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November 13, 2013

The color of life as a coincidence

Filed under: Anthroplogy,Evolution,Evolutionary Genetics,Genetics of taste,Taste — Razib Khan @ 12:35 am

Credit: Eric Hunt

Credit: Eric Hunt

I do love me some sprouts! Greens, bitters, strong flavors of all sorts. I’ve always been like this. Some of this is surely environment. My family comes from a part of South Asia known for its love of bracing and bold sensation. But perhaps I was born this way? There’s a fair amount of evidence that taste has a substantial genetic component. This does not mean genes determine what one tastes, but it certainly opens the door for passive gene-environment correlations. If you do not find a flavor offensive, you are much more likely to explore it depths, and cultivate your palette.

220px-Durio_kutej_F_070203_ime

Dost thou dare?
Credit: W.A. Djatmiko

And of course I’m not the only one with a deep interest in such questions. With the marginal income available to us many Americans have become “foodies,” searching for flavor bursts and novelties which their ancestors might never have been able to comprehend. More deeply in a philosophical sense the question of qualia reemerges if there is a predictable degree of inter-subjectivity in taste perception (OK, qualia is always there, though scientific sorts tend to view it as intractable in a fundamental sense).


But there’s heritability, and then there’s genes. We know that perception in some ways is heritable, but what is perhaps more interesting is if you can peg a specific genomic location to it. Then the evolutionary story becomes all the richer. And so it is with the locus TAS2R16, where a nonsynonymous mutation at location 516 seems to result in heightened sensitivity to bitter tastes. More specifically, it’s rs846664, and the derived T allele is fixed outside of Africa, while the ancestral G allele still segregates at appreciable fractions within African populations. A new paper in Molecular Biology and Evolution puts this locus under a microscope, though it does not come up with any clear conclusions. Origin and Differential Selection of Allelic Variation at TAS2R16 Associated with Salicin Bitter Taste Sensitivity in Africa presents some interesting findings. First, let’s look at the distribution of the variation in their sample populations at the SNP of most particular interest:

Region Population T516G
Outside of Africa Non-Africans 0.000
Ethiopia Semitic 0.059
Tanzania Sandawe 0.083
Ethiopia Omotic 0.093
Ethiopia Cushitic 0.095
Tanzania Iraqw 0.111
West Central Africa Fulani 0.114
Kenya Niger-Kordofanian 0.133
Ethiopia Nilo-Saharan 0.156
Kenya Afroasiatic 0.162
West Central Africa Niger-Kordofanian 0.214
Kenya Nilo-Saharan 0.225
Kenya Luo 0.250
Central Africa Niger-Kordofanian 0.329
Tanzania Hadza 0.333
Central Africa Bulala 0.361
Central Africa Nilo-Saharan 0.367
West Central Africa Afroasiatic 0.462
West Central Africa Nilo-Saharan 0.500

As you can see T is fixed outside of Africa, and varies across many African populations  Previous work implied this, though coverage within Africa was not good. One thing to observe though is that the frequency of A within Africa can not be explained by recent Eurasian admixture. The frequency is way too high for that to be the sole explanation, and in any case there is no evidence that ~33% of the Hadza’s ancestry is of Eurasian provenance (the Hadza being one of the three major groups of African hunter-gatherers, along with the Bushmen and Pygmies).

Within the paper the authors resequenced ~1,000 base pairs across diverse African populations in an exonic region of this gene (the stuff that codes for amino acids). What they discovered is that of the SNPs segregating, 516 in particular was critical toward effecting phenotyping change. Not only did individuals with the T variant notably exhibit stronger bitter sensitivity, but in vitro expression with a reporter was elevated. Because they had such a dense genomic region they could perform various nucleotide based tests to detect natural selection, and, attempt coalescent models to infer genealogical history.

I’m going to spare you some of the gory details at this point. Here’s what they found. First, it does look like the region is under natural selection in many African populations, in particular, the derived haplotype with T at 516 at the center. But this result is not reproduced across all tests. The coalescent simulations make clear why: the mutation is an old variant with deep roots in the hominin lineage. In other words this variation pre-dates H. sapiens. It looks like the T allele has rapidly increased in frequency relatively recently, though more on the order of ~50,000 years, rather than ~10,000.* Basically around the time of the “Out of Africa” event. Additionally, there’s a tell-tale sign that this is being subject to selection within Africa: the genetic differences across populations at TAS2R16 far exceed the genome-wide values (the Fst at this locus is in the top 1% of loci within the African genome). Finally, one should note that the G allele haplotypes seem to be much more strongly constrained, as if they’re under purifying selection. This means that the switch to T is not all gain.

