Category Archives: genetics

The Genetical Book Review: The Mapmaker and the Ghost

So, remember when not all kids books were about teenage wizards and sexy vampires? Well, it turns out that, if you know where to look, you can still find books like that. Enter The Mapmaker and the Ghost, by Sarvenaz Tash.

[Disclaimer: Sarv is a friend of my wife’s. They got to know each other through the fact that both are in the New York area, and both had their debut middle-grade novels come out this year. If you are concerned that this may color the objectivity of this review, may I refer you to the Genetical Book Review’s premise and guidelines.]

The Mapmaker and the Ghost is a story that I would say is of the same general flavor as something like From the Mixed-Up Files of Mrs. Basil E. Frankweiler. The setting is very much our world, and the adventure is on a human scale. In the Mixed-Up Files, a girl and her younger brother run off to the museum, and get caught up in a quest to discover the provenance of a statue. In Mapmaker, a girl (Goldenrod) and her younger brother (Birch) find adventure in the woods at the edge of town, and get caught up in a quest to find a legendary blue rose.

The Mapmaker and the Ghost, by Sarvenaz Tash. Want to buy it already?
Settle down there, sparky! Purchase links will be available at the bottom of the post.

For kids, I think, the human scale makes the story directly relatable to their own lives. At least, that seems to be one of the things that our kid loved about the book. (He was nine at the time he first read it, and has reread it multiple times.) The concerns that the characters have, about curfews and money and permission to go past a certain point in the street, etc., seem to resonate with the experience of childhood in a way that very few authors pull off.

Of course, as in any good adventure, there are exciting things that happen that go well beyond what most children actually experience. But those events have an emotional impact that derives from the realism of the novel. I mean, saving the world from the most evil villain of all time is, of course, exciting, but evading the gaze of a security guard can actually be even more emotionally tense and exhilarating, because it is a situation that a young reader can really embody.

Also, there’s a gang of semi-feral kids with names like “spitbubble” and “snotshot,” a mysterious old lady, a secret lair, and, of course, a ghost.

The book is appropriate for ages 7 through probably about 12. The main character is a girl, but the novel is strongly gendered, and will be engaging for boys and girls. (If you have a son who thinks that they should not read a book like this because it is about a girl, you should definitely buy it, thump him over the head with it, and then watch him enjoy it anyway.)

Now, on with the science!

As I mentioned, the central quest in the novel is the search for a blue rose that blooms in the woods at the edge of town once every fifty years. This is a big deal, because, you know, roses aren’t blue. When you find a rose that is actually blue, it’s blue because it has been dyed blue.

A few years ago, a Japanese company called Suntory made news when they produced the world’s first non-dyed blue rose. They managed this through genetic engineering, taking a gene from a pansy and inserting it into a rose. [Insert juvenile and inappropriate joke here.]

Now, you’re probably looking at this rose and thinking that you have to be pretty colorblind (or have a job in Suntory’s marketing division) to call this “blue.” Fair enough, but, that’s the state of the art at the moment.

Suntory’s “blue” rose, which, while lilac a best, is still pretty cool. As an aside, we could also interpret this as an example of what linguists call “collocational restriction,” where the term “blue” has an idiomatic meaning in the specific context of the phrase “blue rose.” In this case, it might be interpreted as “bluer than a rose normally is,” much as “white coffee” is not actually white, but is at the white end of the distribution of coffee colors. (Image via Wired)

Here is Figure 1 from the publication of Suntory’s work, which shows the biosynthetic pathways responsible for plant color. You don’t find blue roses in nature because roses lack an enzyme in the pathway on the far right, which means that they lack any delphinidin-based anthocyanins.

Anthocyanins are the primary chemicals responsible for 

The gene that the researchers inserted into the rose is the one indicated by F3’5’H in the figure. This enzyme (flavonoid 3′,5′-hydroxylase) is normally absent from roses, which is why they lack the bluish pigments.

Although only one blue rose cultivar has been brought to market (The Suntory “Applause” pictured above), they actually did the transformation with a bunch of different cultivars. Here are a few examples (from the same paper).

In each panel, the flowers on the left are without the F3’5’H gene, and the ones on the right are with it.

