Genomic Imprinting II: Inclusive Fitness and Conflict

So, as we discussed previously, genomic imprinting is the phenomenon where the pattern of expression of an allele differs depending on whether that allele was inherited from your mother or your father. This difference in expression does not depend on differences in the DNA sequence of the two alleles. Your two alleles might have identical DNA sequences, but function completely differently.

For example, one of the two alleles might be epigenetically silenced. That is, because of reversible chemical modifications to the DNA, or to proteins that are closely associated with the DNA, that allele would be inactive. The other allele, with an identical DNA sequence, but different modifications, would be happily chugging along producing its gene product(s). Today's question is, "That seems crazy! Why would you do something like that?"

One of interesting (and by "interesting" I mean "sad") things about evolutionary biologists is that whenever something genuinely new and surprising is found in the world, everyone feels the need to propose an evolutionary explanation for it, whether new explanations are needed or not. So, many attempts to explain the origins of imprinting have been proposed, most of which are consistent with at least some of the data, and a few of which actually make sense. There is one explanation, however, that is far and away the most successful in explaining the distribution and nature of imprinted genes: the "Kinship" or "conflict" theory of imprinting. This theory owes its creation and early development primarily to David Haig (who laid out the theory originally in papers with Mark Westoby and Tom Moore).

The basic idea of the Kinship Theory is that natural selection favors different expression behaviors for maternally and paternally inherited alleles. That is, the optimal level of expression for an allele that is maternally inherited is different from the optimal level for a paternally inherited allele. Now, if you think about that for a minute, it probably seems strange. I mean, if I survive and reproduce, that's equally good for any of my genes, independent of where I got them from, right? Right?

The key is recognizing that natural selection favors allele that pass on the largest number of copies to future generations. ("Isn't that what I just said?") AND, that it doesn't matter whether those copies are passed on directly by my having children, or if they are passed on because because one of my relatives, who has inherited an identical copy of that allele, has children. There are different ways to represent this (which are all mathematically equivalent if you do them right), but the one that I find most intuitive is the idea of "inclusive fitness." Basically, we can think of natural selection as maximizing the inclusive fitness of an allele, which is the fitness of every individual in the population, weighted by the probability that they carry the allele. In the simplest model, this probability is 1 for me, 1/2 for a sibling, 1/8 for a cousin, and so on.

Now, think about your relatives. With the exception of your descendants, your full siblings, and their descendants, all of your relatives are related to you either through your mother or your father. That means that, in general, this inclusive fitness calculation will be different for maternally and paternally derived alleles. Therefore, there will be a conflict, where the phenotype that would maximize the inclusive fitness of your maternally inherited allele will be different from the one that would maximize the inclusive fitness of your paternally inherited allele. If this difference is large enough, it can actually drive alleles to take on two different conditional expression strategies, and, voila, imprinting.

Granted, even in the most extreme cases, this difference is likely to be pretty subtle, which might make it seem strange that this could explain a situation where one of the two alleles is completely turned off, while the other one is cranking away. This phenomenon, where a little conflict leads to a big effect, will be the subject of the next installment.

On sex and singles

So, the post title is clearly designed to pump up pageviews, but those of you who have come here hoping to see photos of me with dollar bills hanging out of my G-string are going to be sadly disappointed. The good news is the money you'll save having your corneas scraped.

This post is actually about the evolution of sex, or "recombination," as the biologists like to call it. The question is, why does sex exist? Or, at a genetic level, why would an organism do something that passes on only half of its genes (by mating with something that donates another half), rather than simply making a genetic copy of itself. This is often referred to as the "two-fold cost of sex." Presumably, there must be an evolutionary benefit to sex that is great enough to overcome this two-fold cost.

As with everything in evolutionary biology, there are an enormous number of theories that have been proposed to explain the evolution of sex, but there are two major arguments. One is that sex allows beneficial mutations that arise on different backgrounds to be recombined onto a single genetic background. This allows adaptive evolution to occur at a faster rate. The other (which is really sort of another side of the same coin) is that sex permits more efficient purging of deleterious mutations.