At this point you may be ready for a story about how some African populations, like Eurasians, underwent a lifestyle change, and diet changes resulted in a shift in sensory perception. That does not seem to be the story. Rather, the authors did not seem to be able to agree upon a neat explanation for what is driving these recent sweeps up from ancient standing genetic variation. They do observe that the variation does tend to cluster geographically, more so than the genome-wide results would imply. There’s likely some adaptation going on, they simply don’t know what. In the introduction and elsewhere you can see that variation at TAS2R16 does correlate with other traits. Not too surprising due to the relatively ubiquity of pleiotropy; one gene with many effects.

Stepping outside of the implications of this specific result, let’s think about what might be a takeaway: something as essential as taste perception might be a side effect of other aspects of evolutionary processes. In other words, we don’t know what the phenotypic target of selection is in this case, but we do have a good handle one of the major side effects, which is sensory perception. How one taste seems like a big deal.** Andthere have been many theories propounded that variation in bitter sensitivity is due to adaptation to poisonous plants and such, but really no one knew, and that was just the most plausible of low hanging fruit. With these results from Africa, where there is more variation in the trait and genes, and good geographic coverage, that seems to be an implausible model to adhere to (one would think the hunter-gatherer Hadza would exhibit the most sensitivity, no?). Many of the traits and tendencies which we humans see as fundamental, essential, and of great import, many actually be side effects of powerful evolutionary forces hammering at the genetic-correlation matrices which define the hidden network of co-dependencies within the genome. So there, I said it. Life is an accident. Enjoy it.

Citation: Campbell, Michael C., et al. “Origin and Differential Selection of Allelic Variation at TAS2R16 Associated with Salicin Bitter Taste Sensitivity in Africa.” Molecular biology and evolution (2013): mst211.

* If it was closer to ~10,000 I think haplotype based tests would come back with something, but they do not.

** Some Epicureans might be accused of reducing the good to taste!

The post The color of life as a coincidence appeared first on Gene Expression.

The color of life as a coincidence

Filed under: Anthroplogy,Evolution,Evolutionary Genetics,Genetics of taste,Taste — Razib Khan @ 12:35 am

Credit: Eric Hunt

Credit: Eric Hunt

I do love me some sprouts! Greens, bitters, strong flavors of all sorts. I’ve always been like this. Some of this is surely environment. My family comes from a part of South Asia known for its love of bracing and bold sensation. But perhaps I was born this way? There’s a fair amount of evidence that taste has a substantial genetic component. This does not mean genes determine what one tastes, but it certainly opens the door for passive gene-environment correlations. If you do not find a flavor offensive, you are much more likely to explore it depths, and cultivate your palette.

220px-Durio_kutej_F_070203_ime

Dost thou dare?
Credit: W.A. Djatmiko

And of course I’m not the only one with a deep interest in such questions. With the marginal income available to us many Americans have become “foodies,” searching for flavor bursts and novelties which their ancestors might never have been able to comprehend. More deeply in a philosophical sense the question of qualia reemerges if there is a predictable degree of inter-subjectivity in taste perception (OK, qualia is always there, though scientific sorts tend to view it as intractable in a fundamental sense).


But there’s heritability, and then there’s genes. We know that perception in some ways is heritable, but what is perhaps more interesting is if you can peg a specific genomic location to it. Then the evolutionary story becomes all the richer. And so it is with the locus TAS2R16, where a nonsynonymous mutation at location 516 seems to result in heightened sensitivity to bitter tastes. More specifically, it’s rs846664, and the derived T allele is fixed outside of Africa, while the ancestral G allele still segregates at appreciable fractions within African populations. A new paper in Molecular Biology and Evolution puts this locus under a microscope, though it does not come up with any clear conclusions. Origin and Differential Selection of Allelic Variation at TAS2R16 Associated with Salicin Bitter Taste Sensitivity in Africa presents some interesting findings. First, let’s look at the distribution of the variation in their sample populations at the SNP of most particular interest:

Region Population T516G
Outside of Africa Non-Africans 0.000
Ethiopia Semitic 0.059
Tanzania Sandawe 0.083
Ethiopia Omotic 0.093
Ethiopia Cushitic 0.095
Tanzania Iraqw 0.111
West Central Africa Fulani 0.114
Kenya Niger-Kordofanian 0.133
Ethiopia Nilo-Saharan 0.156
Kenya Afroasiatic 0.162
West Central Africa Niger-Kordofanian 0.214
Kenya Nilo-Saharan 0.225
Kenya Luo 0.250
Central Africa Niger-Kordofanian 0.329
Tanzania Hadza 0.333
Central Africa Bulala 0.361
Central Africa Nilo-Saharan 0.367
West Central Africa Afroasiatic 0.462
West Central Africa Nilo-Saharan 0.500

As you can see T is fixed outside of Africa, and varies across many African populations  Previous work implied this, though coverage within Africa was not good. One thing to observe though is that the frequency of A within Africa can not be explained by recent Eurasian admixture. The frequency is way too high for that to be the sole explanation, and in any case there is no evidence that ~33% of the Hadza’s ancestry is of Eurasian provenance (the Hadza being one of the three major groups of African hunter-gatherers, along with the Bushmen and Pygmies).

