Romanian.

2) Senescence as the absence of selection.

Imagine one trait that affects the probability that you survive to age ten. Now imagine a second trait that affects the probability that you survive from ten to twenty. Whatever selection is acting on the second trait, it has to be weaker than what is acting on the first one. The reason is that the second trait is under selection only in that subset of the population that survives to be ten.

This argument, of course, blends into the trade-off argument introduced earlier. We can imagine traits that trade off health (and survival) at later ages in exchange for enhanced health at earlier ages. In general, such traits will tend to be favored. Basically, it doesn’t matter how robust you are at eighty if you die at twenty.

Even without such tradeoffs, however, we expect to see natural selection growing weaker with age. Given any rate of death (due to choking on litchi nuts, falling off cliffs, being eaten by tigers, whatever), there will be more people alive at age x than at age x + y, for any y > 0. So, the older you are, the less power natural selection has to fight against entropy – both the familiar entropy of the physical world and the evolutionary entropy of the mutation process.

Some of the evidence in support of this idea comes from the fact that there are certain species that tend to live longer than expected. Included among these are birds, porcupines, and humans. What do those have in common? The reason in each case is different, but each has a reduced rate of predation. If you reduce the death rate, you increase the power of selection to slow down the aging process.

One consequence of this is that we expect all of the different systems that make up our bodies to fail at similar rates. For instance, if the human heart just gives out after 100 years, any and all selection goes away for maintaining anything else (brain, kidneys, liver, etc.) for longer than that. This perspective suggests that there will not be a single tweak that could stop aging. Rather, it would require a whole bunch of tweaks, or maybe something more like a Never-Let-Me-Go-style organ harvesting scheme.

3) Senescence as a fundamental constraint.

These ideas come from the existence of certain universal scaling laws, regularities in the relationship between features like body mass, metabolic rate, and lifespan. There are a lot of ideas out there, but what, exactly, is driving these relationships is not yet understood. However, the relationships themselves seems to be fairly robust.

One of the striking findings in this area is the fact that, among species with a heart, an individual’s lifespan corresponds to about 1.5 billion heartbeats. Small species have fast metabolic rates, fast heartbeats, and short lives. Large species live slower and longer.

Once again, these ideas are not mutually exclusive with the “rates of predation” idea. In fact, when we say that species like birds and humans live “longer than expected,” these scaling relationships determine what “expected” is. For instance, a human with a heartrate of 72 beats per minute might live to have about 3 billion heartbeats.

Whatever the origin of these patterns, their apparent universality suggests the existence of very deep constraints on our biology. While natural selection (or medicine) might be able to alter our lifespans, it may be that such intervention is limited to relatively small changes, maybe a factor of two. Perhaps something human sized that could live for many hundreds of years would have to be based on a fundamentally different biological architecture.

Following the 2012 Mayan-Zombie/Santorum-Paul apocalypse, humans and other land-based vertebrates will become extinct. Eventually, cephalopod-based land dwellers will eventually emerge to fill our vacated ecological niche.
Perhaps they will live longer. Image via Chowgood’s Deviant Art page.

So, overall, I think the likelihood of a single medical advance that dramatically increases our natural lifespans is pretty remote. But, as you’ll see if you read the book, that might be for the best.

Here are just a few references to get you started if you are interested in the evolutionary constraints on lifespan and senescence.

Glazier, D. (2008). Effects of metabolic level on the body size scaling of metabolic rate in birds and mammals Proceedings of the Royal Society B: Biological Sciences, 275 (1641), 1405-1410 DOI: 10.1098/rspb.2008.0118

Mitteldorf J, & Pepper J (2009). Senescence as an adaptation to limit the spread of disease. Journal of theoretical biology, 260 (2), 186-95 PMID: 19481552

Williams, G. C. (1957). Pleiotropy, Natural Selection, and the Evolution of Senescence Evolution, 11 (4), 398-411

Well, that’s all for today! Check back again soon, as The Genetical Book Review will be posting more frequently in 2012.

Buy it now!!

What’s that? You say you want to buy this book? And you want to support Lost in Transcription at the same time? Well, for you, sir and/or madam, I present these links.

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Mitochondria and Hypertension

So, here’s a new thing.

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This is based on a recent paper (citation below) where they identify a point mutation in the mitochondrial DNA that appears to result in hypertension.

So why is this interesting? Well, for me, as an evolutionary theorist who works on intragenomic conflict, it is interesting because the mitochondrial DNA is, in principle, subject to selection pressures different from the rest of the genome. For instance, mitochondrial genes present in a female would, in principle, benefit from skewing the sex ratio of the offspring of that female, since those genes can only be passed on to grandchildren through daughters. Furthermore, since mitochondria are maternally inherited, the intragenomic conflicts over inclusive fitness effects that underlie the phenomenon of genomic imprinting could potentially shape the evolution of mitochondrial genes as well.

