Genomic cold fusion? Part II. Realities of mapping

Mapping to find genomic causes of a trait of interest, like a disease, is done when the basic physiology is not known—maybe we have zero ideas, or the physiology we think is involved doesn’t show obvious differences between cases and controls.  If you know the biology, you won't have to use mapping methods, because you can explore the relevant genes directly.  Otherwise, and today often, we have to go fishing, in the genome, to find places that may vary in association—statistical regularity—with the trait.

The classical way to do this is called linkage analysis.  That term generally refers to tracing cases and marker variants in known families.  If parents transmit a causal allele (variant at some place in the genome) to their children, then we can find clusters of cases in those families, but no cases in other families (assuming one cause only).  We have Mendel’s classical rules for the transmission pattern and can attempt to fit that pattern to the data—for example, to exclude some non-genetic trait sharing.  After all, family members might share many things just because they have similar interests or habits.  Even disease can be due to shared environmental exposures. Mendelian principles allow us, with enough data, to discriminate.

“Enough data” is the catch.  Linkage analysis works well if there is a strong genetic signal.  If there is only one cause, we can collect multiple families and analyze their transmission patterns jointly.  Or, in some circumstances, we can collect very large, multi-generational families (often called pedigrees) and try to track a marker allele with the trait across the generations.  This has worked very well for some very strong-effect variants conferring very high risk for very specific, even quite rate, disorders.  That is because the linkage disequilibrium—the association between a marker allele and a causal variant due to their shared evolutionary history (as described in Part I) ties the two together in these families.

But it is often very costly or impractical to collect actual large pedigrees that include many children each generation, and multiple generations.  Family members who have died cannot be studied and medical records may be untrustworthy, or family members may have moved, refuse to participate in a study, or be inaccessible for many reasons.  So a generation or so ago the idea arose that if we collect cases from a population we may also collect copies of nearby marker alleles in linkage disequilibrium—shared evolutionary history in the population—so that, as described in Part I, a marker allele has been transmitted through many generations of unknown but assumed pedigree, so that the marker will have been transmitted in the pedigree along with the causal variant.  This is implicit linkage analysis, called genomewide association analysis (GWAS), about which we’ve commented many times in the past.  GWAS look for association between marker and causal site in implicit but assumed pedigrees, and is another form of linkage analysis.

When genetic causation is simple enough, this will work.  Indeed, it is far easier and less costly to collect many cases and controls than many deep pedigrees, so that a carefully designed GWAS can identify causes that are reasonably strong.  But this may not always work, when a trait is ‘complex’, and has many different genetic and/or environmental contributing causes.

If causation is complex, families provide a more powerful kind of sample to use in searching for genetic factors.  The reason is simple: in general a single family will be transmitting fewer causal variants than a collection of separate families.  Related to this is the reason that isolate populations, like Finland or Iceland, can in principle be good places to search, because they represent very large, even if implicit, pedigrees.  Sometimes the pedigree can actually be documented in such populations.

If causation is complex, then linkage analysis in families will hopefully be better than big population samples for finding causal contributors, simply because a family will be segregating (transmitting) fewer different causal variants than a big population.  We might find the variant in linkage analysis in a big family, or an isolate population, but of course if there are many different variants, a given family may point us only to one or two of them.  For this reason, many argue that family analysis is useless for complex traits—one commenter on a previous Tweet we made from our course, likened linkage analysis for complex traits to ‘cold fusion’.  In fact, this was a mistake and is incorrect. 

Association analysis, the main alternative to linkage analysis, is just a combining of many different implicit families, for the population-history reason we’ve described here and in Part I.  The more families you combine, whether they are explicit or implicit, the more variation, including statistical ‘noise’, you incorporate.  The rather paltry findings of many GWAS are a testament to this fact, explaining as they have only a small fraction of most traits to which that method has been applied.  Worse, the greater the sample of this type, like cases vs controls, the more environmental variation you may be grouping together, again greatly watering down even the weak signal of many or, probably, by far most genetic causal factors.

In fact, if you are forced to go fishing for genetic cause, you may well be fishing in dreamland because you may simply be in denial of the implications of causal complexity.  In fact, all mapping is a form of linkage analysis.  Instead, one should tailor one’s approach to the realities of data and trait.  Some complex trait genes have been found by linkage analysis (e.g., the BRCA breast-cancer associated genes), though of course here we might quibble about the definition of 'complexity'. 

Sneering at linkage analysis because it is difficult to get big families, or  because even single deep families may themselves be transmitting multiple causes (as is often found in isolate studies, in fact), is often simply a circle-the-wagon defense of Big Data studies, that capture huge amounts of funding with relatively little payoff to date.