Within the paper the authors resequenced ~1,000 base pairs across diverse African populations in an exonic region of this gene (the stuff that codes for amino acids). What they discovered is that of the SNPs segregating, 516 in particular was critical toward effecting phenotyping change. Not only did individuals with the T variant notably exhibit stronger bitter sensitivity, but in vitro expression with a reporter was elevated. Because they had such a dense genomic region they could perform various nucleotide based tests to detect natural selection, and, attempt coalescent models to infer genealogical history.

I’m going to spare you some of the gory details at this point. Here’s what they found. First, it does look like the region is under natural selection in many African populations, in particular, the derived haplotype with T at 516 at the center. But this result is not reproduced across all tests. The coalescent simulations make clear why: the mutation is an old variant with deep roots in the hominin lineage. In other words this variation pre-dates H. sapiens. It looks like the T allele has rapidly increased in frequency relatively recently, though more on the order of ~50,000 years, rather than ~10,000.* Basically around the time of the “Out of Africa” event. Additionally, there’s a tell-tale sign that this is being subject to selection within Africa: the genetic differences across populations at TAS2R16 far exceed the genome-wide values (the Fst at this locus is in the top 1% of loci within the African genome). Finally, one should note that the G allele haplotypes seem to be much more strongly constrained, as if they’re under purifying selection. This means that the switch to T is not all gain.

At this point you may be ready for a story about how some African populations, like Eurasians, underwent a lifestyle change, and diet changes resulted in a shift in sensory perception. That does not seem to be the story. Rather, the authors did not seem to be able to agree upon a neat explanation for what is driving these recent sweeps up from ancient standing genetic variation. They do observe that the variation does tend to cluster geographically, more so than the genome-wide results would imply. There’s likely some adaptation going on, they simply don’t know what. In the introduction and elsewhere you can see that variation at TAS2R16 does correlate with other traits. Not too surprising due to the relatively ubiquity of pleiotropy; one gene with many effects.

Stepping outside of the implications of this specific result, let’s think about what might be a takeaway: something as essential as taste perception might be a side effect of other aspects of evolutionary processes. In other words, we don’t know what the phenotypic target of selection is in this case, but we do have a good handle one of the major side effects, which is sensory perception. How one taste seems like a big deal.** Andthere have been many theories propounded that variation in bitter sensitivity is due to adaptation to poisonous plants and such, but really no one knew, and that was just the most plausible of low hanging fruit. With these results from Africa, where there is more variation in the trait and genes, and good geographic coverage, that seems to be an implausible model to adhere to (one would think the hunter-gatherer Hadza would exhibit the most sensitivity, no?). Many of the traits and tendencies which we humans see as fundamental, essential, and of great import, many actually be side effects of powerful evolutionary forces hammering at the genetic-correlation matrices which define the hidden network of co-dependencies within the genome. So there, I said it. Life is an accident. Enjoy it.

Citation: Campbell, Michael C., et al. “Origin and Differential Selection of Allelic Variation at TAS2R16 Associated with Salicin Bitter Taste Sensitivity in Africa.” Molecular biology and evolution (2013): mst211.

* If it was closer to ~10,000 I think haplotype based tests would come back with something, but they do not.

** Some Epicureans might be accused of reducing the good to taste!

The post The color of life as a coincidence appeared first on Gene Expression.

December 21, 2012

The causes of evolutionary genetics

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.

October 21, 2012

Buddy can you spare a selective sweep

The Pith: Natural selection comes in different flavors in its genetic constituents. Some of those constituents are more elusive than others. That makes “reading the label” a non-trivial activity.

As you may know when you look at patterns of variation in the genome of a given organism you can make various inferences from the nature of these patterns. But the power of those inferences is conditional on the details of the real demographic and evolutionary histories, as well as the assumptions made about the models one which is testing. When delving into the domain of population genomics some of the concepts and models may seem abstruse, but the reality is that such details are the stuff of which evolution is built. A new paper in PLoS Genetics may seem excessively esoteric and theoretical, but it speaks to very important processes which shape the evolutionary trajectory of a given population. The paper is titled Distinguishing between Selective Sweeps from Standing Variation and from a De Novo Mutation. Here’s the author summary:

Considerable effort has been devoted to detecting genes that are under natural selection, and hundreds of such genes have been identified in previous studies. Here, we present a method for extending ...