Sadly (from the theory perspective), the scope of phenomena influenced by mitochondria is fairly limited, with a lot of the effects limited to core metabolism. That’s not to say that core metabolism is not important. Obviously, core metabolism is important to the survival of the individual. In fact the importance of these genes to survival is exactly what tends to make them evolutionarily less interesting. By and large, core metabolism is unlikely to be a significant locus of intragenomic conflict because all of the genes in an individual need that individual to be able to do things like, e.g., make ATP.

From this perspective, then, this mutation is interesting in that it represents an example of a phenotype that can be quantitatively affected by the mtDNA. This particular mutation is likely best interpreted as a mildly deleterious one that happens to exist within a particular family in China. However, it opens up the possibility of mutations with subtler phenotypic effects, which could potentially be subject to divergent selective pressures for different parts of the genome. For instance, if elevated blood pressure during pregnancy results in a greater transfer of resources from mother to offspring, we would expect autosomal and mitochondrial genes to favor different optimal blood pressures.

The other thing that is interesting is the type of mutation it is. It is actually a point mutation in the gene that produces the mitochondrial Isoleucine tRNA. This mutation messes up a site that is cleaved as a part of the normal post-transcriptional processing. The result is that the steady-state level of mitochondrial Isoleucine tRNA is reduced by 46%. This, in turn, impacts the translation of other mitochondrial gene products with protein translation reduced by an average of 32%. So, basically what it does is just muck up mitochondrial function a little bit.

Wang, S., Li, R., Fettermann, A., Li, Z., Qian, Y., Liu, Y., Wang, X., Zhou, A., Mo, J., Yang, L., Jiang, P., Taschner, A., Rossmanith, W., & Guan, M. (2011). Maternally Inherited Essential Hypertension Is Associated With the Novel 4263AG Mutation in the Mitochondrial tRNAIle Gene in a Large Han Chinese Family Circulation Research, 108 (7), 862-870 DOI: 10.1161/CIRCRESAHA.110.231811

Egypt Week – Genetic Conflict and Social Dominance

So, our next scientific Egypt Week post concerns a paper just published in last week’s issue of Nature, where the authors describe novel behavioral effects of the imprinted gene Grb10 in the mouse.

If you’re not familiar, genomic imprinting is the phenomenon where the expression pattern of a gene depends on its parental origin. So, most of your genes come in two copies, one of which came from your mom, and one of which came from your dad. For most genes, the function of the allele, or gene copy, depends just on its DNA sequence. But something like 1% of our genes are imprinted, meaning that they retain a chemical memory of which parent they came from, so that the two gene copies will function differently, even if the DNA sequences are identical.

The most widely accepted theory for the evolutionary origin of gene expression suggests that it is the result of an intragenomic conflict between maternally and paternally inherited gene copies. That is, from a gene’s-eye point of view, natural selection acts differently on maternally and paternally derived alleles.

Many imprinted genes in mammals have growth effects in early development, and these most of these effects are well described by models where selection favors more growth (and a greater demand on maternal resources) when alleles are paternally derived, and less growth (preserving more maternal resources for the mother’s other offspring) when maternally derived.

There is also evidence for large-scale imprinted gene expression in the brain, and evidence that these imprinted genes may have substantial effects on cognition and behavior. We are still at the early stages of describing these effects, and at even earlier stages of understanding the relevant evolutionary pressures.

Elsewhere on this blog, I have begun writing a series of primers on genomic imprinting, links to which can be found here, if you are interested in more background.

Today’s paper describes the effects of the two parental knockouts of the Grb10 gene. Grb10 is a particularly interesting imprinted gene, because it is maternally expressed in many peripheral tissues, but paternally expressed in the central nervous system. So, when you knock out the maternally inherited copy, you get a complete loss of function in the periphery, but don’t impact Grb10 expression in the brain. Conversely, when you knock out the paternally inherited copy, you lose gene function in the brain, but leave expression in the periphery unaffected.

The phenotype of the maternal knockout is more or less what is expected in terms of growth effects, and is consistent with previous studies of this gene. Theory predicts that if a growth-related imprinted gene is maternally expressed, it likely functions as a suppressor of growth. When the maternal copy of Grb10 was knocked out, the result was overgrowth, due to the loss of this growth-suppressing function.

The knockout of the paternally inherited results in a behavioral phenotype associated with increased social dominance, as indicated by two specific behaviors. The first dominance behavior was observed in a “tube test.” In this test, two mice who don’t know each other are forced to encounter each other in a tube. In this setting, the knockout mice are less likely to back down than the wild-type (normal) mice are.

The second observation was an increase in allogrooming and barbering. Let’s pause for a moment to talk about what that means. Allogrooming is where one individual grooms another individual (in contrast to autogrooming, where you groom yourself). Barbering is where the grooming gets out of hand, and the groomee gets big bald (and sometimes bruised and bloody) patches.

Now, intuitively, you might assume that grooming behavior is submissive, like the handmaid combing out the princess’s hair. In mice, at least, it’s not like that. If you have a pet mouse, and it is grooming you, it is actually being dominant. It’s more like when you sit your little sister down in a chair and put makeup on her – the goal is NOT to make her look good. And, if you are feeling really mean, you give her a haircut, too.

