Category Archives: genomic imprinting

On Ronin and the importance of physical colleagues





As an aside, I also had the chance to meet Craig McClain, Assistant Director of Science at NESCent and doyen of the group blog Deep Sea News. He was as nice as their blog is awesome.

Some people say that biologists grow to resemble the organisms that they study. You be the judge.


But I’m not sure that would actually work.










Genomic Imprinting at Darwin Eats Cake


If you’re actually interested, I’ve got a set of primers on imprinting that I’ve been working on here. You can find links to them here.

Or you can just forge ahead:

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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

Genomic Imprinting VI: Hemimethylation




The allele-specific maintenance of the methylation state depends on the fact that methylation occurs at “palindromic” sequences. When we’re talking about language, a palindrome is a word or phrase that contains the same sequence of letters when read forwards or backwards, like “a man, a plan, a canal, Panama,” or “eat tea.” In genetics, a palindrome is where the nucleotide sequence on one strand of the DNA is the same as the sequence on the complementary strand (which is read in the opposite direction).








In the next installment, we’ll talk about another epigenetic mechanism, histone modification, and the possibility of an analogous propagation mechanism for propagating those epigenetic marks.


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.


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.






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.




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.




Genomic Imprinting V: DNA methylation and gene silencing



There are a number of modifications involved in imprinting, but for the moment, we’re going to focus specifically on the simplest and best-understood mechanism: DNA methylation.

The two horizontal lines in this picture represent the two copies of a gene.  The big, solid box is the part of the gene that actually codes for the protein. The open box is the promoter region, which is the part of the DNA sequence responsible for regulating expression of the gene. The lollipop things indicate DNA methylation on cytosine residues (the “C” of the A, C, G, T alphabet that makes up DNA).






Next time, we’ll talk about how these methylation patterns are maintained through development, and how the two gene copies are able to maintain distinct epigenetic states across multiple rounds of cell division and DNA replication. Make sure to tune in, because it’s really slick!




Genomic Imprinting IV: Escalation Between Loci

So, in the previous installment, we introduced the “Loudest Voice Prevails” principle, which describes the evolutionarily stable pattern of gene expression at an imprinted locus where there is an intragenomic conflict over the total level of gene expression. Basically, the allele that favors lower expression becomes transcriptionally silenced. Expression from the other allele (the “louder” voice) evolves to the level that maximizes its inclusive fitness. In this sense, the active allele at an imprinted locus “wins.”




To think about this, let’s return to our analogy from last time, where Pat and Chris are sharing an office, but disagree about what temperature the office should be kept at. Recall that genes are totally passive aggressive, so Pat and Chris don’t compromise or communicate. They just use the tools at their disposal to move the office closer to their preferred temperature. Pat wants the office at 71 degrees. Chris wants it at 70.

We saw that if Pat and Chris both have space heaters, eventually Chris’s space heater is off, while Pat’s holds the temperature at 71. On the other hand, if they both have air conditioners, Pat will turn his/her A/C off, and Chris will get to have the room at 70.



     (1) Mechanical limitation. There will be some limit beyond which gene expression / activity can not increase. Once one of the genes reaches its limit, the other will win. Like if Pat’s Tufnel-brand space heater goes to eleven, Pat wins. Of course, this will depend on the mechanisms through which the two genes exert their influence. For instance, if Chris’s air conditioner is actually a combination air conditioner / food processor / exfoliator, Chris might have to turn it way way up to get the air conditioning equivalent of a little bit of space heating. Similarly, a gene product might perform multiple tasks, and this pleiotropy could limit its competitive ability in the arms race.

     (2) Production costs. One difference between the single-locus solution and the two-locus solution is the level of energy consumption. If Chris’s space heater is off, Pat’s holds the temperature at 71. If Chris’s air conditioner is maxed out at ten, Pat’s space heater (which goes to eleven, remember) holds the temperature at 71. The difference is that the second solution comes with a huge-ass electricity bill. Can this sort of cost actually halt the escalation? Maybe. This requires either that there are diminishing returns to increased escalation, or that there are accelerating costs to production (like utility rates where your thousandth kilowatt-hour costs more than your first one).