Let me use an analogy that requires us to take a walk down memory lane. You kids may not know this, but a long time ago, music came on albums, which contained a bunch of songs. The problem with the album system was that most bands would put out one good song, and then fill the rest of their album up with crap. So, to get a collection of good songs, you had to buy a whole bunch of other songs that you didn't actually want. Sure, you could buy the 45, but who did that, seriously?

So, in this analogy, the first theory, the one about beneficial mutations, is like how you would take all of your albums and put the best songs together on a mix tape that you give to a girl you're trying to impress. Yes, back then, this was done non-ironically by people who were not hipsters. She would then listen to the first few songs out of a sense of politeness, make some awkward comment about how knowledgeable you are, and then mysteriously change her phone number.

One of the great things about the advent of mp3s and digital music sales is that it is easier to hide your embarrassing musical taste. It used to be that your friends would always pull out your Night Ranger album and make fun of you. Now you can rock out to Ke$ha and just close your computer when someone knocks on your office door.

Also, and more relevantly, it is easier and more natural now to buy individual songs. So, you don't ever wind up owning a whole pile of non-I'm-Gonna-Be-(500-Miles) Proclaimers songs. Music has undergone a transition to where it is more like our second theory, where recombination permits the elimination (through failure to purchase) of deleterious mu(sic)tations.

I'd write more, but there's a pile of cash on the dresser that I need to count.

On evolution and sequels

So, there are a lot of things in evolution that seem like they are moving in one direction, when actually they are moving the opposite way. Or maybe it's the other way around – I forget. For instance, one of the things that we know is that the vast majority of naturally occurring mutations are deleterious. That is, just like your crotchety old grandfather always said, children are, on average, a little bit worse than their parents (and the music they listen to is A LOT worse). Yet, somehow, evolution is able to maintain a level of function in the face of these deleterious mutations, and even to create new adaptations.

The reason is natural selection. Children will be worse than their parents on average, but there will be variation. Some will be a lot worse, and some only a little worse. Some may even be a bit better. The key is that the better children will, on average, produce more grandchildren than the worse children will (so your nagging mother was also right). It's a bit like walking the wrong way on one of those people-movers at the airport.

Of course, there is also noise in the system. Sometimes a big rock falls on the "fittest" individual in a way that has little to do with that individual's genotype. And sometimes an individual carrying a lot of deleterious mutations starts a polygamous cult and has about a hundred kids. But on average, the filtering effects of selection seem to counterbalance, or even outweigh the effect of those deleterious mutations.

This got me wondering if there was maybe something similar going on with movie sequels. The conventional wisdom in most quarters is the movie sequels suck. Sure, there is the occasional Godfather II, but for every one of those, it seems like there are a hundred films that are closer to Highlander II. So, I did a little study [1], in which I compared three classes of films: movies that got sequels, movies that are sequels, and random movies. Two scores from Rotten Tomatoes were collected for each movie: the "tomatometer" score, which is the percentage of reviews of the movie that were positive, and the user score, which is the average rating (out of 10) by users of the site.

The average scores are:

Movies with sequels: 59.2% positive 5.92 average (coincidence, or Illuminati plot?)
Movies that are sequels: 44.8% positive 5.16 average
Random movies: 45.7% positive 5.21 average

So, what's our conclusion here? Well, it seems like sequels are, on average, pretty darn similar in quality to the random sample of movies. The outlier is the set of movies that get sequels made. So, maybe we think that sequels suck because we tend to mentally compare them with the originals, and, like our high-school sports careers, they fail to live up to expectations. Maybe sequels suck because movies suck, and a sequel is no more or less likely to suck than anything else. Or is there something about sequelness in itself?

We can drill a little deeper by dividing our movies into five quintiles (with ten movies each) based on the tomatometer scores of the originals:

Bottom quintile:
Movies with sequels: 17% positive 3.6 average
Sequels of movies: 15% positive 3.6 average

Second quintile:
Movies with sequels: 45% positive 5.2 average
Sequels of movies: 22% positive 4.0 average

Third quintile:
Movies with sequels: 58% positive 5.9 average
Sequels of movies: 49% positive 5.3 average

Fourth quintile:
Movies with sequels: 82% positive 7.0 average
Sequels of movies: 64% positive 6.1 average

Top quintile:
Movies with sequels: 94% positive 7.9 average
Sequels of movies: 74% positive 6.8 average

What this makes it look like is that there really is something about making a sequel that makes your movie suck more than the original. For the most part, you can expect a 15-20% drop in the number of favorable reviews going from the original to the sequel, even if the sequel was only average to begin with. The one exception is the bottom quintile, where you can expect your sequel to suck just about as much as the original did. This may be a boundary effect, as the average number of positive reviews is bounded at zero. This is the great thing about making "Baby Geniuses 2" is that it is virtually impossible to underperform "Baby Geniuses." On the other hand, with a tomatometer score dropping from 2% to 0%, the baby geniuses somehow managed it.

