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A few days ago I was browsing Haldane’s Sieve,when I stumbled upon an amusing discussion which arose on it’s “About” page. This “inside baseball” banter got me to thinking about my own intellectual evolution. Over the past few years I’ve been delving more deeply into phylogenetics and phylogeography, enabled by the rise of genomics, the proliferation of ‘big data,’ and accessible software packages. This entailed an opportunity cost. I did not spend much time focusing so much on classical population and evolutionary genetic questions. Strewn about my room are various textbooks and monographs I’ve collected over the years, and which have fed my intellectual growth. But I must admit that it is a rare day now that I browse Hartl and Clark or The Genetical Theory of Natural Selection without specific aim or mercenary intent.

R. A. Fisher

Like a river inexorably coursing over a floodplain, with the turning of the new year it is now time to take a great bend, and double-back to my roots, such as they are. This is one reason that I am now reading The Founders of Evolutionary Genetics. Fisher, Wright, and Haldane, are like old friends, faded, but not forgotten, while Muller was always but a passing acquaintance. But ideas 100 years old still have power to drive us to explore deep questions which remain unresolved, but where new methods and techniques may shed greater light. A study of the past does not allow us to make wise choices which can determine the future with any certitude, but it may at least increase the luminosity of the tools which we have iluminate the depths of the darkness. The shape of nature may become just a bit less opaque through our various endeavors.

Figure from “Directional Positive Selection on an Allele of Arbitrary Dominance”, Teshima KM, Przeworski M

So what of this sieve of Haldane? As noted at Haldane’s Sieve the concept is simple. Imagine two mutations, one which expresses a trait in a recessive fashion, and another in a dominant one. The sieve operates by favoring the emergence out of the low frequency zone where stochastic forces predominate of dominantly expressing variants (i.e., even if an allele confers a large fitness benefit, at low frequencies the power of random chance may still imply that it is highly likely to go extinct). An example of this would be lactase persistence, which in the modal Eurasian variant seems to exhibit dominance. The converse case, where beneficial mutations are recessive in expression suffer from a structural problem where their benefit is more theoretical than realized.

The mathematics of this is exceedingly simple, a consequence of the Hardy-Weinberg dynamics of diploid random mating organisms. Let’s use the gene which is implicated in variation in lactase persistence as an example, LCT. Consider two alleles, LP and LNP, where the former confers persistence (one can digest lactose sugar as an adult), and the latter manifests the conventional mammalian ‘wild type’ (the production of lactase ceases as one leaves the life stage when nursing is feasible). LP is clearly the novel mutant. In a small population it is not unimaginable that by random chance the frequency of LP rises to ~10%. What now? At HWE you have:

p2 + 2pq + q2 = 1, where q = LP allele. At ~10% the numbers substituted would be:

(0.90)2 + 2(0.90)(0.10) + (0.10)2

This is where dominance or recessive expression is highly relevant. The reality is that LP is a dominant trait. So in this population the frequency of LP as a trait would be:

(0.10)2 + 2(0.90)(0.10) = 19%

Now imagine a model where LP is favored, but it expresses in a recessive fashion. Then the frequency of the trait would equal q2, the homozygote LP-allele proportion. That is, 1%. Though population genetics is often constructed on an algebraic foundation, the results lend themselves to intuition. A structural parameter endogenous to the genetic system, dominant or recessive expression, can have longstanding consequences in terms of the likely trajectory of the alleles. Selection only “sees” the trait, so a recessive trait with sterling qualities may as well be a trait with no qualities. In contrast, a dominantly expressed allele can cut like a scythe through a population, because every copy “counts.”

In preparation for this post I revisited the selection on Haldane’s Sieve in the encyclopediac Elements of Evolutionary Genetics. The authors note that this phenomenon, though of vintage character as these things can be reckoned is a field as young as evolutionary genetics, is still a live one. The dominance of favored mutations in wild populations, or the recessive character of deleterious ones in laboratory stock, may reflect the different regimes which these two genes pools are subject to. The nature of things is such that is easier to generate recessive mutations than dominant ones (i.e., loss is easier than gain), so the preponderance of dominant variants in wild stocks subject to positive selective pressure lends credence to the idea that evolutionary rather than development forces and constraints shape the genetic character of many species.