The researchers argue that the behavioral effect is specific to social dominance, as tests designed to look at anxiety, locomotion (moving), olfaction (smelling), and aggression all found no differences between these knockouts and wild-type (normal) mice.
A conflict-based interpretation of these behavioral results would suggest that, for some reason, maternally inherited genes place a greater premium on establishing social dominance than do paternally inherited genes. (In the nervous system, the gene is paternally expressed, and knocking it out increased dominance behaviors. This implies that the gene normally acts to limit dominance behaviors.)

A bemedallioned Hosni Mubarak helps to illustrate the intragenomic conflict over social dominance behaviors. Natural selection favors alleles that enhance socially dominant behaviors when they are maternally derived, but limit socially dominant behaviors when paternally derived. The study was performed in mice, and it is important to note that the patterns of imprinted gene expression can vary among species, so we can not extrapolate from these results to the influence of Grb10 on human cognition and behavior. However, mice and rats are closely related, so we are probably safe extrapolating to Mubarak.

The next question is why would alleles favor more socially dominant behaviors when maternally derived? Fundamentally, at this point we have no idea. This is where the modeling has to come in. In this type of situation it is always possible to come up with a host of possible explanations, all of which sound plausible, and all of which would predict that a paternally expressed gene would limit dominance. The key thing is to model each of those explanations formally, so that we know what key ecological and demographic factors underlie the explanation. Then, we find other species where those factors differ, and examine the imprinting status and phenotypic effect of Grb10 in those species.

For the less politically oriented, the intragenomic conflict over social dominance is like this. Nadya “Octomom” Suleman is like your maternally inherited genome, while the guy with the moustache and the milk bottle is like your paternally inherited genome. Image from the Daily Mail.

Peace be upon you.

Garfield AS, Cowley M, Smith FM, Moorwood K, Stewart-Cox JE, Gilroy K, Baker S, Xia J, Dalley JW, Hurst LD, Wilkinson LS, Isles AR, & Ward A (2011). Distinct physiological and behavioural functions for parental alleles of imprinted Grb10. Nature, 469 (7331), 534-8 PMID: 21270893 [1]


[1] Disclosure: I didn’t really intend for Egypt Week to devolve into blog-posts-about-papers-by-collaborators-of-mine week, but there you have it. I have an ongoing collaboration with Anthony Isles, and know some of the other authors.

Egypt Week – Corruption and Cooperation

This post was chosen as an Editor's Selection for So, our next Egypt Week feature is a theoretical paper on a topic closely related to the last post. Once again, we are interested in understanding the mechanisms that are responsible for encouraging or enforcing cooperation, thereby facilitating collective action. Last time, we talked about a paper that found that “altruistic” or “third-party” punishment is common in large-scale, complex societies, but is rare in small-scale societies, while “spiteful” punishment is universal.

Many empirical and theoretical studies of cooperation focus on punishment as a mechanism for enforcing societal norms. Basically, you set up a situation where the group benefits if people cooperate, but each individual benefits by not cooperating. If mechanisms exist to punish people for not cooperating, you get cooperation. Which is to say that the existence of punishment changes the individuals’ incentives. The benefits of not cooperating are outweighed by the cost of being punished. No big mystery there.

But what if punishment itself is costly? Punishment can stabilize cooperation, but what stabilizes punishment? Some models rely on an infinite succession of punishments, where people punish people who fail to punish people who fail to cooperate, and people punish people who fail to punish people who fail to punish people who fail to cooperate, and people punish … well, you get the idea.

Today’s paper asks if cooperation can be enforced by corrupt punishment. That is, while punishment is still treated as costly, punishers are not necessarily cooperators themselves, as is commonly assumed in models of this sort. Furthermore, the corrupt punishers (“policers”) suffer a lower cost when punished than do non-punishers (“civilians”).

A corrupt policer looks forward to a cushy retirement, thanks to his hypocritical enforcement of others’ cooperation. Little does he suspect how a new, young partner, who colors outside the lines, but has a heart of gold, will turn his whole life upside-down, with hilarious consequences.

The model shows that in the presence of a modest power imbalance, cooperating civilians and corrupt policers can coexist. That is, a moderate level of corruption is consistent with, and can even stabilize cooperation. However, when the power imbalance becomes large, corrupt policers overrun the population, the system breaks down, and cooperation is lost.

The first part of the result is nice because it provides a degree of robustness to the “cooperation through punishment” paradigm, as it does not require the punishers to be acting altruistically themselves.

The second part of the result is perhaps more directly relevant to Egypt Week. Societies can function in the presence of a degree of inequality, and they can tolerate a certain amount of hypocrisy from their leaders. But too much hypocrisy and inequality is inconsistent with the type of collective action that governments are meant to facilitate.

It is heartening to see that when a less corrupt alternative presents itself, people are still capable of collective action on a massive scale.

Peace be upon you.

Úbeda, F., & Duéñez-Guzmán, E. (2010). POWER AND CORRUPTION Evolution DOI: 10.1111/j.1558-5646.2010.01194.x [1] [2]


[1] This is an online, ahead-of-print publication, which is why there are no page numbers, but it should be findable through the DOI.