If you read Japanese (or trust Google Translate), you can check out more information at Suntory’s dedicated blue-rose webpage, which features topics such as “Legend,” “Brand Concept,” and “Applause Wedding” (new!).

The authors note that there are various things one could imagine doing to make roses even bluer, including tinkering with the pH, getting other pigments in there, etc. How easy these next steps are going to be is less clear, though. It’s hard to tinker without breaking stuff. Perhaps genuinely blue roses will continue to be the symbol of unattainability, and limited to great kids’ books.

Katsumoto, Y., Fukuchi-Mizutani, M., Fukui, Y., Burgliera, F., Holton, T. A., Karan, M., Nakamura, N., Yonekura-Sakakibara, K., Togami, J., Pigeaire, A., Tao, G.-Q., Nehra, N. S., Lu, C.-Y., Dyson, B. K., Tsuda, S., Ashikari, T., Kusumi, T., Mason, J. G., & Tanaka, Y. (2007). Engineering of the Rose Flavonoid Biosynthetic Pathway Successfully Generated Blue-Hued Flowers Accumulating Delphinidin Plant Cell Physiol., 48 (11), 1589-1600 DOI: 10.1093/pcp/pcm131


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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.

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Mutational Analysis in Poetry and Biology

So, Robert Pinsky wrote a cool little piece in Slate the other day titled “In Praise of Memorizing Poetry – Badly.” In it he argues for a particular benefit to be gotten from misremembering a poem: that it brings into focus the choices that were made in the poem, the the consequences of using one word rather than another. He illustrates his argument with Yeats’s “On Being Asked for a War Poem,” which he presents like this:

“On Being Asked for a War Poem” 

I think it better that in times like these
A poet’s mouth be silent, for in truth
We have no gift to set a statesman right;
He has had enough of [something] who can please
A young girl in the indolence of her youth,
Or an old man upon a winter’s night.

He talks about misremembering the [something] as “glory” or “indolence” or “striving” before rediscovering Yeats’s original “meddling.”

In the case of “meddling,” the result of the exercise is to highlight the historical context in which Yeats was writing. Yeats was an Irish poet writing about World War I in 1915. At the time, Ireland was still part of the United Kingdom, and was actively involved in the war. However, some Irish nationalists used the war as an opportunity initiate a rebellion against English rule. And, in fact, the Irish War for Independence began pretty much as soon as World War I ended.

During Easter week of 1916, Irish rebels seized control of several key buildings
in Dublin and declared independence from England. Yeats wrote a poem about it.

Yeats’s poem was written in response to a request by Henry James, and was originally titled “To a friend who has asked me to sign his manifesto to the neutral nations.” In all of this context, the choice of “meddling” seems to point to a degree of ambivalence towards the war, even presaging Ireland’s own neutrality in World War II.

Now, of course, all of this information is, in principle, available to anyone who has both the original text and access Wikipedia. However, for Pinsky, it is this forgetting, the substitution of “meddling” with “glory,” that serves as the catalyst for this particular close reading. And I doubt that, in the absence of some similar impetus, very many people would have focused on this particular aspect of the poem.

In biology, similar mistakes, in the form of mutations, provide one of our most important windows into the structure and function of biological systems. These mutations are sometimes the product of targeted mutagenesis, but can also result from naturally occurring mutations.

A lot of our coarse-grained knowledge of many systems comes from loss-of-function, or knockout mutations, where a mutation removes a particular gene, or renders it nonfunctional. For example, in 1976, Sharma and Chopra first described a recessive mutation in the fruitfly Drosophila melanogaster. Flies inheriting two copies of the mutation exhibited various developmental defects, the most obvious of which involved wing formation. So, the mutation, and later the gene, became known as “wingless.”

This is typical in genetics, where a gene will be given a name based on the phenotypic consequences of losing that gene. So, a gene required for wings becomes “wingless,” a gene required for heart formation might be called “heartless,” and so on.

Kim Jong Il relaxes with some brews.
Due to the nature of the discovery process in biology, many genes wind up with names that are more like the opposite of what the gene actually does. This is sort of like how the least democratic countries always wind up with the word “Democratic” in their names, or how Citizens United succeeded in dramatically curtailing most citizens’ abilities to control their own government.