And yet things are not quite so tidy. Haldane’s Sieve, and the framework of dominant versus recessive alleles, operates differently in the area of sex chromosomes. In many lineages there is a ‘heterogametic sex’ which carries only one functional chromosome for most of the genome. In mammals this is the male (XY), while in birds this is the female (ZW). As males have only one functional copy of most genes on the sex chromosome, the masking effect of recessive expression does not apply to them in mammals. This may imply that because of the exposure of many deleterious recessive variants to natural selection within the heterogametic sex one would see different allelic distributions and genetic landscapes on these chromosomes (e.g., more rapid adaptation because of the exposure of nominally recessive alleles in the heterogametic sex, as well as more purifying selection on deleterious variants). But the reality is more complex, and the literature in this area is somewhat muddled. More precisely, it seems phylogenetically sensitive. Validation of the theory in mammals founders once one moves to Drosphila.

And that is why research in evolutionary genetics continues. The theory stimulates empirical exploration, and is tested against it. Much of the formal theory of classical evolutionary genetics, which crystallized in the years before World War II, is now gaining renewed relevance because of empirical testability in the era of big data and big computation. This is an domain where the past is not simply of interest to historians. Scientists themselves, chasing the next grant, and producing the expected stream of publications, may benefit from a little historical perspective by standing upon the shoulders of giants.

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A story in The Los Angeles Times seems to point medical implications of being a sickle cell carrier, Sickle cell trait: The silent killer:

At least 17 high school and college athletes’ deaths have been tied to sickle cell trait during the past 11 years. The group includes Olivier Louis, a player at Wekiva High School near Orlando, who died on Sept. 7, 2010, following his first football practice.

You have surely heard about sickle cell anemia. It is a recessive disease which expresses in those who carry two sickle cell alleles. T-boz of TLC has the disease for example due to her homozygosity. But the allele also famously confers some resistance against malaria, which explains its concentration in regions which have historically been malarial. Sickle cell is arguable the classic case of heterozygote advantage driving the emergence of a recessive disease. The frequency of the allele is balanced at the equipoise between the proportion of people who are more susceptible to malaria if its proportion is too low and those who express sickle cell anemia if its proportion is too high. This advantage is obviously context sensitive. The standard assumption is that in a non-malarial environment selection pressure against anemia will drive the frequency of the allele down over time as heterozygotes don’t impose a floor in the proportion of the mutant allele. This seems to have occurred among African Americans, they’re ~80% West African, but their frequency of the sickle cell anemia allele is less than {0.80*(the West African proportion)} from what I know (remember that the median number of generations which an African American’s black ancestors have been in the USA is probably ~10).

But this ignores the reality that there’s more to heterozygote advantage than just advantage. When talking about the genetics of recessive diseases as a first approximation it makes good sense to focus on the dominance-recessive dichotomy. You’re fixated upon the disease which expresses in the homozygotes. But quite often the heterozygote also exhibits some phenotypic deviation from the “wild type” homozygote. Just not enough to pass the threshold of notice for a medical geneticist. The stories above were all in abnormal situations, as the body was pushed toward its physiological limits. Heterozygote carriers of sickle cell may start deviating from the phenotype of wild type homozygote only at the tail of the range of likely environments, but it still goes to show that “dominance” of the wild type is contextual. It’s convenient terminology which has an obvious meaning and allows us to model the world efficiently with a minimum of cognitive overhead, but it’s a construct of our making mapped onto the distribution of reality.