[2] Disclosure: The first author on this paper is a long-time friend and colleague, and we have worked together on issues of intragenomic conflict. Here is photographic evidence of our friendship, from when we were traveling around Lyon, France like Thelmo and Louis following the 2010 SMBE meeting:

On our way to the Palais de Justice, we accidentally activated our Wonder-Twin Powers. Francisco took the shape of an evolutionary biologist, and I took the form of a French trash can. Photo by Gleek.

Egypt Week – Spiteful versus Altruistic Punishment

So, welcome to the first Egypt Week edition of Lost in Transcription. We’re going to kick it off with an anthropology paper that uses a cross-cultural approach to study the origins of human punishment and cooperation.

If you’re not familiar with this vein of research, let me set the stage for you. The “problem” of cooperation when people talk about it in anthropology, biology, and economics is this. If you take a super naive view of natural selection, it would say that we should have evolved to ruthlessly pursue our own self interest. In particular, if we have an opportunity to cheat and get away with it, the logic of self interest suggests that we should. From this perspective, the whole idea of successfully engaging in collective action seems absurd.

Contrary to this naive expectation, we observe that people do forego opportunities to pursue their own narrow self interest, and the history of civilization is one of successful collective action on an enormous scale.

Of course, at some level, we know what the answer is.[1] Natural selection does not act only on the short-term self interest of the individual, but favors behaviors that enhance survival, reproduction, and the propagation of the genes carried by the individual. Those things are all affected by more that just who gets the biggest piece of the pie in a given interaction. Other factors that come in to play include selection on kin or social groups, the establishment and enforcement of social norms, and systems of reward, punishment, and reputation.

So, much of the work in this field focuses on trying to figure out which among these various effects has played the greatest role in the origin of the enormous capacity for cooperation that underlies all human societies.

This paper uses a standard set of experimental protocols, applied to twelve societies that differ enormously in size and complexity of social organization. The societies studied span the range from the Hadza, hunter-gatherers from Tanzania, to the people of Accra, the capital city of Ghana. Each experiment is a two-player or three-player game in which the players make decisions that determine how money is distributed. The goal here is to measure the degree of “altruism” in each society, the degree of “second-party” punishment (how willing are people to punish someone who is not generous to them), and the degree of “third-party” punishment (how willing are people to punish someone who is not generous to someone else).

The first experiment used was the Dictator Game (DG), in which the experimenter provides Player 1 with an allotment of money, and Player 1 determines how that money will be divided between themselves and Player 2. The game is played once, and is played anonymously, so there is nothing to stop Player 1 from offering nothing to Player 2. This experiment establishes a baseline level of cooperation or altruism, quantified by the average proportion of the money that Player 2 receives.

The second experiment is the Ultimatum Game (UG). This is like the Dictator Game, but Player 1 proposes a division of the allotment of money, and Player 2 can either accept or reject this proposal. If Player 2 rejects, both players walk away with nothing. This measures the willingness to punish ungenerous individuals who make low offers. Note that for any non-zero offer, Player 2 actually has to give up money in order to punish Player 1, making this a “spiteful” form of punishment.

The third experiment is the Dictator Game, but involves a third player, who receives an allotment of money from the experimenter. After Player 1 determines how the primary allotment will be divided between him/herself and Player 2, this third player has the option of paying back a portion of their allotment in order to have three times that amount taken away from Player 1. This again measures the willingness to punish an ungenerous offer, but this time the punishment is “altruistic” rather than “spiteful,” since the punisher was not actually the one who suffered the ungenerous offer.

A few general patterns emerged from this set of experiments.

(1) Small-scale societies were less generous (Player 1 made lower offers) across all three games compared with larger societies.

(2) Second-party punishment was observed at similar rates across all societies. Thus, in the small-scale societies, individuals “expect to get a fair share even when they do not want to give a fair share.”

(3) Third-party punishment was much more common in larger societies. And, in fact, in those larger societies, third-party, “altruistic” punishment occurred more often than “spiteful” second-party punishment.

Taken together, what these patterns support the idea that human cooperation may have emerged first in the context of spiteful punishment, rather than through altruistic or community-oriented enforcement of social norms. They suggest that third-party punishment arises only with the establishment of more complex societies. In particular, once a society exceeds a certain size, it becomes difficult to keep track of individual reputations. In such groups, collective-action problems require the existence of institutions that promote and reward third-party punishment.

Peace be upon you.

Marlowe, F., Berbesque, J., Barrett, C., Bolyanatz, A., Gurven, M., & Tracer, D. (2010). The ‘spiteful’ origins of human cooperation Proceedings of the Royal Society B: Biological Sciences DOI: 10.1098/rspb.2010.2342 [2]


[1] Editorial note: This is a version of the answer that comes up again and again in science. The world is a complicated place. We (scientists) come in and try to describe it using a really simple model. Then we feign surprise that the simple model does not adequately describe the behavior of the system that we are supposedly modeling. We declare that there is a paradox and build a field around resolving it. This is all fine, as it is just the way that science works, but it is worth remembering that many of the “problems” in science are really artifacts of simplistic models that have achieved an iconic status.