October 15, 2012

Don’t trust an archaeologist about genetics, don’t trust a geneticist about archaeology

Filed under: Anthroplogy,Evolutionary Genetics,Human Evolution — Razib Khan @ 1:38 pm

Who to trust? That is the question when you don’t know very much (all of us). Trust is precious, and to some extent sacred. That’s why I can flip out when I realize after the fact that someone more informed than me in field X sampled biased their argument in a way they knew was shady to support a proposition they were forwarding. What’s the point of that? Who cares if you win at a particular bull-session? You’re burning through cultural capital. And not that most of my interlocutors care, but I’m likely to never trust them again on anything.

In any case, this came to mind when I ran across a James Fallows’ post at The Atlantic. Here’s a screenshot of the appropriate section, with my underlines:


The PNAS link is wrong. The correspondent is actually linking to an article in Quaternary International. And they do point out that there are possible problems with draft quality sequences due to contamination. But I didn’t find the paper too persuasive. There are two issues. First, the Denisova genome is very good quality. So you can be more ...

October 2, 2012

What is going on with plant domestication?

Filed under: Domestication,Evolutionary Genetics — Razib Khan @ 11:44 pm

PNAS has a paper on barley domestication out right now. It is nicely open access, so read it yourself, and come right back! I have to admit that I did not like the paper too much. It seemed to derive far too many conclusions from a few rudimentary (for today at least) phylogenetic methods. In particular I’m very skeptical of the idea that there are two barely lineages here which diverged ~3 million years B.P. But this isn’t particularly strange when it comes to the phylogenetic origins of cultivars. There have been long debates about whether there was one origin for rice, or several. Setting aside my major issues with this paper I wonder if perhaps our expectations and prejudices derived from the fact that animals are to a great extent the “null” organisms are muddying our interpretation of results from plants. The number of loci here seem sufficient to dismiss the possibility of introgression, but I’m not sure that the rate of evolution across these markers is quite so clock-like.

In any case, to understand domestication, and I suspect human evolution, these results from plants are going to have to be cleared up and systematized. Illumination would be helpful, but until then ...

September 16, 2012

What the substrate tells

Filed under: Evolution,Evolutionary Genetics,Genetics,Genomics — Razib Khan @ 7:26 pm

One of the weird things about genetics is that it encompasses both the abstract and the concrete. The formal and physical. You can talk to a geneticist who is mostly interested in details of molecular mechanisms, and is steeped in structural biology. For these people genes are specific and material things. In contrast there are other geneticists who focus more on genes as units of analysis. In this case genes are semantic labels for the mediators within an intersection of phenomena. Recall that genetics predates the knowledge of its concrete substrate by 50 years! By the 1920s Mendelian genetics had been fused with evolutionary biology to create a systematic framework in which we could understand the patterns of inheritance across the generations. In the 1950s the DNA revolution was upon us, but as W. D. Hamilton recalls this had only a minimal impact on the evolutionary genetic thinkers of the era. With the Lewontin and Hubby allozyme paper in the mid-1960s this sort of benign disciplinary evasion was no longer possible; the field of molecular evolution came into its own.*

Today with genomics these human-imposed artificialities are fading away. Consider the concept of genetic recombination. Originally an ...

Nature’s Oracle finally out in 2013

Filed under: Evolutionary Genetics,Nature's Oracle,W. D. Hamilton — Razib Khan @ 1:03 pm

Jerry Coyne alerts me to the fact that Ullica Segerstrale’s Nature’s Oracle: A Life of W. D. Hamilton is finally near publication. Specifically, early 2013. Coyne has looked at he pre-publication text, so it is probably in revision, though the meat has already been laid upon the bones. Hamilton was one of the preeminent evolutionary biologists of the second half of the 20th century. Though to my knowledge he never wrote an autobiography as such the details of his life was liberally strewn out across dozens of books. You can find them in Segerstrale’s Defenders of the Truth: The Sociobiology Debate, or The Darwin Wars. He makes a cameo appearance in Robert Trivers’ Natural Selection and Social Theory, as well as The Price of Altruism, a scientific biography of Hamilton’s collaborator George Price.

But the best place to go for understanding Hamilton as he understood himself are his collected papers, which have biographical sections laying out the scientific, cultural, and historical context for a given publication. They are, in chronological order Narrow Roads of Gene Land: The Collected Papers of W. D. Hamilton Volume 1: Evolution of Social Behaviour, Narrow Roads of Gene ...

September 12, 2012

An ontology of genetic diversity

Filed under: Evolution,Evolutionary Genetics — Razib Khan @ 11:23 pm

Implicit in the title The Origin Of Species is the question: why the plural? In other words, why isn’t there a singular apex species which dominates this planet? One can imagine an abstract system where natural selection slowly but gradually sifts through variation and designs a best-of-all-replicators. And yet on the contrary it seems that our planet has exhibited an overall tendency of going from lower to higher diversity. The age of stromatolites may be the last epoch when we had the best-of-all-replicators.