     (4) Side effects. What if turning up Pat’s space heater also makes the music louder in the office? What if Chris’s air conditioner draws so much power that it causes occasional brown-outs? This is the other way in which the escalation between imprinted genes might be self limiting. If we consider a monolithic “growth phenotype” in isolation, then each allele has a simple, monolithic optimum. But genes are seldom like that. A paternally expressed allele may benefit from increased expression due to the effect of that increased expression on growth. But what if that increased expression has other consequences, as well? Maybe those other effects are detrimental to the allele’s inclusive fitness. If those deleterious side effects outweigh the growth-related benefits, then natural selection will not drive further escalation.

In future installments, we’ll look at some specific examples of escalating genes. But first, we’ll step back and look at some of the other features and consequences of imprinted genes.



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.




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.



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.


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.








Parthenogenesis: now in snakes!

So, as if my friends on the religious right needed more reasons to be afraid of snakes, now they are threatening to undermine the nuclear family, which is clearly defined in the Bible as a mommy, a daddy, and two overachieving children. A recent paper in Biology Letters has studied two litters of offspring from a female Boa constrictor, totaling 22 baby snakes. All of the babies are female, and all of them have a rare, recessive color trait that is exhibited by the mother, but by none of the possible fathers.

What the researchers were able to demonstrate was that these baby snakes do not have a father at all. Rather, they are all parthenogenetic products of the mother. The researchers typed the offspring at eight microsatellite loci, and all the daughters were homozygous at all of the loci, matching in each case one of the two maternal alleles.

Note to self: No Boa constrictors on the island!

Several interesting things here. First, the implication is that these daughters are genome-wide homozygotes. This suggests a complete absence of lethal recessive mutations in the mother’s genome. This seems surprising, but let’s do a quick back of the envelope calculation. Let’s assume there are about 10,000 genes in the snake where a loss-of-function mutation is lethal. Say the coding region for each gene is about 1000 nucleotides long, and that, say 1/10 of those nucleotides are fixed, in the sense that a mutation obliterates the gene’s function. That would be a lethal mutational target of 100 nucleotides for each gene. Assuming a mutation rate of 10-9, mutation-selection balance at each locus would have loss-of-function mutations circulating at a frequency of about 1 in 3000. So, we would expect each maternal half-genome to contain, on average, about 3 lethal recessive mutations. Assuming that those mutations are Poisson distributed, there is about a 5% chance that it would contain no such mutations. So, not super likely, but not out of the question either. And, that probability would be higher if the mutational target is smaller, or if the Boa population has undergone significant inbreeding, which would have driven the frequency down.

Second, there’s a weirdness with the sex chromosomes. Now, in mammals, sex is determined by whether you have two X chromosomes, in which case you are a female, or an X chromosome and a Y chromosome, in which case you are a male. Everyone inherits an X chromosome from their mother, and you inherit either an X or a Y from your father. So, if you don’t have any sons, it’s not your wife’s fault. Snakes also have chromosomal sex determination, but use a ZW system. Males have two Z chromosomes, while females have a W and a Z. It turns out that every one of the parthenogenetic daughter snakes is actually WW. That’s some serious weirdness on which I have little insight. The one thing we can say is that you would never see a YY male. The Y chromosome is a shriveled little thing that does not do much other than tell you to be male, while the X does all the work. The snake W chromosome, on the other hand, is a real chromosome, that is, in fact, impossible to distinguish from the Z under the microscope.

Finally – and this is the reason I’m writing about this here – this tells us something about genomic imprinting. In mammals, there appear to be at least 50-100, possibly as many as 1000 imprinted genes, which are expressed from only one of the two copies. So, if there are 200 imprinted genes, there will be, say, 100 of them that are expressed only from the paternally inherited copy. If you produce parthenogenetic offspring, they will inherit two maternally derived alleles at each of these loci, which will be like having 100 of your genes knocked out, and is almost guaranteed to be lethal. In fact there are a number of genetic disorders in humans that result from uniparental inheritance of just a small subset of imprinted genes, and these produce fairly severe phenotypes. So, the fact that these parthenogenetic snakes appear to be perfectly viable implies that there are few – or quite possibly no – imprinted genes in this species.

Booth, W., Johnson, D., Moore, S., Schal, C., & Vargo, E. (2010). Evidence for viable, non-clonal but fatherless Boa constrictors Biology Letters DOI: 10.1098/rsbl.2010.0793

Update: Two follow-up posts here and here.

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.