[2] Disclosure: Frank Marlowe, who is the first author on this paper, is a friend, and we have written a paper together on the genetic and ethnographic evidence regarding sex-biased migration in humans.

Mathematicians and Mongeese: Peeing to Defend Territory? or Mates?

So, you may have heard about Tihomir Petrov, the math professor at Cal State, Northridge who was arrested for urinating on his colleague’s office door. Campus security got video footage of Petrov in the act when they set up video cameras following the discovery of “puddles of what they thought was urine.”

You may be asking yourself, what the heck was this dude thinking? How should we interpret the behavior of this Homo mathematicus (not that there’s anything wrong with it) specimen?

What Professor Petrov was probably thinking.

Fortunately, once again, Science!™ has an answer for you. Urine is commonly used as a scent marker to deter competitors. But deter them from what? Traditionally, it has been assumed that scent marking is primarily used to defend territory against intruders, thereby safeguarding resources such as food and space. However, some recent studies have suggested that scent marking may be used to defend mates and mating opportunities. One of the difficulties in studying such a question, however, is that in many systems, competitors for territory and competitors for mates are the same individuals.

A recent study by a group of researchers in the UK, Uganda, and Switzerland have attempted to separate out these two forms of competition in a study of the wild banded mongoose. This species lives in large social groups that share a territory. Thus territorial competition occurs primarily between different social groups, whereas competition over mates occurs primarily within groups.

“Anal gland secretion (AGS) and urine samples were collected under anaesthesia during routine trapping events”  Image licensed under creative commons from Mike Rohde’s Flickr photostream.

The researchers found that the mongoose populations marked uniformly throughout their territory, and did not appear to increase the frequency of marking in those regions where two territories overlapped. This suggests that, in this species at least, defense of mates and mating opportunities represents a major contribution to scent-marking behavior, perhaps more so than territorial defense.

So, can we extrapolate from the behavior of the wild banded mongoose to the behavior of wild banded mathematician Tihomir Petrov? Of course we can! Should we extrapolate? Absolutely not! But, here at Lost in Transcription, we’re all about the possible, so here is the take-home message. Castle and Beckett should look beyond professional disputes between the two mathematicians. They need to be looking at the love-triangle angle (Love angle4?) for motive.

Alternate theory: As Northridge is, like, the pr0n capital of the country, Petrov might not have been the original urinator. When he saw that the cameras had been set up, he might have assumed that he had been cast in a movie, and that peeing on the floor was what was expected of him. Just sayin’.

Jordan, N., Mwanguhya, F., Kyabulima, S., Rüedi, P., & Cant, M. (2010). Scent marking within and between groups of wild banded mongooses Journal of Zoology, 280 (1), 72-83 DOI: 10.1111/j.1469-7998.2009.00646.x

Genomic Imprinting III: The Loudest Voice Prevails

So, it’s been a while since the last installment of the Primers on Imprinting feature, but they should be posted with greater regularity in the upcoming weeks. This time we’re going to introduce something that we will see again in future installments: small differences in selection lead to large differences in behavior.

Last time, we introduced the most widely discussed and most successful explanation of the evolutionary origins of genomic imprinting, the “kinship” or “conflict” theory. According to this theory, imprinted gene expression is a consequence of the fact that natural selection acts differently on alleles depending on their parent of origin. There are several ways to think about the origin of this differential selection, but we talked about it in terms of the framework that I find most intuitive: inclusive fitness.

As we also noted last time, even in the cases where the asymmetry in selection on maternally and paternally derived alleles is sufficiently large to drive the evolution of imprinted gene expression, the actual magnitude of this asymmetry is actually incredibly small. Why? Well, even for a allele with large effects on the survival and reproduction of related individuals, the dominant factor in the inclusive fitness of that allele is still going to be the survival and reproduction of the individual organism carrying that allele around.

But, the standard pattern observed with imprinted genes is that the allele-specific expression is all or nothing. For example, an allele might be expressed when it is inherited from a male, but completely silent when inherited from a female. So this small difference in the optimal expression levels of the maternally and paternally derived alleles leads to – in a way – the largest possible difference in the realized expression levels of the two alleles.

I like to think of this in terms of an analogy. Imagine that Pat and Chris share an office, and that they have a slight disagreement over the temperature they want the office at. Say Pat wants the office to be at 71 degrees (Fahrenheit), while Chris wants it to be 70. Each of them has control over a small space heater, and this is the only mechanism that they have for manipulating the temperature. [1]

What’s going to happen? Let’s say the temperature is 70 degrees. Pat will turn up his/her space heater until the temperature reaches 71. In response, Chris will turn his/her space heater down until the temperature comes down to 70. They will go back and forth like this until, eventually, Chris’s space heater is completely turned off. Pat will then turn his/her space heater up to get the room to 71. Then we’re done. Chris is unhappy about the temperature of the room, but no longer has any ability to make it any cooler.