More subtle mutations, which alter the behavior of a gene or its gene product without completely eliminating it function, are more closely analogous to the misremembering that Pinsky is talking about, however. In a way, a knockout mutation of an important gene is more like just removing one whole line from Yeats’s poem, without regard for grammar, rhyme scheme, coherence, etc. What you would wind up with is a mess that fails in many ways, and is probably not terribly instructive – just like in biology.

Point mutations, which might alter a single amino acid in a protein, provide a more targeted and interpretable set of changes. Such a mutation might cause a small shift in the binding behavior of the protein, or might cause a slight change in the timing of the gene’s expression.

Like in the poetry case, these mutations are more likely to be revealing of the fine tuning part of the creative process, where mutations of small effect arise and are subjected to natural selection. In some populations – things like certain viruses, which have a very large population size and strong selective constraints – it might even be reasonable to think that these alternate, mutant forms have been explored and rejected by past natural selection. In other cases (e.g., large mammals, with relatively small effective population sizes), the most common form we find in nature might not represent some finely tuned optimum, but may simply be a form that works well enough.

Similarly, when we read a Yeats poem, we are inclined to assume that every single word has been chosen with extreme care, that a host of plausible alternatives were considered and rejected by the poet before he settled on just exactly the right word, in this case, “meddled.” I think we are inclined to agree with Pinsky’s final assessment, that “by memorizing his poem imperfectly, I had received a creative writing lesson from a great poet.”

However, a lot of poems in the world, even very good ones, are probably more like large mammals, with many of the word choices working well enough, but not necessarily representing some optimum, even a local one. (There is of course, the question, in biology and in poetry, of to what extent one can talk coherently about optima, but that’s a post for another day.) But this process, deliberate or accidental tinkering, is critical both to the creation of great things, and to understanding how greatness is created.

Sharma RP, & Chopra VL (1976). Effect of the Wingless (wg1) mutation on wing and haltere development in Drosophila melanogaster. Developmental biology, 48 (2), 461-5 PMID: 815114

Genomic Imprinting at Darwin Eats Cake

So, I’ve posted the new Darwin Eats Cake, which is about genomic imprinting. I tried to do some explaining in the comic, but I suspect that there is not enough information there for the thing to make sense unless you already have at least a passing familiarity with the phenomenon.

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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Why do we make odd faces when we orgasm? A romance in three parts

So, Guillaume’s Mailbag has continued on its mission to provide an adaptive explanation for every existing trait. The most recent trait Guillaume has been tackling was submitted by John Wilkins, who asked, “Why do we make odd faces when we orgasm?”

In case you missed when I’ve plugged him before, JoHn Wilkins (no recent relation) is a philosopher of science in Australia. His most recent book is Species: A History of the Idea, and he runs an excellent blog called Evolving Thoughts. He recently concluded an excellent series of posts on “Atheism, agnosticism and theism” in which he discusses, among other things, what it means to have a belief. You can find the start of that series here.

But back to the face of orgasm. Guillaume took three full strips to answer this one, so I’ve waited until he was done to post them here. I think I’ve finally figured out how to make these full-page versions more readable on the blog, but it involved lowering the resolution of the JPEG, so, for higher-res versions of these three comics, head on over to Darwin Eats Cake. The first of the series of three can be found here.

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For those who are interested, a couple of vole and oxytocin citations are provided below to get you started. The vole literature is actually quite extensive and all interesting. I’ve included a relatively recent paper, which will contain citations to a lot of the other work. No peer-reviewed publications are yet available on the eating and mating habits of Ursus philorgasmii.

