Epigenetics and Homosexuality

So, last week featured a lot of news about a paper that came out in the Quarterly Review of Biology titled “Homsexuality as a Consequence of Epigenetically Canalized Sexual Development.” The authors were Bill Rice (UCSB), Urban Friberg (Uppsala U), and Sergey Gavrilets (U Tennessee). The paper got quite a bit of press. Unfortunately, most of that press was of pretty poor quality, badly misrepresenting the actual contents of the paper. (PDF available here.)

I’m going to walk through the paper’s argument, but if you don’t want to read the whole thing, here’s the tl;dr:

This paper presents a model. It is a theory paper. Any journalist who writes that the paper “shows” that homosexuality is caused by epigenetic inheritance from the opposite sex parent either 1) is invoking a very non-standard usage of the word “shows,” or 2) was too lazy to read the actual paper, and based their report on the press release put out by the National Institute for Mathematical and Biological Synthesis.

That’s not to say that this is a bad paper. In fact, it’s a very good paper. The authors integrate a lot of different information to come up with a plausible biological mechanism for epigenetic modifications to exert influence on sexual preference. They demonstrate that such a mechanism could be favored by natural selection under what seem to be biologically realistic conditions. Most importantly, they formulate their model into with clear predictions that can be empirically tested.

But those empirical tests have not been carried out yet. And, in biology, when we say that a paper shows that X causes Y, we generally mean that we have found an empirical correlation between X and Y, and that we have a mechanistic model that is well enough supported that we can infer causation from that correlation. This paper does not even show a correlation. It shows that it would probably be worth someone’s time to look for a particular correlation.

As a friend wrote to me in an e-mail,

I found it a much more interesting read than I thought I would from the press it’s getting, which now rivals the bullshit surrounding the ENCODE project for the most bullshitty bullshit spin of biology for the popular press. A long-winded-but-moderately-well-grounded-in-real-biology mathematical model does not proof make.


Okay, now the long version.

The Problem of Homosexuality

The first thing to remember is that when an evolutionary biologist talks about the “problem of homosexuality,” this does not imply that homosexuality is problematic. All it is saying is that a straightforward, naive application of evolutionary thinking would lead one to predict that homosexuality would not exist, or would be vanishingly rare. The fact that it does exist, and at appreciable frequency, poses a problem for the theory.

In fact, this is a good thing to keep in mind in general. The primary goal of evolutionary biology is to understand how things in the world came to be the way they are. If there is a disconnect between theory and the world, it is ALWAYS the theory that is wrong. (Actually, this is equally true for any science / social science.)

Simply put, heterosexual sex leads to children in a way that homosexual sex does not. So, all else being equal, people who are more attracted to the opposite sex will have more offspring than will people who are less attracted to the opposite sex.

[For rhetorical simplicity, I will refer specifically to “homosexuality” here, although the arguments described in the paper and in this post are intended to apply to the full spectrum of sexual orientation, and assume more of a Kinsey-scale type of continuum.]

The fact that a substantial fraction of people seem not at all to be attracted to the opposite sex suggests that all else is not equal.

Evolutionary explanations for homosexuality are basically efforts to discover what that “all else” is, and why it is not equal.

There are two broad classes of possible explanation.

One possibility is that there is no biological variation in the population for a predisposition towards homosexuality. Then, there would be nothing for selection to act on. Maybe the potential for sexual human brain simply has an inherent and uniform disposition. Variation in sexual preference would then be the result of environmental (including cultural) factors and/or random developmental variation.

This first class of explanation seems unlikely because there is, in fact, a substantial heritability to sexual orientation. For example, considering identical twins who were raised separately, if one twin is gay, there is a 20% chance that the other will be as well.

Evidence suggests that sexual orientation has a substantial heritable component. Image: Comic Blasphemy.

This points us towards the second class of explanation, which assumes that there is some sort of heritable genetic variation that influences sexual orientation. Given the presumably substantial reduction in reproductive output associated with a same-sex preference, these explanations typically aim to identify some direct or indirect benefit somehow associated with homosexuality that compensates for the reduced reproductive output.