Two things about this outcome. First, a small disagreement over the ideal temperature has led to a large divergence in the strategies: Chris’s space heater is all the way off, while Pat’s is on and doing all the work. Notice that the outcome would be exactly the same, in principle, if Chris’s ideal temperature were 70.9 degrees, or even 70.999 degrees. [2]

Second, Pat wins. This is a consequence of the fact that we are talking about space heaters, and that Pat prefers the higher temperature. If, instead of space heaters, Pat and Chris each had control of an air conditioner, Chris would be the winner. At equilibrium, Pat’s air conditioner would be all the way off, and the room would be at 70 degrees.

This is also the way it works with alleles at an imprinted locus. Let’s consider the case of a gene where increased expression results in increased prenatal growth. The inclusive fitness argument says that the optimal amount of this growth factor is higher for an allele when it is paternally inherited than when it is maternally inherited. Say this patrilineal optimum is 105 units, while the maternal optimum is 95 units.

If the gene is not imprinted we might expect it to produce about 100 units, with each allele producing 50. However, once the evolutionary dynamics of imprinting take over, the pattern of expression will evolve to one where alleles are transcriptionally silent when maternally inherited, but where a paternally expressed allele is making 105 units.

For a growth-suppressing gene, where increased expression actually reduces prenatal growth, we expect the opposite pattern, where alleles are silenced when paternally inherited, but are expressed when maternally inherited. This set of predictions – that imprinted growth enhancers will be paternally expressed, and imprinted growth suppressors will be maternally expressed – matches the empirically observed pattern by and large, although there are a few counterexamples that are not fully understood at the moment.

This pattern of allele silencing has been dubbed the “loudest voice prevails” principle. The phenotype evolves to the optimum of the allele favoring higher expression. Now, you can argue that this is the sort of thing that does not really need its own name. Fair enough. It’s really just saying that the evolutionarily stable state of the system is an edge solution. But, “loudest voice prevails” is sort of catchy, and has the advantage of reminding us which allele is expressed at equilibrium.

The Haig 1996 citation is the paper that introduces the phrase. The other three citations are papers published around the same time that use different mathematical frameworks to address the evolution of gene expression at an imprinted locus. Generically speaking, the answer is the one described here, although the Spencer, Feldman, and Clark paper identifies certain regimes in parameter space where apparently different results can be obtained. In a future post, we will delve into the differences in the assumptions and conclusions of different modeling frameworks as they have been applied to imprinting.

Now, what if you consider more than one imprinted gene? What if Pat and Chris each have a space heater and an air conditioner? We’ll talk about that next time.

Haig, D. (1996). Placental hormones, genomic imprinting, and maternal-fetal communication Journal of Evolutionary Biology, 9 (3), 357-380 DOI: 10.1046/j.1420-9101.1996.9030357.x

Mochizuki A, Takeda Y, & Iwasa Y (1996). The evolution of genomic imprinting. Genetics, 144 (3), 1283-95 PMID: 8913768

Haig, D. (1997). Parental antagonism, relatedness asymmetries, and genomic imprinting Proceedings of the Royal Society B: Biological Sciences, 264 (1388), 1657-1662 DOI: 10.1098/rspb.1997.0230

Spencer HG, Feldman MW, & Clark AG (1998). Genetic conflicts, multiple paternity and the evolution of genomic imprinting. Genetics, 148 (2), 893-904 PMID: 9504935


[1] Of course, in the real-life situation, we might assume that Pat and Chris would discuss the situation and come to some sort of agreement. This is a key difference between people interacting in strategic situations and genes evolving under natural selection. Alleles at a locus are like people sharing an office, where both of them are incredibly passive aggressive. If it helps, imagine that Pat and Chris won’t talk to each other.

[2] In practice, of course, there is going to be some minimum level of disagreement required in order to trigger this passive-aggressive escalation. In this analogy, the minimum level will be set by a combination of things such as the sensitivity of Pat and Chris to small changes in temperature, the precision with which the space heaters control the temperature of the room, and the extent to which they care about each other’s comfort. Similar reasoning holds in the case of genes, and we will address this in a future installment of the series, where we ask why there are any genes that are not imprinted.

The Cost of Christmas

So, if you haven’t already, you’ll probably soon receive the credit card bill with all of your Christmas purchases on it. Was it worth it? Well, was it, punk?

If you’re like most people, some of your presents were probably intended to impress someone. The question is, what’s the best kind of present for that? Should I give the girl from math class diamond earrings, or new batteries for her calculator? Should I give my boss a mug, or a gift certificate to Glamour Shots?

Fortunately, Science!™ has the answer. Today’s journal club entry concerns a model of gift-giving that considers three different types of gift that differ in their cost to the giver and their value to the recipient. “Cheap” gifts are, well, cheap. “Valuable” gifts are expensive to give, and have value to the recipient. The interesting category is the third one, the “extravagant” gifts, which are expensive to give, but have little inherent value to the recipient.

The specific context is gift-giving and mating. The model is of a sequential game with three or four stages. First, the male offers a gift to the female. Second, the female either accepts or rejects the gift. Third, she chooses whether or not to mate with the male. Then, in one version of the game, the male decides whether or not to stick around and contribute to the care of the offspring.