Ross HE, Cole CD, Smith Y, Neumann ID, Landgraf R, Murphy AZ, & Young LJ (2009). Characterization of the oxytocin system regulating affiliative behavior in female prairie voles. Neuroscience, 162 (4), 892-903 PMID: 19482070

Carmichael MS, Warburton VL, Dixen J, & Davidson JM (1994). Relationships among cardiovascular, muscular, and oxytocin responses during human sexual activity. Archives of sexual behavior, 23 (1), 59-79 PMID: 8135652

Although at least one study suggests that, in men, prolactin is actually more strongly correlated with orgasm than oxytocin is:

Krüger TH, Haake P, Chereath D, Knapp W, Janssen OE, Exton MS, Schedlowski M, & Hartmann U (2003). Specificity of the neuroendocrine response to orgasm during sexual arousal in men. The Journal of endocrinology, 177 (1), 57-64 PMID: 12697037

The Genetical Book Review: White Cat

So, welcome back to the Genetical Book Review, where we use concepts from evolutionary biology and genetics to talk about novels. In this installment, we are going to talk about White Cat, written by Holly Black. This is the first book in the Curse Workers fantasy series, the second book of which is set to be published in April. Holly Black may be familiar to some readers as one of the authors of The Spiderwick Chronicles.

White Cat is, broadly speaking, the same flavor of book as the Spiderwick series. The story has a contemporary setting, but in an alternate history in which a subset of people, known as “curse workers” or just “workers,” possess special abilities. The book’s protagonist, Cassel, comes from a worker family, but has no special abilities himself. One of his brothers is a “luck worker,” who is able to give people good (or bad) luck, while his other brother is a “body worker,” meaning that he is able to hurt people. His mother is an “emotion worker” who is able to manipulate people by, for example, convincing them that they are in love with a particular person. His grandfather is a “death worker,” who is able to kill people with his touch.
In fact, all workers’ skills require that the worker touch their target. Thus, in this alternate history, everyone wears gloves, and approaching someone with bare hands represents a potential act of aggression. In this world, curse workers are subject to “blowback,” which results from a sort of conservation law. For instance, whenever Cassel’s grandfather uses his ability to kill someone, a part of his body dies, such that when we first meet him, his fingers are blackened stumps, the consequence of a lifetime of death work.
Artist imitates art. Holly Black dons eponymous gloves in an effort not to accidentally curse herself when she touches her face. Image from the Holly Black website.
In this alternate history, curse work has been outlawed, so that curse workers live somewhat in the shadows and are employed by organized crime families. Much of the book’s social commentary focuses on issues that arise from this situation. There are discussions that parallel arguments about prohibition and drug legalization. There is a political movement to require people with abilities to register with the authorities. These subjects are handled largely in subtext, providing a layer to the book that will be interesting to adult readers.
I won’t go on further here about the premise or plot, as describing more would risk revealing some of the book’s twists. In terms of summary judgment, let me just recommend the book. It is fast moving and well written, and easily the sort of book you might find yourself finishing in a single sitting. It has some dark elements that might make it inappropriate for younger independent readers, so I would not necessarily buy it for your grade-school son or daughter. On the end of the spectrum, if you are an adult who enjoys this genre of young-adult fiction (e.g., if you like the Bartimaeus trilogy by Jonathan Stroud), I suspect you’ll have a great time reading this book, which is aimed at an older age bracket than Spiderwick.
What we will focus on here is the nature of the genetic variation that underlies the ability to perform curse work. The ability clearly has a genetic basis and seems to run strongly in families. There is also an explicit discussion of the fact that there is a high frequency of workers in Australia, due to a high frequency of the trait in the founding population.
The premise of a magical ability with a genetic basis underlies many fantasy franchises, including Harry Potter, X-Men, and television’s Heroes. In each case, there is some variation in the extent of the ability among those who have it, but there is fundamentally a binary distinction between those with abilities and those without them.
The clean, binary division between wizards and muggles means that no matter how enthusiastically you grip that broom between your legs, you’re never actually going to fly. Image of the fourth annual Quidditch World Cup. A real thing that real people do. For real.
Franchises differ in how they conceive of the structure of variation among those with abilities. In Heroes and X-Men, for instance, each mutant has unique abilities. (Or, to the extent that two mutants share abilities, it is generally looked upon as a lack of creativity or lack of attention to detail on the part of the writers.) By contrast, in Harry Potter, witches and wizards have, by and large, the same set of abilities. They differ in the degree of proficiency they display in different skills, but the variation seems to be fairly continuous.