One popular variant is the idea that homosexuals somehow increase the reproductive output of their siblings (e.g., by helping to raise their children). Or that homosexuality represents a deleterious side effect of selection for something else that is beneficial, like how getting one copy of the sickle-cell hemoglobin allele protects you from malaria, but getting two copies gives you sickle cell anemia.

It was some variant of this sort of idea that drove much of the research searching for “the gay gene” over the past couple of decades.  The things is, though, those searches have failed to come up with any reproducible candidate genes. This suggests that there must be something more complicated going on.

The Testosterone Epigenetic Canalization Theory

Sex-specific development depends on fetal exposure to androgens, like Testosterone and related compounds. This is simply illustrated by Figure 1A of the paper:

Figure 1A from the paper: a simplified picture of the “classical” view of sex differentiation. T represents testosterone, and E represent Estrogen.

SRY is the critical genetic element on the Y chromosome that triggers the fetus to go down the male developmental pathway, rather than the default female developmental pathway. They note that in the classical model of sex differentiation, androgen levels differ substantially between male and female fetuses.

The problem with the classical view, they rightly argue, is that androgen levels are not sufficient in and of themselves to account for sex differentiation. In fact, there is some overlap between the androgen levels between XX and XY fetuses. Yet, in the vast majority of cases, the XX fetuses with the highest androgen levels develop normal female genitalia, while the XY fetuses with the lowest androgen levels develop normal male genitalia. Thus, there must be at least one more part of the puzzle.

The key, they argue, is that tissues in XX and XY fetuses also show differential response to androgens. So, XX fetuses become female because they have lower androgen levels and they respond only weakly to those androgens. XY fetuses become male because they have higher androgen levels and they respond more strongly to those androgens.

This is illustrated in their Figure 1B:

Sex-specific development is thus canalized by some sort of mechanism that they refer to generically as “epi-marks.” That is, they imagine that there must be some epigenetic differences between XX and XY fetuses that encode differential sensitivity to Testosterone.

All of this seems well reasoned, and is supported by the review of a number of studies. It is worth noting, however, that we don’t, at the moment, know exactly which sex-specific epigenetic modifications these would be. One could come up with a reasonable list of candidate genes, and look for differential marks (such as DNA methylation or various histone modifications) in the vicinity of those genes. However, this forms part of the not-yet-done empirical work required to test this hypothesis, or, in the journalistic vernacular, “show” that this happens.

Leaky Epigenetics and Sex-Discordant Traits

Assuming for the moment that there exist various epigenetic marks that 1) differ between and XX and XY fetuses and 2) modulate androgen sensitivity. These marks would need to be established at some point early on in development, perhaps concurrent with the massive, genome-wide epigenetic reprogramming that occurs shortly after fertilization.

The theory formulated in the paper relies on two additional suppositions, both of which can be tested empirically (but, to reiterate, have not yet been).

The first supposition is that there are many of these canalizing epigenetic marks, and that they vary with respect to which sex-typical traits they canalize. So, some epigenetic marks would canalize gonad development. Other marks would canalize sexual orientation. (Others, they note, might canalize other traits, like gender identity, but this is not a critical part of the argument.)

The model presented in this paper suggests that various traits that are associated with sex differences may be controlled by distinct genetic elements, and that sex-typical expression of those traits may rely on epigenetic modifications of those genes. Image: Mikhaela.net.

The second supposition is that the epigenetic reprogramming of these marks that normally happens every generation is somewhat leaky.

There are two large-scale rounds of epigenetic reprogramming that happen every generation. One occurs during gametogenesis (the production of eggs or sperm). The second happens shortly after fertilization. What we would expect is that any sex-specifc epigenetic marks would be removed during one of these phases (although it could happen at other times).

For example, a gene in a male might have male-typical epigenetic marks. But what happens if that male has a daughter? Well, normally, those marks would be removed during one of the reprogramming phases, and then female-typical epigenetic marks would be established at the site early in his daughter’s development.