These sorts of deep questions about variation drive many of the research projects in evolutionary biology. Often one focuses on a narrow zone of interest. An organism for example which might serve as an illustrative model for more general processes. Or, a particular dynamic which interlocks with other processes to form a whole phenomenon. But on occasion you have to sit and ponder the whole shebang. Why genetic diversity? More specifically, why not more diversity of genetic diversity? The issue here is what is sometimes termed Lewontin’s paradox.

Consider two populations. One population goes through an extreme bottleneck, while the other maintains a large population over the generations. What would you presume in regards to ...

July 8, 2012

The wages of a life science Ph.D. (not high!)

Filed under: Culture,Evolutionary Genetics,Graduate School — Razib Khan @ 5:31 pm

A few people have emailed me about this article in The Washington Post, U.S. pushes for more scientists, but the jobs aren’t there. Other people cover this area well (for example), so I’m not going to say much. But first, ignore the article in the paper, and read the original survey which the article is based on: Science & Engineering Labor Force.


What the newspaper article added in terms of value was interviewing a small number of people. This is fine I suppose, but it adds no real substantive value, because you can’t really obtain a representative sample. Additionally, if you look at the employment data in the PDF I link to above you see that though things aren’t peachy for Ph.D.s, they are often far better than for people with less education. In other words you can’t just compare a science Ph.D. to some idealized full-employment world with 100% job satisfaction. In the real world everyone has to hustle now, and often it is better to hustle with a doctorate than not. What the PDF attached does illustrate is that the cost of forgone wages probably hits life science Ph.D.s in particular. The perpetual postdoc ...

June 25, 2012

Sleeping like a Neandertal

Forgot to highlight one of the coolest abstracts from SMBE 2012, A genomewide map of Neandertal ancestry in modern humans:

2. The map allows us to identify Neandertal alleles that have been the target of selection since introgression. We identified over 100 regions in which the frequency of Neandertal ancestry is extremely unlikely under a model of neutral evolution. The highest frequency region on chromosome 4 has a frequency of Neandertal ancestry of about 85% in Europe and overlaps CLOCK, a key gene in Circadian function in mammals. The high frequency, Neandertal-derived variant is specific to Europeans; it is not very common in East Asians. This gene has been found in other selection scans in Eurasian populations, but has never before been linked to Neandertal gene flow


One of the predictions of assimilation of a large intrusive population with a small but long endemic population is that there will be biased representation of adaptive alleles from the latter into the former. In other words, if genome-wide admixture is on the order of 5% from the latter into the former, alleles which confer local fitness benefits will be present in the descendants of the asymmetric admixture in proportions of out ...

Sleeping like a Neandertal

Forgot to highlight one of the coolest abstracts from SMBE 2012, A genomewide map of Neandertal ancestry in modern humans:

2. The map allows us to identify Neandertal alleles that have been the target of selection since introgression. We identified over 100 regions in which the frequency of Neandertal ancestry is extremely unlikely under a model of neutral evolution. The highest frequency region on chromosome 4 has a frequency of Neandertal ancestry of about 85% in Europe and overlaps CLOCK, a key gene in Circadian function in mammals. The high frequency, Neandertal-derived variant is specific to Europeans; it is not very common in East Asians. This gene has been found in other selection scans in Eurasian populations, but has never before been linked to Neandertal gene flow


One of the predictions of assimilation of a large intrusive population with a small but long endemic population is that there will be biased representation of adaptive alleles from the latter into the former. In other words, if genome-wide admixture is on the order of 5% from the latter into the former, alleles which confer local fitness benefits will be present in the descendants of the asymmetric admixture in proportions of out ...

April 8, 2012

What do you think about group selection?

Filed under: Evolutionary Genetics,Group Selection — Razib Khan @ 8:50 pm

I just received a review copy of E. O. Wilson’s The Social Conquest of Earth. One of the reasons why this book is “hot” is that Wilson has recently been revisiting the “levels of selection” debates, and significantly downgraded kin selection in the pantheon of evolutionary dynamics (at least in his mind). There has been a lot of talk on the blogs about Wilson’s ideas, in large part because of his partisan position on the Nowak vs. most other biologists debate, in favor of Nowak.

I don’t know if I’ll have time to review the book (a reality I honestly explained already to the people working at the publisher), but, it did get me thinking: what are the opinions of biologists in relation group selection? My personal experience is that opinions actually vary by discipline and by department. It’s hard to get a real sense, because people tend to be in their own “bubble.” With that in mind, I’ve put together a small survey to assess opinions. My core audience here are people who consider themselves biologists, though I can’t prevent someone with strong opinions from participating obviously!

So, a survey on group selection. You can see the ...