We could say the franchises differ in the extent to which the mutant phenotype is canalized. In contemporary usage, the term canalization is used to refer to mechanisms that buffer the phenotype against genetic and/or environmental variation. It is an inherently relative term, in that it makes no sense to talk in isolation about a trait being canalized or not. However, it is sometimes possible to compare the extent to which a trait is canalized in two systems. For example, if the pattern of wing veins in one species of fly is invariant in response to changes in the temperature at which the flies are raised, while the pattern in a second species changes with temperature, we could say that the patterning was more canalized (with respect to temperature) in the first species than the second. The term comes from a metaphor in which different genetic variants or environmental influences get channeled into a “canal” representing normal development.
The canalization concept is usually used in the context of stabilization of the wild-type, but we can just as easily talk about canalization of a mutant phenotype. In Heroes and X-Men, it seems that the mutant phenotype is almost completely uncanalized. These franchises employ the “Anna Karenina Principle.” To quote the most over-quoted Tolstoy passage ever, “Happy families are all alike; every unhappy family is unhappy in its own way.” Despite the fact that a specific mutation is responsible for the superpowers in Heroes and X-Men, some interaction involving the mutation (presumably with other loci in the genome) results in a wildly different phenotype in each individual.
Whenever scientists want to say that something breaks in all sorts of different ways, while at the same time establishing their credentials as cultured intellectuals, they cite the “Anna Karenina Principle,” referencing a book that they know to be important, even if they have not actually read it themselves. This mapping of a diverse array of scientific observations onto a single reference represents a kind of literary canalization.
In the Harry Potter books, the genetic basis for wizardry is less clearly articulated, but the trait appears to be more canalized than the analogous traits in Heroes and X-Men. If there were less variation in the abilities of different witches and wizards in different areas of magic, we would say that the trait was even more highly canalized.
While canalization is often currently thought of as a buffering mechanism that applies to the entire phenotype, when the idea was first introduced by C. H. Waddington, he was also interested in the idea of cell-type differentiation. He introduced the concept of the “epigenotype” to refer to distinct sets of traits that could develop from the same underlying genotype. The cells in your brain and the cells in your liver have the same set of genetic material, but the morphology and behavior of the cells is wildly different. Thus, in this original concept of canalization involved the notion of multiple, distinct canals, each of which uses some sort of buffering to produce a stereotyped outcome.
Waddington represented development as a ball following one of a set of distinct, stereotyped pathways, like the character arcs on “reality” television.
The curse-worker phenotype in White Cat is like this notion of canalization. There are a handful of very distinct types of curse work that seem to occur in fairly well defined relative frequencies. Based on Cassel’s family, the capacity to do curse work seems to be strongly genetic, but the type of curse work one is able to do may be largely stochastic. It is sort of like Plinko: the genetic mutation hurls you onto the board of being a worker, but then random processes determine which curse-work canal you wind up following.
A Plinko contestant drops a hockey-puck type thing onto a board with a bunch of pegs on it to determine which kind of curse work he will spend his life doing. Genetics works exactly like this.
There is another form of canalization that we can see in the world of White Cat, a sort of historical canalization. Like many books in this genre, White Cat takes place in a world much like our own, but with a couple of key changes. Part of the appeal of many science fiction and fantasy books of this sort is seeing how the author takes a couple of key changes and imagines how history might play out differently. What if the Roman Empire had never fallen? What if Germany had won World War II? What if Martin Sheen had only had one son? And so forth.
The characters in White Cat occupy a world that is as precisely like our own as it can be and still support the premise of the story. The forces of history are so highly canalized that you can rewind the tape hundreds of years and give a small fraction of people magical powers, and you still wind up with Facebook. Tolstoy would be proud.

WADDINGTON, C. (1942). Canalization of Development and the Inheritance of Acquired Characters Nature, 150 (3811), 563-565 DOI: 10.1038/150563a0

Update: I had originally described the book as having been written by Michael Frost and Holly Black, which is what it says on the Kindle version, where I read it. Upon further investigation, it seems that Michael Frost is responsible for the cover art, but not the writing in the book. Everywhere else, Holly Black is the only listed author, so I have corrected my review accordingly. It strikes me as odd that the only place where he would be listed as a co-author is on the Kindle, where there is no cover art, but there you have it.

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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.