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[1] Not-very-scientific study methodology:

In order to collect a sample of sequels, I went to Rotten Tomatoes, and searched for "2" and "II," discarding anything that was obviously not a sequel, or for which there was no rating information available. This yielded a list of 50 movies, including "2 Fast 2 Furious," but not "Aliens." For each of these, I got the "tomatometer" score and the average user rating for that movie and for the movie of which it was the sequel.

For the random sample, I went to The Movie Insider, and used their list of January-June 2009 releases. I discarded anything that was a foreign film or documentary that had an initial release date prior to 2009. The rationale here was that if a documentary is shown at film festivals in 2007, and then gets a major theatrical release in 2009, this is not a random movie. It is a movie that has already undergone a fairly intense selection process. In the end, this list had 75 movies in it.

The study was not double-blind or vetted by anyone else, and undoubtedly contains errors in both transcription and judgment. However, hopefully it is close enough for analogic use.

Why "Lost in Transcription"?

So, I like to imagine that people are reading this blog, that they are intrigued by its content, and it's got them wondering, "Why is this blog called 'Lost in Transcription'?" As I noted in the pilot, the aim here is to talk about poetry and science, particularly those parts of science that are related to my own research, where I can claim some degree of expertise. The title is meant to bridge between these two worlds.

First, in the literary domain, it is a play off of the phrase "lost in translation," which appears any time there is a discussion of either literature, of cultural differences, or of Scarlett Johansson that goes on for longer than ten minutes. Within poetry, its two most famous appearances are as the title of a James Merrill poem (perhaps the best poem ever written about working a jigsaw puzzle), and in a quotation attributed to Robert Frost, that "Poetry is what gets lost in translation."

Within genetics, translation refers to the process by which an RNA sequence is read to generate an amino acid sequence. In a related process called transcription, DNA serves as a template for the synthesis of RNA. One of the topics that I work on is genomic imprinting, where one of the two gene copies in a cell has its transcription silenced. So, in a strictly literal sense, a better title would have been something like "loss of transcription," but if you are willing to stretch with me, we could imagine that at a genetic locus that is subject to genomic imprinting, the genetic information from one of your two parents is Lost in Transcription.

On aging, conservatism, and experimental economics

So, it is standard conventional wisdom that people are liberal when they're young, and conservative when they're old. To the extent that we interpret "liberal" as "eager for change" and "conservative" as "against change," this trajectory is only natural. Especially in the modern world, where things are changing all the time, it may simply come down to a difference in experience: you're less likely to pine for the way the world was thirty years ago if you weren't alive thirty years ago.

But what I am really interested in here is the apparent trend where people become more conservative with respect to economic policies. In this context, the argument about familiarity does not seem to hold. In the United States, the government's economic policies have been trending more conservative for decades, and the familiarity argument would predict that older people should be, on average, more liberal. However, there is a different aspect of familiarity that may be relevant, as it pertains to our beliefs about human nature.

A key aspect of the economic debate between liberals and conservatives is a difference in the assumptions they make about how people will behave when left to their own devices. If you will forgive me for painting complex things with a simple brush, the cartoon versions of these are something like this. Conservatives believe that people are inherently self-serving and lazy, and will work hard only if they are given tangible incentive to do so. From this perspective, progressive tax structures and government programs like welfare and social security are problematic because they take away the incentive to earn money. Liberals, by contrast, believe that everyone is trying hard, that inequality comes largely from societal structures that are beyond individuals' control, and that people should not be punished for the inherent unfairness of society (except maybe those at the top of the pay scale, who have benefitted most from those inequalities).