This $305 luxury frisbee is an example of an extravagant gift.

The conclusion of the paper is that there are many combinations of parameter values that will lead to males giving extravagant gifts. There are two critical features of the model that seem to be necessary in order to get this result.

First, there is uncertainty. The female has a guess about the quality of the male (or, equivalently, in the version of the model with paternal care, the probability that he will stick around after mating). By accepting the gift, she gains additional information about his quality or intentions. Similarly, the male is uncertain about the quality and intentions of the female – whether it is worth it for him to stick around after mating, and whether or not she is a gold-digger, who will just take his gift and skip town with his cousin.

[Editorial note: the term “gold-digger” is from the paper. Those of you who know me know me know that I would never have gone with such a politically incorrect term. I would have used “■■■■■■■■■■”.]

[[Meta-editorial note: parts of the previous editorial note have been redacted.]]

The other key feature is that there must be some cost to the female in accepting the gift.

Now, there are lots of parameters in a model like this, and several equilibrium solutions are possible. The interesting one is the one where males give cheap gifts to unattractive females (females whom they judge, with some uncertainty, to be of low quality), and give extravagant gifts to attractive females.

The key to getting the interesting equilibrium is that the ability or willingness to provide and extravagant gift has to correlate with the male’s quality or intentions. For example, a male can’t afford to spend two-months salary on a diamond ring every time he wants to have a one-night stand. Therefore, an extravagant engagement ring becomes a reliable indicator of his intentions. Ideally, the gift has to have no inherent value to the female, for example, if it were impossible to sell the engagement ring for cash money. Recall also that it has to cost her something to accept the gift. Then, taking the gift constitutes a commitment on her part as well. Otherwise, she benefits most from accepting the gift and walking away.

In the salacious application-to-human-mating case, this cost to the female is easiest to envision as a reputation cost (e.g., the risk of being labeled as a ■■■■■■■■■■). In certain species, where females mate with multiple males, store the sperm, and then use it selectively, there may be direct opportunity costs that do not require catty moralizing.

Just one last point.

The paper starts with, “Gift-giving is a feature of human courtship”. The authors cite Geoffrey Miller’s 2000 book, The Mating Mind. If the paper were being written today, I assume they would have cited more recent work by Hefner and Harris.

Sozou, P., & Seymour, R. (2005). Costly but worthless gifts facilitate courtship Proceedings of the Royal Society B: Biological Sciences, 272 (1575), 1877-1884 DOI: 10.1098/rspb.2005.3152

Where stalkers become friends: Geo-tagging on Flickr

So, you probably remember this from the most recent episode of The Mentalist / Bones / Castle / Criminal Minds / Numb3rs:


SASSY JUNIOR DETECTIVE: Nothing. All of our leads have dried up like Cher’s ovaries.

GRUFF SENIOR LAW ENFORCEMENT OFFICIAL: We’ve got to wrap this thing up. I’ve got the mayor breathing down my neck.

MAYOR: Hhhhhhhhhh. Hhhhhhhhhh.

G.S.L.E.O.: And now he’s drooling.

S.Y.P.D.: We’ll keep after it, but we’re a bit short-handed after half of the department was beheaded and, ironically, eaten by The Vegan Killer.

G.S.L.E.O.: I don’t want excuses. I want someone behind bars.

S.J.D.: You and my alcoholic ex wife.

SOCIALLY INAPPROPRIATE GENIUS: Actually, we know that the comptroller picked up his dry-cleaning on Wednesday. The same Wednesday that the chimney sweep showed up at the wedding in a curiously un-besooted pair of dungarees. Thus, the heiress was murdered by the delivery man who brought the Martinizing agents to the dry cleaners, also on Wednesday. Also, he was her half brother.

And, scene.

Thanks to research just published in PNAS by a group out of Cornell, we are now one step closer to living in a dystopian panopticon in which our associations can be inferred by any monkey with a laptop. Soon, Patrick Jane will be back to doing parlor tricks, Richard Castle will be back to making a living as an imaginary writer, and everyone else will be in prison for consorting with each other.
More specifically, the authors investigate whether they can infer a social connection between two people on the basis of their having been at the same place at the same time on multiple occasions, using data from Flickr. They look at 38 million pictures that contain both a timestamp and a geo-tag, indicating the time, latitude, and longitude at which the picture was taken. They define a co-occurrence of two Flickr users as having pictures taken within a time t of each other and within the same geographic region: a square(ish) region of length s latitude or longitude degrees on each side. The social dimension of the data comes from Flickr’s networking functions, which allow users to specify their links to others. 
They find that the greater the number of co-occurrences for a pair of users, the more likely it is that they are friends. This is not particularly surprising, although the magnitude of the effects are quite striking. For example, here is one graph from the paper:
Part of Figure 2D from the paper. In this case, the spatial range for co-occurrence is defined by s = 1.0 degrees (about 55 miles by 65 miles where I live). The different curves correspond to different time windows.