The idea here is that sometimes this reprogramming does not happen. So, maybe the daughter inherits an allele with male-typical epigenetic marks. If the gene influences sexual orientation by modulating androgen sensitivity, then maybe the daughter develops the (male-typical) sexual preference for females. Similarly, a mother might pass on female-typical epigenetic marks to her son, and these might lead to his developing a (female-typical) sexual preference for males.

So, basically, in this model, homosexuality is a side effect of the epigenetic canalization of sex differences. Homosexuality itself is assumed to impose a fitness cost, but this cost is outweighed by the benefit of locking in sexual preference in those cases where reprogramming is successful (or unnecessary).

Sociological Concerns

Okay, if you ever took a gender-studies class, or anything like that, this study may be raising a red flag for you. After all, the model here is basically that some men are super manly, and sometimes their manliness leaks over into their daughters. This masculinizes them, which makes them lesbians. Likewise, gay men are gay because they were feminized by their mothers.

That might sound a bit fishy, like it is invoking stereotype-based reasoning, but I don’t think that would be a fair criticism. Nor do I think it raises any substantial concerns about the paper in terms of its methodology or its interpretation. (Of course, I could be wrong. If you have specific concerns, I would love to hear about them in the comments.) The whole idea behind the paper is to treat chromosomal sex, gonadal sex, and sexual orientation as separate traits that are empirically highly (but not perfectly) correlated. The aim is to understand the magnitude and nature of that empirical correlation.

The other issue that this raises is the possibility of determining the sexual orientation of your children, either by selecting gametes based on their epigenetics, or by reprogramming the epigenetic state of gametes or early embryos. This technology does not exist at the moment, but it is not unreasonable to imagine that it might exist within a generation. If this model is correct in its strongest form (in that the proposed mechanism fully accounts for variation in sexual preference), you could effectively choose the sexual orientation of each of your children.

Image: Brainless Tales.

This, of course, is not a criticism of the paper. The biology is what it is. It does raise certain ethical questions that we will have to grapple with at some point. (Programming of sexual orientation will be the subject of the next installment of the Genetical Book Review.)

Plausibility/Testability Check

The question one wants to ask of a paper like this is whether it is 1) biologically plausible, and 2) empirically testable. Basically, my read is yes and yes. The case for the existence of mechanisms of epigenetic canalization of sex differentiation seems quite strong. We know that some epigenetic marks seem to propagate across generations, evading the broad epigenetic reprogramming. We don’t understand this escape very well at the moment, but the assumptions here are certainly consistent with the current state of our knowledge. And, assuming some rate of escape, the model seems to work for plausible-sounding parameter values.

Testing is actually pretty straightforward (conceptually, if not technically). Ideally, empirical studies would look for sex-specific epigenetic modifications, and for variation in these modifications that correlate with variation in sexual preference. The authors note that one test that could be done in the short term would be to do comparative epigenetic profiling of the sperm of men with and without homosexual daughters.

As Opposed to What?

The conclusions reached by models in evolution are most strongly shaped by the set of alternatives that are considered in the model. That is, a model might find that a particular trait will be selectively favored, but this always needs to be interpreted in the context of that set of alternatives. Most importantly, one needs to ask if there are likely to be other evolutionarily accessible traits that have been excluded from the model, but would have changed the conclusions of the model if they had been included.

The big question here is the inherent leakiness of epigenetic reprogramming. A back-of-the-envelope calculation in the paper suggests that for this model to fully explain the occurrence of homosexuality (with a single gene controlling sexual preference), the rate of leakage would have to be quite high.

An apparent implication of the model is that there would then be strong selection to reduce the rate at which these epigenetic marks are passed from one generation to the next. In order for the model to work in its present form, there would need to be something preventing natural selection from finding this solution.

Possibilities for this something include some sort of mechanistic constraint (it’s just hard to build something that reprograms more efficiently than what we have) or some sort of time constraint (evolution has not had enough time to fix this). The authors seem to favor this second possibility, as they argue that the basis of sexual orientation in humans may be quite different from that in our closest relatives.