A biological approach?

Many linkage and association analyses are done because we don’t understand the basic biology of a trait well enough to go straight to ‘candidate’ genes to detect, prevent, or develop treatment for a trait.  Today, even though this approach has been the rule for nearly 20 years now, with little payoff, the defense is often still that more, more and even more data will solve the problem.  But if causation is too complex this can also be a costly, self-interested, weak defense.

If we have whole genome sequence on huge numbers of people, or even everyone in a population, or in many populations so we can pool data, that we will find the pot of gold (or is it cold fusion?) at the end of the rainbow.

One argument for this is to search population-wide genome sequenced biomedical data bases for variants that may be transmitted from parents to offspring, but that are so rare that they cannot generate a useful signal in huge, pooled GWAS studies.  This usually will still be in the form of linkage analysis if a marker in a given causal gene is transmitted with the trait in occasional families but the same gene is identified, even if via different families.  That is, if variation in the same gene is found to be involved in different individuals, but with different specific alleles, then one can take that gene seriously as a causal candidate.

This sometimes works, but usually only when the gene’s biology is known enough to have a reason to suspect it.  Otherwise, the problem is that so much is shared between close family members (whether implicitly or explicitly in known pedigrees) that if you don’t know the biology there will be too much to search through, too much co-transmitted variation.  Causal variation need not be in regular ‘genes’, but can be, and for complex traits seems typically to be, in regulatory or other regions of the genome, whose functional sites may not be known.  Also, we all harbor variation in genes that is not harmful, and we all carry ‘dead’ genes without problems, as many studies have now shown.

If one knows enough biology to suspect a set of genes, and finds variants of known effect (such as truncating a gene’s coding region so a normal protein isn’t made) in different affected individuals, then one has strong evidence s/he has found a target gene.  There are many examples of this for single-gene traits.  But for complex traits, even most genes that have been identified have only weak effects—the same variant most of the time is also found in healthy, unaffected individuals.  In this case, which seems often to be the biological truth, there is no big-cause gene to be found, or a gene has a big-cause only in some unusual genotypes in the rest of the genome.

Even knowing the biology doesn't say whether a given gene's protein code is involved rather than its regulation or other related factors (like making the chromosomal region available in the right cells, downregulating its messenger RNA, and other genome functions).  Even in multiple instances of a gene region, there may be many nucleotide variants observed among cases and controls.  The hunt is usually not easy even knowing the biology--and this is, of course, especially true if the trait isn't well-defined, as is often the case, or if it is complex or has many different contributors.

Big Data, like any other method, works when it works.  The question is when and whether it is worth its cost, regardless of how advantageous for investigators who like playing with (or having and managing) huge resources.  Whether or not it is any less ‘cold fusion’ than classical linkage analysis in big families, is debatable.  

Again, most searches for causal variation in the genome rest on statistical linkage between marker sites and causal sites due to shared evolutionary history.  Good study design is always important.  Dismissal of one method over another is too often little more than advocacy of a scientist’s personal intellectual or vested interests.

The problem is that complex traits are properly named:  they are complex. Better ideas are needed than what are being proposed these days.  We know that Big Data is ‘in’ and the money will pour in that direction.  From such data bases all sorts of samples, family or otherwise, can be drawn.  Simulation of strategies (such as with programs like our ForSim that we discussed in our recent Logical Reasoning course in Finland) can be done to try to optimize studies. 

In the end, however, fishing in a pond of minnows, no matter how it’s done, will only find minnows. But these days they are very expensive minnows.

Genomic cold fusion? Part I. Rational and irrational aspects of mapping

I’m sitting here on a smooth, quiet train from Zurich to Innsbruck, a few days after the mini-course that we taught in Helsinki. In this post I want to make a few reflections on things said by people reacting to Facebook or Twitter messages about the course, comments that were too short to do justice to what we actually said.

In particular, the issues have to do with the nature of genome mapping strategies and what they are or mean.  There seems to be a good bit of confusion in this area, perhaps because of a lack of proper explanation of what these methods do, and why and how they work.

First, nobody should be doing mapping, looking for genes causally responsible for traits, unless they have some legitimate reason for believing that a trait is substantially affected by genes—that is, that variation in the trait or risk of a trait like a disease is causally associated with variation in a particular spot in the genome.  Such a reason, at best, would be that the trait seems to segregate in families as if caused by a single Mendelian factor.  If the evidence is weaker than that—as it so often is—then mapping becomes the more problematic.