The Genetical Book Review: Middlesex

So, welcome to the first installment of Lost in Transcription’s newest feature: The Genetical Book Review. For the maiden voyage, we’ll cover the 2002, Pulitzer-prize-winning Middlesex by Jeffrey Eugenides.

You’re surprised? Because you assume that an eight-year-old Pulitzer winner must already have been reviewed?

Fair enough. But, here’s the gimmick: we’ll use the genetics angle to talk about some things that have not already been covered extensively elsewhere.

First, though, the precis and value judgement. If you’ve not read the book, or read about it, it follows three generations of the Greek-American Stephanides family, who traipse through a slice of historical events in Smyrna and Detroit over the course of nearly a century. It’s sort of a Forrest Gump for the NPR set. Cal Stephanides and his relatives witness genocide at the hands of the Turks, emigrate to America, build cars for Henry Ford, and run booze during prohibition. They are present for the founding of the Nation of Islam and the 1967 Detroit race riots. They flee to the suburbs and watch Watergate unfold on the television.

As in Forrest Gump, some of the historical context feels a bit like pandering, an attempt to draw the reader in through nostalgia. On the other hand, many of the events are local enough to be only passingly familiar to most readers, so there’s learning to be had. More importantly, those events are always portrayed through the lens of how they shaped the trajectories of the characters in the book. And, they are charmingly and engagingly written, with a varied style that is pleasurable to read.

Basically, if your book group has not already read this book, and you’re sick of plodding stories about alcoholic mothers and victims of sexual abuse, but want something with some literary gravitas (so that you don’t lose social status by suggesting it to your book-group frenemies), this is the book for you!

There you have it. Hit the jump for the role of genetics in the book.

The book is written in a memoir style, told by Cal, who periodically takes on the persona of a chromosome being passed down, or an egg sitting in an ovary as s/he relates the events from previous generations. I say “s/he” because – and I’m not giving anything away here – the key twist to the coming-of-age story is that Cal is intersex, having ambiguous genitals as a result of a recessive, genetic 5-alpha-reductase deficiency.  For reasons reaching back to Smyrna, Cal’s condition is not identified at birth, and our protagonist is raised as a female, Calliope. It is not until puberty hits that Calliope discovers her condition and transforms into her male alter ego, Cal.

The 5-alpha-reductase gene encodes an enzyme that converts testosterone into dihydrotestosterone (DHT). In early development, testosterone is responsible for certain internal male reproductive structures, such as the vas deferens, while DHT is responsible for the external genitalia. Upon the onset of puberty, testosterone drives the male increase in muscle mass and deepening of voice, while DHT is responsible for the growth of facial hair. One of the reasons for the female-to-male switch that happens at puberty is that there are actually two different 5-alpha reductases. The type 2 enzyme is the one that is primarily responsible for DHT production, particularly in early development, and it is this enzyme that Cal lacks. The other one, the type 1 enzyme, is substantially upregulated at puberty, which results in an uptick in DHT production.

So, there are two things that combine at puberty to drive the sudden appearance of male characteristics: (1) Testosterone and DHT start sharing the load for creating external male-typical characteristics, and (2) a second pathway appears for the generation of DHT.

I have to say, as I have read about this disorder, I have been impressed with the depth of understanding that Eugenides seems to have brought to the novel.

[As a side note, this disorder was first identified in the remote village of Salinas in the Dominican Republic, where it occurred in about 2% of live births. Locally, these individuals are known as “guevedoces.” Whenever I have seen reference to the guevedoces, it is followed by the phrase “literally ‘penis at twelve.'” Actually, it turns out that ‘gueve’ is derived from ‘huevos,’ which is slang for ‘balls.’ Thus, a better translation might be “balls at twelve.” Although, if you’re going to precede your translation with “literally,” you would need to acknowledge that this slang for ‘balls’ is literally the word for ‘eggs.’ Of course, referring to the appearance of male sexual characteristics at the onset of puberty as “eggs at twelve” is just weird and confusing, because it sounds like something you would order at Denny’s, and because it is sort of the exact opposite of what is going on.]