Another issue is that the same locus may have dominant and recessive effects on different traits. Most genes have many effects, so in some dimensions it will be dominant and in others it will be recessive. Additionally in many it will be additive. There is some evidence for example that the genes which are implicated in the recessive expression of blue eyes in Europeans may have an additive effect on skin color toward lightening, with a slight dominance bias perhaps. In other words, the expression levels of melanin controlled by these loci in the eye manifest recessively in terms of down-regulation, but express somewhat dominantly in relation to down-regulation! So very similar phenotypic consequences in the same trait value direction have different dominance deviations in different tissues.

This brings me to the broader issue: dominance can be an artifact of the social construction of the trait. For example, eye color is generally “binned” into distinct categories. That’s because that’s how human perception seems to work on a cognitive level. This is also true for skin color, but there is more texture and nuance in description, likely because of the larger perceptual target of the trait. Therefore it’s not surprising that scientists have developed methods for measuring lightness or darkness of skin on a quantitative scale using reflectometers. Whether you bin traits into categories or measure them on a continuous scale may change our understanding of genetic inheritance.

Skin color is an easy character to illustrate this because as humans we’re cued toward it, and, its genetic architecture has been well elucidated. Two genes have variants which explain most of the between population difference between Africans and Europeans in pigmentation, SLC24A5 and KITLG. To the left you see charts which show the effect of the variants on the distribution of complexion in sets of African Americans. The researchers used a quantitative index of complexion, where lower values represent lighter skin color. Since African Americans are ~20% European in ancestry they have skin lightening alleles segregating within their population, and so are an ideal population to test the effects of these variants. The top panels show individuals who carry two copies of the European/light allele, the bottom panel individuals who carry two copies of the African/dark allele, and the middle panel heterozygotes. Observe that the heterozygote seems to exhibit a value closer to the European/light homozygote than the the African/dark homozygote! This finding is replicated on both of these genes.

There need to be proper caveats in not over extrapolating from one particular context (the effect size may be influenced by genetic background, so substituting the same genotypes into a European-Asian admixed population may lead to differing results). But, is there a general perception that light skin is dominant to dark in inheritance? In the West of course not. That’s because social paradigms shape our perceptions. In the United States Salma Hayek, Thandie Newton, and Gabrielle Union are all “actresses of color,” despite their objective difference in complexion. That’s due to a social norm where everyone is first binned into white vs. non-white (before non-whites are further subdivided), with a high threshold for what counts as white. When you reframe the argument in this way then the fact that Thandie Newton’s complexion on a reflectometer may be closer to her English father than her African mother has less weight than the fact that she is not white-skinned, period. Dark is dominant to light purely as an artifact of social norms which sharply constrain what counts as light.

This cognitive and cultural filter looms large in sciences which require a layer of abstraction between raw description and explanatory models. To a great extent this applies to all sciences. We need models and approximations to make sense of the data mess. In the case above with sickle cell trait confusions engendered by this human “middle-ware layer” can be deadly, giving the false perception that heterozygotes who carry a disease allele are functionally equivalent to homozogytes. For all practical purposes they probably are. Most humans aren’t going to engage in sporting activities to such an extent that the differences between wild type and carrier are going to manifest on the margins of the environmental distribution of exposure. But on an individual level awareness of carrier status and its possible functional relevance may be important in the era of personalized medicine.

The medical relevance of this discussion also illustrates that just because something is socially constructed doesn’t mean that it doesn’t have concrete consequences and utility. Dominance is to a great extent a coarse category which we map onto reality for the sake of our own comprehension. It has great upsides, in terms of differentiating between carriers and non-carriers, and highlighting the risk of recessive Mendelian diseases expressing when two carries come together (e.g., cystic fibrosis). Just because it’s a construct doesn’t mean we should discard dominance, we just need to keep it in perspective, and understand that it’s not “real” in a deep fundamental sense. Then again, I don’t think mathematics is “real” either. But it’s awful useful, isn’t it? You’ll probably accede to that if you’re not a Platonist.

Image credit: Mutuwandi

• Category: Science • Tags: Dominance, Genetics, Health, Medicine 
Razib Khan
About Razib Khan

"I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. If you want to know more, see the links at"