Another look at mtDNA

The new article in The American Journal of Human Genetics, A “Copernican” Reassessment of the Human Mitochondrial DNA Tree from its Root, is open access, so you should check it out. The discussion gets to the heart of the matter:

Supported by a consensus of many colleagues and after a few years of hesitation, we have reached the conclusion that on the verge of the deep-sequencing revolution…when perhaps tens of thousands of additional complete mtDNA sequences are expected to be generated over the next few years, the principal change we suggest cannot be postponed any longer: an ancestral rather than a “phylogenetically peripheral” and modern mitogenome from Europe should serve as the epicenter of the human mtDNA reference system. Inevitably, the proposed change could raise some temporary inconveniences. For this reason, we provide tables and software to aid data transition.

What we propose is much more than a mere clerical change. We use the Ptolemaian geocentric versus Copernican heliocentric systems as a metaphor. And the metaphor extends further: as the acceptance of the heliocentric system circumvented epicycles in the orbits of planets, switching the mtDNA reference to an ancestral RSRS will end an academically inadmissible conjuncture where virtually all mitochondrial genome ...

January 16, 2012

The milkmen

Dienekes and Maju have both commented on a new paper which looked at the likelihood of lactase persistence in Neolithic remains from Spain, but I thought I would comment on it as well. The paper is: Low prevalence of lactase persistence in Neolithic South-West Europe. The location is on the fringes of the modern Basque country, while the time frame is ~3000 BC. Table 3 shows the major result:

Lactase persistence is a dominant trait. That means any individual with at least one copy of the T allele is persistent. As Maju noted a peculiarity here is that the genotypes are not in Hardy-Weinberg Equilibrium. Specifically, there are an excess of homozygotes. Using the SJAPL location as a potentially random mating scenario you should expect ~7 T/C genotypes, not 2. Interestingly the persistent individual in the Longar location also a homozygote.


HWE makes a few assumptions. For example, no selection, migration, mutation, or assortative mating. Deviation from HWE is suggestive of one of these dynamics. The sample size here is small, but the deviation is not to be dismissed. Recall that lactase persistence has dominant inheritance patterns. If the trait was being positively selected for you would only need one copy. The enrichment of homozygotes is unexpected if selection in situ is occurring here. It can not be ruled out that one is observing the admixture of two distinct populations. One generation of random mating would generate HWE, but when populations hybridize in realistic scenarios this is not always a plausible assumption. Rather, assortative mating often persists over the generations, slowing down the diminishing of population substructure.

Stepping back from speculation in this case what can we say? First, the LCT locus has a large mutational target. The trait of lactase persistence has arisen multiple times via different mutational events across the Old World. But, there does seem to be one particular variant which is found from Spain to Northern India. There is some circumstantial evidence that the allele had its origin somewhere in Central Eurasia, but currently its modal frequency is in Northern Europe, Scandinavia and Germany. The region in the genome around this mutation is characterized by a very long haplotype. It is one of the most definitive loci as a candidate for natural selection in the human genome. There is now a fair amount of ancient DNA evidence that lactase persistence in Europe is a feature of the last ~5,000 years or so. Among the modern Basques the frequency of the allele is 66 percent.

For me the key issue is teasing apart the role of migration and selection in each specific case. It does not seem to be correct that the frequency of the -13910T LCT allele in Basques and Punjabis is reflective of the frequency of recent common ancestry. That implies that natural selection is at work at this locus. On the other hand, the haplotype which is present in both the Basque and Punjabis is likely to be descended from a common set of individuals, implying that there is a genealogical chain connecting these two very distinct and distant Eurasian populations. Therefore, we can potentially make some inferences about the power of migration in spreading distinctive alleles. Often we partition selection from genealogical information, because selection so often serves to distort the signal. But the genealogical patterns may lay at the heart of the distribution of different natural selective events at the LCT locus.

Overall, I would say that the results from ancient DNA are disordering and clouding simple elegant models. One hopes and presumes that as sample sizes increase in this domain we’ll start to see more clarity as new paradigms crystallize.

Citation: European Journal of Human Genetics, 10.1038/ejhg.2011.254

January 8, 2012

James F. Crow profile

Filed under: Evolutionary Genetics,James F. Crow — Razib Khan @ 10:28 pm

The University of Madison-Wisconsin, has a long piece up on the late James F. Crow. Much recommended.

January 5, 2012

James F. Crow, 1916-2012

Filed under: Evolution,Evolutionary Genetics,Genetics,James F. Crow — Razib Khan @ 2:01 am

Sad news. John Hawks passes along that James F. Crow has died. Further mention from the National Center For Science Education. A little over 5 years ago I sent Crow an email with only minimal expectation of response, asking about an interview. He responded in less than 24 hours! I think it says a lot about the man that he would respond to sincere questions out of the blue from basically a nobody. Here is his Wikipedia entry. And remember that Genetics has commissioned a series of retrospective essays in Crow’s honor.