On the other hand this explanation could form a part of the explanation for homosexuality with much lower leakage rates.

What Happened with the Press?

So, how do we go from what was a really good paper to a slew of really bad articles? Well, I suspect that the culprit was this paragraph from the press release from NIMBios:

The study solves the evolutionary riddle of homosexuality, finding that “sexually antagonistic” epi-marks, which normally protect parents from natural variation in sex hormone levels during fetal development, sometimes carryover across generations and cause homosexuality in opposite-sex offspring. The mathematical modeling demonstrates that genes coding for these epi-marks can easily spread in the population because they always increase the fitness of the parent but only rarely escape erasure and reduce fitness in offspring.

If you know that this is a pure theory paper, this is maybe not misleading. Maybe. But phrases like “solves the evolutionary riddle of homosexuality” and “finding that . . . epi-marks . . . cause homosexuality in opposite-sex offspring,” when interpreted in the standard way that I think an English speaker would interpret them, pretty strongly imply things about the paper that are just not true.

Rice, W., Friberg, U., & Gavrilets, S. (2012). Homosexuality as a Consequence of Epigenetically Canalized Sexual Development The Quarterly Review of Biology, 87 (4), 343-368 DOI: 10.1086/668167

Update: Also see this excellent post on the subject by Jeremy Yoder over at Nothing in Biology Makes Sense.

11 thoughts on “Epigenetics and Homosexuality”

  1. I haven’t read the paper yet, though it’s certainly on me to-read list for the upcoming week. What caught my eye here was the “As Opposed to What?” question. There are a few issues I’m seeing with the explanations that were put forth, but notably there are two main concerns:

    (1) Why is homosexuality, the kind observed in people, not typical of other species more generally? If this was supposed to be some kind of design constraint, it seems like a rather species-specific one. If other species managed to solve it, why not ours?

    (2) The “not enough time” argument would appear to imply that homosexuality is a relatively new thing. This would further imply that, at some point in the past, homosexuality was very rare in the population and managed to become more prevalent until it represented somewhere between 1- 10% of the population, depending on what sample we’re talking about. For something that is (nearly) the fitness equivalent of being born sterile, explaining how it came to reside at the frequency it does in the first place would require a rather interesting explanation as well.

    Greg Cochran has a suggestion which you might find interesting, pieces of which are found here: http://gc.homeunix.net/home/post/5

    1. There is certainly a fair amount of homosexuality, or at least homosexual behavior, that has been observed in various other species. The question is to what extent is this homologous to human homosexuality. If these are all examples of the same phenomenon, then the “not enough time” argument seems like a hard one to support. If human homosexuality does not have the same genetic / epigenetic / neurological basis as homosexuality in other species, then the “not enough time” argument is potentially in play.

      One challenge of those arguments is that they are difficult to test. In most circumstances, we don’t have a good, quantitative handle on how fast some hypothetical trait “should” evolve.

      In terms of the origin of human homosexuality, the argument presented here would be that there was some sort of new, or perhaps increased selection to canalize attraction to the opposite sex. The solution that natural selection found was one that had the consequence of occasionally producing offspring that were attracted to the same sex. If the benefits of the canalization are strong enough, and the production of homosexual offspring is rare enough, this could be favored.

      I’ll go read the Cochran thing. Thanks for the comment.

    2. It’s been my impression that a good deal of the documented “homosexuality” in other animals doesn’t refer to an exclusive same-sex sexual attraction, but rather talks about transient homosexual behaviors, some of which, such as two female gulls raising a clutch of eggs together, isn’t even sexual in nature.

      It also seems a bit strange to posit that heterosexual sexual attraction would need “canalizing” and then postulate that, as a result of that need for the trait to develop more reliably in the face of variable environments, the trait often develops in precisely the opposite direction (i.e. it needs to develop a heterosexual orientation reliably, and, in the process of doing that, doesn’t do that). “Occasionally” in this argument isn’t something like 1 in 10,000, which might make that argument plausible, but rather 1 in 100 to about 1 in 10, if we’re using that 8% statistic. That would seem to be awfully poor canalization.