The probability that two randomly selected Flickr users are friends is less than 1 in 7000 [Corrected. Original post said 1 in 700]. However, if two users have uploaded pictures from the same 1 degree by 1 degree region within a day of each other on five different occasions, there is nearly a 60% chance that they are friends. If they have done it more than eight times, the chance is more than 90%.

In other words, if you and your accomplice both upload photos from the same dry cleaner every Wednesday, even a non-genius will be able to figure out that you know each other. This is how Strangers on a Train will end in the 2032 remake starring Freddie Highmore and Abigail Breslin.

For those interested in looking at more pretty graphs, the article is Open Access, and can be found here.

For those interested in mounting a futile defense against the Orwellian State, more information about geo-tagging and privacy can be found here, including ways in which you may inadvertently be sharing location information without meaning to.

Crandall, D., Backstrom, L., Cosley, D., Suri, S., Huttenlocher, D., & Kleinberg, J. (2010). Inferring social ties from geographic coincidences Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1006155107

The Distribution of Dominance

So, as you have no doubt surmised from the title of this post, the cash-strapped Republican Party is going to start using their abundant frequent “flyer” points to pay their debts.

I’m kidding, of course. The GOP doesn’t pay its debts!

Actually, we’re going to talk about a paper just out in Genetics by Aneil Agarwal and Michael Whitlock. They provide a very thorough analysis of data on the fitness effects of homozygous and heterozygous gene deletions in yeast.

But let’s back up for a minute first.

The authors are interested in understanding the distribution of dominance, in the population-genetic sense. Traditionally, the dominance is represented by h, and the strength of selection by s. Usually, we define the fitness of the wild-type (hypothetically not carrying any mutations) as 1. Then, we consider the fitness effect of a mutation in a particular gene. In this case, we’re going to focus on deleterious, or harmful mutations, which reduce fitness. If an individual carries two copies of the deleterious mutation, they have a fitness of 1-s, so that small values of s mean weak selection, and large values of s mean strong selection. The dominance refers to the relative fitness of an individual carrying only one copy of the deleterious mutation. This heterozygous fitness is 1-hs. If h equals 1, the deleterious mutation is completely dominant, meaning that having one copy of it is just as bad as having two. If h equals 0, the deleterious mutation is completely recessive, and having one defective copy of the gene is just as good as having two functional copies.

So, what is a typical value of h? Does it depend on s? How much does it vary from gene to gene? The conventional wisdom is that most deleterious mutations are recessive. This is why you should not have children with close relatives. I carry a bunch of recessive mutations, as does my wife. As long as we have different ones, our son inherits a bunch of mutations – but only one copy of each – so they’re recessive in him as well. If we were closely related, we would carry many of the same mutations, and there would be a decent chance that our son would inherit two defective copies of the same gene, which could have various health consequences.

Charles Darwin and his first cousin Emma Wedgwood were married in 1839. 170 years later, they were portrayed by real-life-non-first-cousin couple Paul Bettany and Jennifer Connelly (not pictured).

However, population geneticists don’t care about things like this just because of the implications for human disease. Dominance has a major impact on the eventual fates of individual mutations, and can influence other evolutionary processes, like speciation. Often, in order to model some other process, we have to make some sort of assumption about the distribution of fitness effects of mutations. Traditionally, a researcher would pull this distribution out of his or her asc. This is one of the biggest contributions that this paper will make to the field. It provides a nice, empirically based distribution of dominance effects that can feed into other evolutionary studies.

The results also confirmed (with much greater confidence than was previously the case) the relationship between h and s which had been suggested by some previous studies. They find that larger values of s tend to go with smaller values of h. Consistent with the conventional wisdom about not marrying your cousin, strongly deleterious genes tend to be pretty recessive. More surprisingly, most mildly deleterious mutations had fairly high h values. In fact, the mean value of h over all deleterious mutations was 0.8 – quite dominant. However, when the average is weighted by the fitness effect s, it drops to 0.2.

The authors also point out that this negative relationship between h and s has implications for the evolution of dominance. This pattern is most consistent with theories in which dominance is shaped by indirect selection. For example, deleterious mutations might be recessive if the protein produced by the gene were selected for overexpression to enhance a metabolic pathway, or to buffer the performance of that pathway in certain environments. Then, loss of one copy of the gene encoding that protein might not have a major effect on function (half of too much being still enough). Alternatively, recessiveness could come from feedback mechanisms that upregulate the functional copy of the gene when not enough of the gene product is being made.

The point is that in either of these cases (among others), recessiveness is driven by selection to maintain the function of the gene. The more important the gene is (the larger the value of s associated with it), the stronger this selection will be, and the more recessive deleterious mutations will become. Therefore, mechanisms like these predict the observed negative relationship between h and s.

On a historical note, this type of buffering process was proposed by one of the giants of population genetics, J. B. S. Haldane way back in 1930. Haldane passed away on December 1, 1964.

R. I. P., J. B. S.

Agrawal, A., & Whitlock, M. (2010). Inferences About the Distribution of Dominance Drawn from Yeast Gene Knockout Data Genetics DOI: 10.1534/genetics.110.124560