Now, the most obvious difference between young people and old people is that old people have a lot more experience with other people than young people do. That is, we tend to start out with positive views about human nature, but over time we interact with more and more people, they disappoint us, and we become progressively more cynical. Many conservatives see this as evidence in favor of their position: we start naive, and become conservative when we learn what people are actually like. However, I want to suggest a different explanation, having to do with asymmetries in how we perceive positive and negative deviations from our expectation. Intuitively, this comes down to the fact that we notice whenever we get stopped by a red light, but often don't notice when we hit a green light. Therefore, we perceive that stoplights are red more often than they actually are.

This also happens in the economic domain, as has been extensively documented by experimental economists in a variety of "public goods" games. The basic structure of these games is as follows. You have a group of people, say 10, and you give each of them some money, say $10. Each person can then contribute a fraction of their $10 to the "pot." The money in the pot is the multiplied by some factor, say 5, and then distributed equally among the ten players. So, if no one contributes anything, everyone gets to keep the $10 they were given at the beginning. If everyone contributes the full $10, the pot has $100, which is multiplied by 5 to give $500, which is distributed back to the players, and everyone walks away with $50.

The ideal thing for the group as a whole is for everyone to contribute the maximal amount. However, the ideal thing for the individual is to contribute nothing (and to hope that everyone else contributes the maximum). For example, if I contribute nothing, and everyone else contributes $10, I walk away with $55, and everyone else walks away with $45. If I contribute $10, and no one else contributes anything, I'll get $5, and everyone else will get $15. From an "economic rationality," "Nash equilibrium" perspective, the thing to do is contribute nothing. However, this is not what happens in practice.

In a wide variety of experimental setups, what people actually do is contribute about 50% of what they are initially given. So, the typical outcome in our experiment would be that everyone contributes about $5, which makes $50 in the pot, which is multiplied to $250, and everyone walks away with $30 (the $5 they kept plus $25 from the pot). Across a broad range of cultures, ages, quantities of money, etc., people come into these experiments with a somewhat liberal perspective, as they seem to both trust the good will of the other players, and care about the results for the group as a whole.

However, if we play the game over and over again, an interesting thing happens: the average contribution gradually declines, until eventually, no one is contributing anything to the pot. Based on interviews with the participants in these games, economists believe that they understand this trend. Let's say that one person contributes $5, which is the average among the group, but some people contribute $4, and some $6. This person will not really think about the people who gave $5 of $6, but will think a lot about the people who gave $4, get pissed off, and reduce their contribution in the next round. While it is mathematically trivial that people, on average, contribute the average amount to the pot, it seems to be psychologically true that people perceive themselves on average as having made an above-average contribution.

What I think is that something analogous happens over the course of the lifetime of an individual. We meet some people who are hard working, and some who are lazy, but there is this perceptual bias that means that the lazy, selfish people we meet weigh more heavily in our developing opinions about "what people are like."

The other interesting finding from these experiments is that it is remarkably easy to reset the spiral of cynicism. If you take the participants out of the room, give them a cup of coffee, and let them use the bathroom, when they go back in, they often go right back to contributing 50% on average. So, note to Democratic lawmakers, if you can figure out how to let the country drink a collective cup of coffee and use the collective bathroom, you may find a dramatic increase in support for social programs and a progressive tax structure.

Genomic Imprinting I

So, one of the things that I study is genomic imprinting. What is that, exactly?

Even if you're not a biologist, you are probably familiar with the fact that, for most of your genes, we carry two different copies, or alleles. You get one of those alleles from your mom, and one from your dad. Those two alleles could be the same (have identical DNA sequences) or different (usually only at a small number of positions within DNA sequence). If they are different, then the consequences of those alleles on your traits, like how tall you are or what color your eyes are, are determined by the dominance relationship between those two alleles. For example, the main allele responsible for red hair (at the MC1R locus) is recessive in relationship to alleles for brown or black hair. So, if you have only one copy of the red-hair allele, you will probably have dark hair. Importantly, in terms of what follows, it does not depend whether the recessive red-hair allele you have came from your mother or father.