If we don’t know the part of the genome that affects the trait, then we use many measured variable sites, called markers, that span the genome with the idea that wherever the causal site is, it will be near one of our markers.  Essentially, that is, we are searching for statistically significant associations between the marker and trait, based on some basically subjectively chosen measure, like a p-value, in samples that we believe are appropriate for detecting causal effects.

What is perhaps not widely appreciated, is the nearly essential way that such searches rely on evolutionary assumptions.  We say ‘nearly’ because if one happens by huge luck to genotype the causal site itself, the test for association may be a bit more direct, as we’ll try to explain.

Mapping is based on evolutionary history

Evolution, or population history, generates the variation that causes the trait effect, and the variation we use as markers.  Mutational events generating these variants occur when they occur, and we choose markers based on the idea that they vary in our chosen type of sample, and that the instances of a given marker allele (variant) are descendant copies of some original mutation.  These instances of the same allele are said to be identical by descent (IBD) from that common ancestral copy.  Sets of instances of the marker also mark nearby chromosomal regions that have been passed down the same chain of descent.  That shared region is called a haplotype, and it gradually shortens over the post-mutation generations by a process called recombination.

If at some later time in the history of the haplotype ‘tagged’ by the marker variant another mutation occurs in a gene and alters that gene’s effects to generate the trait we are interested in, then the marker variant will be present in subsequent descendant copies of that twice-hit haplotype, and the causal signal will be associated with the presence of the marker variant.  This is called linkage disequilibrium (LD), and is the reason that mapping works.  That is, mapping works because of shared evolutionary (population) history of the marker and causal variants.

An hypothetical, simple example

[I’m continuing this post a couple of days from when I started it on the train to Innsbruck, and now finishing it in a nice hotel in Old Town, overlooking the Inn river.  Beautiful!]

Let’s say that we have a marker at which some people have a G nucleotide and others a T.   And let’s say the disease causal site, D, is near the G/T site, and that the D mutation, wherever it is on the chromosome, is near a copy of the chromosome that has the G on it at the marker site.  Then, what we hope is that the disease will be associated with the G—that enough more people with the disease will have the G than people without the disease.  This is the kind of association between trait-cause and marker that mapping is looking for.  But what can make it happen?

If we’re lucky everyone with the D allele at the causal site will have the trait (the ‘D’ mutation is fully penetrant, as we’d say).  And if there has been no recombination, and no other way to get the trait, then nobody with a T at the marker will also have the D variant—none of the T-bearers will have the disease.  Cases will have the G, controls the T.

This sort of perfect association depends on when the D-mutation, wherever it is on the chromosome, occurred relative to the mutation that produced the T at the marker.  We usually pick marker sites because we know that the variation (here, G vs T) is common in the population, and that means that the mutation is rather old.  Enough generations have passed for there to be a substantial fraction of T-bearing, and G-bearing people in the population.

If the ‘D’ mutation occurred right after this G-T marker’s mutation, then all copies of the G variant at the marker will also have the trait.  But if the trait-mutation occurred much later, then only a few of the G-bearing chromosomes will have the D-causing trait.  The association, even if true, will be weak.  If the D-site is far from the G-T marker site, then if the D-causing mutation occurred long enough ago for most G-bearers also to have the trait, but there’s a trap: in this case there will have  been enough time for recombination to switch the D-site onto a T-bearing marker chromosome.  The G-D association will no longer be perfect.

Likewise, if there are many different causes of the trait, then some cases will not be due to the D-variant (tagged by the G-allele at the nearby marker), even if the latter really is also a cause.  We’ll have cases with the T-marker variant, and in this case it’s not because of recombination.  The more causes of the trait the weaker the association between a specific marker, like the G-T one. 

Science or cold fusion?

So mapping is a multiple-edged sword.  Now, there are several ways to try to find trait-associated parts of the genome.  One is called linkage mapping, the other association mapping (genomewide association, or GWAS).  And one can also think that causal sites can be found not  by relying on linkage-disequilibrium, but simply by looking for causal variants directly.

These various strategies have their strong and weak points, and there is just as strong disagreement as to which to apply when.  That’s why someone can, sometimes sneeringly, claim that this or that approach is ‘cold fusion’—that it’s imaginary, and won’t or can’t work.  But since mapping for complex traits is not doing very well—as we’ve posted many times (and many others have repeatedly observed), we are usually explaining only a rather small if not trivial fraction of causation by mapping, the issues are serious, regardless of the vested interests of those contending with these issues.