December 27, 2011

The Genetical Theory of Natural Selection

I flog R. A. Fisher’s The Genetical Theory of Natural Selection a fair amount on this site. You don’t need to understand everything in the book, nor do you have to agree with everything in it, but it is a great point of departure toward understanding evolutionary genetics. I’ve noted that you can get it free in PDF format. But if you want to browse it online in a easier format, here you go:

(original link courtesy of Unz.org)

December 19, 2011

The last word on dog genesis is not nigh!

Filed under: Dogs,Domestication,Evolution,Evolutionary Genetics,Genetics,Genomics — Razib Khan @ 11:00 am

In my post below Rob commented:

Surely the genetic evidence is pointing towards a single domestication event (see http://news.sciencemag.org/sciencenow/2011/11/new-data-fuels-dogfight-over-the.html?ref=hp)

My general response is not to accept the latest press release about the genetic origin of dogs. I keep track of the literature and it’s rather fluid. For example, I woke up this morning, and this is what showed up in my RSS, Modern dogs are more Asian fusions than Euro pups, study finds:

Results from the study, which examined the DNA of 642 dogs, suggest that European and American canine breeds were much more influenced by dogs from Southeast Asia than by ancient Western dogs or by dogs from the Middle East, as was previously thought.

Findings from the study by collaborators in California, Iran, Taiwan and Israel appear online in the journal Public Library of Science (PLoS) One.

“The two most hotly debated theories propose that dogs originated in Southeast Asia or the Middle East,” said study co-author Ben Sacks, director of the Canid Diversity and Conservation Group in the Veterinary Genetics Laboratory in the UC Davis School of Veterinary Medicine. The laboratory is an international leader in animal genetics research and provides DNA testing and forensic analysis for numerous wildlife, companion animal and livestock species.

“In contrast to those theories, our findings suggest that modern European and American dogs are overwhelmingly derived from dogs that were imported from Asia since the silk trade, rather than having descended directly from ancient dogs native to Europe,” Sacks said. “Therefore, previous arguments against Europe as a potential site of dog origins, based on modern European dog DNA, must be reconsidered, and our high-resolution Y-chromosome data from indigenous dogs of the Middle East and Southeast Asia now provide the means to test this hypothesis using ancient European dog DNA.”

I assume that as man’s best friend dog genetics is going to be where human genetics is in a few years. I’m not well aware of how good the dog reference genome is, though I hear the cat genome isn’t very good. After whole genome analysis gets going with humans I assume people will start looking at domesticates, companion animals as well as those with more direct economic productivity implications.

November 29, 2011

When trees turn into brambles

Filed under: Evolution,Evolutionary Genetics,Genetics,Genomics — Razib Khan @ 1:00 pm

Genetics is powerful. The origins of the field predate Gregor Mendel, and go further back to plain human common sense. Crude theories of inheritance in the 19th century gave way in the early 20th to Mendelism, which happens to be a very powerful formal system for predicting the patterns of transmission of information from generation to generation. But I suspect that the popular accolades showered upon genetics would be more muted if it were not for the concrete discovery of the biophysical medium of that pattern of inheritance, DNA. By visualizing strands of DNA packaged into chromosomes one can gain a substantive understanding of Mendelian processes previously somewhat abstracted (e.g., recombination). In concert with the centrality of genetics at the heart of evolutionary science has been the ascendance of its methods in the older field of systematics. The phylogenetic tree is not only intuitive, but it has concrete reality in the sequences of base pairs or structural elements within the genome.

Whatever skepticism there might be about the dynamic phenomenon of evolution, the material aspect of modern genetics rooted in molecular biology is one of he primary wedges by which one can introduce an element of doubt into minds of a skeptic. The correlation between phylogeny and sequence identity of organisms which were previously adduced to exhibit some sort of biological relationship on the tree of life can not be dismissed out of hand. But this mode of thinking has limits, albeit due to the quirks of human psychology.


I began to think about this when reading Brian Switek’s post, Inside the Columbian Mammoth, Signs of a Woolly Cousin. It’s long and wide-ranging, so let me spotlight the section of particular interest to me:

On an anatomical basis, woolly and Columbian mammoths would be expected to be cousins which diverged from a common ancestor sometime between one and two million years ago. This is not what the genetic investigation found. “[T]he Huntington mammoth mitogenome is largely indiscernible from those of endemic North American WMs [woolly mammoths]”, Enk and co-authors wrote. The genetic readout of the Utah mammoth fell deep within the genetic diversity of woolly mammoths previously sampled from Alaska. This did not appear to be a case of contamination or mistaken identity – at a genetic level, researchers could barely distinguish a Columbian mammoth found in Utah from Alaskan woolly mammoths. What could this mean?