    3. I agree that this is maybe the weakest point in the theory.

      One problem is that most of the data on sexual orientation in other species is pretty anecdotal, in my opinion. There is certainly a lot of behavior that could or could not be interpreted as sexual, and it is often difficult to know to what extent those behaviors have any analogs in human behavior.

      Fundamentally, this resolves itself if and when someone identifies specific genes and epigenetic marks that fit with the theory. Then, one could look at the homologous sites in other species, and we could get a handle on the evolutionary history of the system, even in the absence of quality data on sexual orientation in other species.

  2. I don’t know what I’m talking about here…I’m an artist who reads the odd Scientific American now and then, and not a geneticist. But, when anti-“homosexual” activists say that such sexuality must be chosen because no Gay gene has been found, I’ve been saying for several years that:

    A. It turns out that we have many fewer genes than was thought when the search for the Gay gene started, therefore that shouldn’t surprise anyone. Patterns of gene interactions could take the place of individual genes protein coding for what an individual gene might do.

    B. Epigenetics and new discoveries about the actions of micro-RNA on gene regulation might have something to do with our sexual orientations. Maybe I had a lucky guess?

    C. As far as civil rights and equality under the law goes, causation is merely interesting. Mutually consenting, tax paying adults don’t need to explain why they love whom the love.

    So, did I get anything right?

    1. A. Yes, once you throw in substantial interactions among multiple genes, basically anything can happen. In the present context, if sexual orientation is influenced by highly nonlinear interactions among genes, then 1) it is not surprising that one can not identify specific genes, even if there is heritability, and 2) it is not surprising that homosexuality would persist at a substantial frequency in the population, even if there were substantial natural selection against it.

      In a way, actually, what this paper is doing is proposing a specific form of non-linear interaction.

      B. Yes, epigenetics and other complications open up the possibility of novel explanations for a lot of things that have been difficult to understand under the more traditional paradigm.

      C. Absolutely. This is a question that is interesting to evolutionary biologists because it seems counterintuitive. Whenever you have something counterintuitive, understanding it allows you to understand the complexity of the evolutionary process better. Biology, like all of science, has nothing to say about equality, etc. Fundamentally, you have to choose what your moral values are. Sometimes, then, science can help to steer you towards the best ways to promote those values. Science can not determine your values.

      That being said, if one’s values have any resonance with ideas of individual freedom and happiness, then I think one has to support civil rights and equality under the law regardless of sexual orientation. That holds whether homosexuality is genetic, epigenetic, cultural, or “individual choice,” whatever that means.

  3. If today’s homosexual rate in human are significantly higher than in other species, or if the rates in human and in other species today are higher than historical observations, it’s entirely possible that environmental pollution has played a hand into the changes, be it influencing the epigenets in the womb, or developmental, hormonal changes later in life. I haven’t read the original paper, but if that’s not considered, it would seem an oversight.

    1. Certainly there is evidence, for instance, that people reach puberty earlier than they used to. This could be due to increased access to nutrients or exposure to hormones in the food supply (and/or any of a number of other things). It is conceivable that environmental changes could also affect the development and expression of sexual orientation.

      The problem is that we really don’t have good data on changes in sexual orientation over time. What little data exists is deeply confounded with cultural variation in the acceptance of various forms of sexual behavior.

      Is homosexuality more common in humans than in other animals? It’s a hard question to answer, in part because it is difficult to know how exactly to relate specific behaviors in other species to those in humans. Even if true, it would be difficult to disentangle this from the whole host of changes in cognition and behavior that have occurred during human evolution.

  4. Thanks for the very enlightening analysis of the paper. I think any self-aware LGBT person would affirm that at no point in their lives (and for that matter, at no point in my own life as gay man) did they (nor did I) consciously choose their sexual orientation. The idea of non-linear interaction of genes is a very interesting one. I completely agree with your viewpoint that civil rights and morals should not be determined by biology. But I do think that the biological enquiry is important inasmuch as it can refute dated theories of homosexuality being a product of defunct post-natal psychosexual development.

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