Incest is one of the recurring themes in the book, which traces the paths through which Cal came to inherit two defective copies of the 5-alpha-reductase gene. This particular disorder is straight-up recessive, so if you have one functional copy of the gene, you develop normally.

Cal’s grandparents on his/her father’s side are brother and sister. They hailed from the same tiny village outside of Smyrna, were orphaned, and fell in love. Their immigration to America permitted them the opportunity to fabricate a non-consanguinous past. The interesting thing is that the inbreeding involving Cal’s grandparents bears absolutely no responsibility for Cal’s condition. Their son, Milt is unaffected, which means that he inherited one defective gene copy from one of his parents. It doesn’t actually matter whether the other parent carried a copy or not.
More specifically, what is required for the story is that Milt be a carrier, but not express the condition. If one of his parents is a carrier, the probability that he is a non-expressing carrier is 1/2. If both of his parents are carriers, the probability that he is a non-expressing carrier is 1/2. It will not have escaped your attention that 1/2 = 1/2.

There is a second case of inbreeding, however, that does contribute to Cal’s condition. Milt and his wife, Tessie, are second cousins, and each of them is heterozygous for the deficiency. Now, statistically speaking, the fact that Milt and Tessie are second cousins barely counts as incest. For a rare disorder such as 5-alpha-reductase deficiency, the elevation in risk due to a second-cousin marriage is small. How small? Let’s see.

Assume that the frequency of the defective version of the gene is q = 0.001, or one in a thousand. This is in the ballpark of what we might expect for a recessive mutation maintained at mutation-selection balance. The probability that an outbred individual inherits two defective copies is approximately q2, or one in a million. What if the mother and father are related? If their degree of relatedness is r, then the probability that their child will inherit two copies is:

         p = q (r/2q (1 – r/2))

What is this r thing? Well, if they are brother and sister, r = 1/2, so the probability p would be about 0.00025. For first cousins, r = 1/8, and p = 0.0000634. For second cousins, r = 1/32, and p = 0.0000166.

That is, for second cousins, the probability goes from one in a million to about one in 60,000. Basically, you will have a bigger impact by taking prenatal vitamins.

Diane Paul and Hamish Spencer published an interesting piece a couple of years ago about the history of the stigmatization of first-cousin marriage, particularly in the United States. They make a number of interesting points, and I recommend the article, which can be found here. It is short, fascinating, open access, and requires no background in genetics to follow.

One of the points they make is that there is pretty much no way to interpret a ban on first-cousin marriage as anything other than eugenics. And yet, somehow, this prohibition has managed to escape that label. Another of their points is that the genetic risks associated with first-cousin marriage are actually small compared with a lot of behaviors that are completely acceptable in our society, such as women having children over the age of 40, or the use of in vitro fertilization techniques. (That second one was not mentioned by them, but it’s true.) So, there is some inconsistency there, which they trace to nineteenth century misconceptions about heredity and prejudice against immigrants and the rural poor.

But, back to the book.

To recap, in terms of causal things leading to Cal’s genetic composition, the fact that his/her parents are second cousins matters. The fact that the grandparents are brother and sister does not. Why, then, does the story, much of which is driving towards Cal’s conception, spend so much more attention on the (genetically) irrelevant grandparental love story?

Obviously, I can’t speak to the author’s intention, but to me, having two separate incidents provides a nice, clean separation between the psychological and genetic consequences of incest. Cal’s grandmother is wracked with guilt about her transgression, and this guilt drives the story in several places. In fact, one of the motifs in the book is that action (or, often, lack of action) is often motivated by superstitious beliefs. –– Sorry about the vagueness here. I’m in spoiler-avoidance mode. –– Hypothetically speaking, let’s say one of the characters is eating toast, and then that character’s mother falls down and breaks her hip. The character would blame him/herself for eating toast and refuse to eat toast again for a long time. You get the idea.

Anyway, my point is that by having two separate incests, we are able to distinguish more clearly between the genetic consequences of consanguinity from the EWWWW consequences of knocking boots with your sister.

Paul, D., & Spencer, H. (2008). “It’s Ok, We’re Not Cousins by Blood”: The Cousin Marriage Controversy in Historical Perspective PLoS Biology, 6 (12) DOI: 10.1371/journal.pbio.0060320

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