As I said, there’s a lot more detail in Brian’s post, so do read it. But one thing I want to emphasize: I think the results from the mammoth are far less surprising in light of what we’re finding from other widespread large mammals. Consider the polar bears:

The bear family, Ursidae, is believed to have split off from other carnivorans about 38 million years ago. The Ursinae subfamily originated approximately 4.2 million years ago. According to both fossil and DNA evidence, the polar bear diverged from the brown bear, Ursus arctos, roughly 150,000 years ago. The oldest known polar bear fossil is a 130,000 to 110,000-year-old jaw bone, found on Prince Charles Foreland in 2004. Fossils show that between ten to twenty thousand years ago, the polar bear’s molar teeth changed significantly from those of the brown bear. Polar bears are thought to have diverged from a population of brown bears that became isolated during a period of glaciation in the Pleistocene.

More recent genetic studies have shown that some clades of brown bear are more closely related to polar bears than to other brown bears, meaning that the polar bear is not a true species according to some species concepts. Irish brown bears are particularly close to polar bears. In addition, polar bears can breed with brown bears to produce fertile grizzly–polar bear hybrids, indicating that they have only recently diverged and are genetically similar. However, because neither species can survive long in the other’s ecological niche, and because they have different morphology, metabolism, social and feeding behaviors, and other phenotypic characteristics, the two bears are generally classified as separate species.

Long story short: the polar bear as a cluster of phenotypic characteristics may predate the polar bear as a distinctive cluster of genes! Now from John Hawks’ weblog, When anthropological and geological facts collide:

I am concerned with this passage today because of a re-emerging mismatch of evidence from the morphology of Middle Pleistocene humans and the genetics of Neandertals. Some paleoanthropologists have asserted that Europeans of the Middle Pleistocene were the exclusive ancestors of Neandertals. I have in the past written that Middle Pleistocene Europeans were among the ancestors of Neandertals, with sustained gene flow from other populations including Africa. The Sima de los Huesos people, maybe 600,000 years old, resembled the (much) later Neandertals in several aspects of their anatomy, as did other Middle Pleistocene Europeans. The genetic differences between living people and the ancient Neandertal genomes appear consistent with the emergence of distinct African and Neandertal populations only within the last 400,000 years or less.

Such a recent date seems a poor match for the morphological evidence of Neandertal ancestry in Europe. I can think of several ways to make these morphological and genetic comparisons concordant with each other, all of which balance some shift in one body of inference against the other. As long as we can’t pin down the human mutation rate within a factor of two (“What is the human mutation rate?”), there’s a lot of room to make different population models consistent with the genetic data.

I have been told that the most recent genomic data indicating the red wolf is a wolf-coyote hybrid of post-Colubmian vintage is perplexing to some who have accepted the fossil evidence of a far older derivation from the gray wolf stock. But remember that fossils rely on visible phenotypes, which may diverge from what genes tells us. The modern red wolf may simply be the latest instantiation of a constellation of characteristics which have bubbled out of the froth of the morphological background repeatedly for nearly a million years!

With the expansion of genomics from humans to a wide range of species I suspect that we’ll see a lot more blurring of distinctions between species on the margins. This will be particularly true of those lineages with wide and continuous distributions. It will also be most salient and surprising for mammalian populations, where our prejudices about the primacy of a biological species concept are most strongly developed.

In a phylogenetic sense when you shift the grain of analysis to a finer scale the tree of life becomes much more of a bramble in many cases. We understand this intuitively when it comes to pedigrees which we constrain to within our demarcated species. Many of us have the same ancestor over and over in our lineage as we go back into the past. Similarly, why should we presume that closely related lineages have parted for all of eternity when they speciate? If you pull back far enough monophyly is obviously a pervasive phenomenon, but in many scenarios we’re talking on the scale of ten million years, not one million. In hindsight it seems strange that people thought Neanderthals and African hominins could not interbreed despite a maximal separation on the order of ~500,000 years (in reality it seems plausible there was some gene flow between the two lineages in any case prior to the Neanderthal’s absorption into the Neo-African modern populations).

The second issue is that we must sometimes dethrone genetics from its determinative role in our understanding of how life is properly cataloged and evaluated. It may be that some phenotypes are recapitulated repeatedly from the ancestral genetic variation pool. This may have happened with the polar bear morph. Perhaps it happened with the mammoth lineages, as the Ice Ages waxed and waned. And perhaps it happened with the hominins of northern Eurasia! In the United States genetic criteria have become critical in application of the Endangered Species Act. Genes are concrete and often clear and distinct. Their physical reality and precision though may deceive us in the end. Does it matter if the red wolf of today is a recent hybrid of the gray wolf and coyote, while the red wolf of 10,000 years before the present was a 10,000 year old hybrid between the gray wolf and coyote?

Image credit: Zephyris, PIRN.

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