If you are a biologist, you already knew all of that, but you may or may not be familiar with imprinted genes. About one percent (or possibly more) of our genes are imprinted. For these genes, it does matter which allele came from your mother and which one came from your father. That's because imprinted genes retain a chemical memory of which parent they came from, and function differently depending on their parental origin. More specifically, at an imprinted locus, alleles are subjected to epigenetic modifications in the germ lines (ovaries or testes). These epigenetic modifications can be chemical modifications applied directly to the DNA itself, or modifications to proteins that are closely associated with the DNA. These modifications alter how the allele functions, without modifying the DNA sequence itself. The key thing is that, for imprinted genes, the epigenetic modifications that are established in the male germ line are different from those established in the female germ line. So the allele that came from your father will function differently from the allele that came from your mother, even if the DNA sequences are identical.

In the simplest cases, one of the two alleles is inactivated, or turned off. The effect of that gene on a given trait, then, depends only on the active allele. To return to the red-hair example, imagine that the MC1R locus was imprinted (which it is not, as far as we know), and that only the paternally inherited copy was expressed. Now, if you had one copy of the red-hair allele, and one of the more common dark hair allele, you would not necessarily have dark hair. Your hair would be dark if your red-hair allele came from your mom, but if it came from your dad, your hair would be red.

Of course, as with all things in biology, once you start looking at the details, everything becomes a lot messier and more confusing. But, that is the basic gist.

Genomic imprinting was one of the biggest surprises to come out of molecular biology in the past few decades. Both the origins of imprinting of particular genes, and the effect of imprinting on the evolution of those genes, are interesting questions that we will return to in future posts. At some point along the way, we will get deeper into those messy and confusing details.

Humanity as an emergent property: of douches and douchbags

So, why is it an insult to call someone a douchebag?

The "douche" part is easy. Anything associated with the crotchal region, however tangentially, eventually makes its way into the lexicon as an insult. These terms are insults because they carry a connotation of being "dirty," physically and/or morally. However, I think that most people would agree that calling someone a douchebag is a step up in the degree of insult, and that is what is curious. If we naively try to interpret its meaning based on what a douchebag actually is, it should be, if anything, a milder insult, if not a complement, as it is an implement with the specific function of remedying the very dirtiness that is the basis of any crotch-related insult.

Obviously, that is not the right way to parse "douchebag." When we call someone a douchebag, we are really calling them a douche + bag. It works through analogy to the other "-bag" insults, like dirtbag or scumbag. Suffixes like "-bag," "-sack," and "-bucket" function as as intensifiers, or perhaps insultifiers. They can be productively added to just about anything, and it sounds more insulting. "Jerkbag" sounds worse than "jerk." In many contexts (e.g., volleyball), calling someone a "wall" might be a complement. Calling someone a "wallsack" would be mostly confusing, but could probably safely be interpreted as an insult.

I think that these modifiers implicitly deny the emergent humanity of the insultee, by reducing them to no more than the sum of their constituent parts. Stick with me here. The fact is, the very thing that makes us human -- or alive for that matter -- is not the components that make us up, but rather the complex relationships among those components. To quote Patty Loveless, "Break us down / to our elements, / and you might think He failed. / We're not copper for / one penny or / even iron for one nail." [1] The critical attribute of a bag or a sack is that its contents are disordered, and that complex functional or structural relationships among those contents are unlikely to exist. If someone calls you a douchebag, they are both calling you a douche and implying that your value is not greater than the sum of your parts.

What I like is that the productive family of suffixes "-bag," "-sack," etc. implies a sophisticated, if unconscious, understanding that the essence of our humanity is a classic emergent property, not derivable from a simple summation of our human components. For those of you who aspire to greater explicitness when insulting people (I know you're out there), let me suggest the following variant next time you are thinking of calling someone a scumbucket: "high-entropy scum."

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[1] This is not technically true anymore, since the introduction of copper-plated zinc pennies in 1982. According to Wikipedia, penny weighs about 2.5 grams, and is now about 2.5% copper, which means that it takes about 62 mg of copper to make a penny. According to the Copper Development Association, the human body contains perhaps 100-200 mg of copper, depending on the size of the particular human body in question. So, we are, in fact, copper for one penny, but most of us are not copper for four pennies. In Patty's defense, the song was released in 1994, and, given that coins can commonly last for 25 years or more, the majority of the pennies in circulation at the time may well have been of the pre-1982 variety, containing 15 to 20 people worth of copper.