In our next post we’ll discuss some of these issues about methods.

Choose a blog post and vote!

Choose your favorite blog post among the nominees at 3 Quarks Daily, and vote here!  (There are 3 MT nominees -- just sayin'!)

Blogging isn't catastrophic, but the opposite could be.

Ken and I just had an article published in Evolutionary Anthropology:

Catastrophes in evolution: Is Cuvier's world extinct or extant?

It's open access, so no need for a subscription to read it.

It's the second one we've done (first one is here). The piece is largely the product of many discussions we've had, mainly over email, and these discussions were sparked by posts we had each written for the MT.

Beyond how satisfying it was to have these discussions with Ken and to write this paper with him, it was a great excuse to read Elizabeth Kolbert's articles in The New Yorker (here and here) as well as her wonderful book that accompanies them:

Although the subtitle's irksome if you're not keen on separating human behavior from nature, the book's incredibly insightful. And, it's captivating if you just love tales of exploration and discovery, and if you eat up details about kit, gear and extraordinary travel conditions. It was sometimes difficult to read through my jealousy, and I consider that reason alone to recommend this read, regardless of the compelling scientific history, the exciting albeit depressing cutting-edge knowledge, as well as the important political message that only peeks out, from under the enormous pile of scientific evidence, in her final paragraphs.

It's because of our ongoing discussions and writings and then also Kolbert's, that Ken and I got to thinking about whether and how extinction, background and mass extinctions, and especially Cuvier's pre-Darwinian notions of "catastrophism" are playing out in paleoanthropology right now. This is the overall theme of our piece linked above.

Kolbert deals briefly with Neanderthals near the end of her book. However, Ken and I weren't so much concerned with what happened to the Neanderthals as whether, for instance, we could fairly consider what happened to them to be "extinction" given what we know about their DNA living on inside, probably, billions of us today. And, because of those genetic circumstances, it naturally made us wonder whether anything we call "extinct" truly is and if it is, how could we know? This of course begs for a thoughtful consideration of species and adaptation and, seemingly, all the ol' evolutionary chestnuts that are terribly difficult to crack.

I don't think that what Ken and I contributed in Evolutionary Anthropology was far different from anything that could have occurred before blogs were invented, but blogging certainly did facilitate it. What's more, if I didn't have The Mermaid's Tale, if I wasn't routinely reading it and writing for it, I probably wouldn't be thinking this regularly and this deeply about many of these marvelous things in the first place, especially not with the unimaginably wonderful benefit of engaging with Anne and Ken.  What a catastrophe that would be.

Nominate a blog post for the 3 Quarks Daily science writing prize

If you write about science or if you read about science, and if you like making new friends, earning praise and winning money, or if you would like science writers to make new friends, earn praise and win money, then you should definitely, by the August 22 deadline, nominate something for this:

The 5th annual 3 Quarks Daily science writing prize!

Information here: http://www.3quarksdaily.com/3quarksdaily/2014/08/frans-b-m-de-waal-to-judge-5th-annual-3qd-science-prize.html

3QD editor Abbas Raza says:

We are very honored and pleased to announce that Frans de Waal has agreed to be the final judge for our 5th annual prize for the best blog and online writing in the category of science. Details of the previous four science (and other) prizes can be seen on our prize page.

What a fantastic judge they scored this year.

Last round of this contest--thanks to readers of the MT who voted and to the 3QD editors and that year's judge, Sean Carroll--I won the Charm Quark for "Forget bipedalism, what about babyism?"*

It's a wonderfully inspiring thing to experience and I'm so excited for the writers who will win this year's contest. Please help to make it a good contest by nominating what's turned you on, lit you up, wizened, informed, enlightened, or inspired you.  All you have to do is choose something about science that you like, dating back only as far as August 10, 2013, and then post the URL to it in the comments section HERE.

Each person can only nominate one link, which encourages writers to nominate one of their own. So don't be humble or shy or insecure. Do it!

And if you're not a writer, nominate a link that you've really enjoyed reading. Support your science writers in this often thankless service!

This isn't a ploy to get you to nominate one of mine. For good fun, I already nominated this one anyway:

Here's my entry to the @3QD science writing contest. It's in honor of the late great @ElroyBeefstu http://t.co/SFE6XKxHO3
— Holly Dunsworth (@HollyDunsworth) August 18, 2014

But if Ken, Anne, Dan, Jim, Reed or another guest writer posted something here, or if another writer posted something anywhere else in the last year that stuck with you or that struck you, then for the love of science and science writing, please nominate them before the August 22 deadline!


*Which now has deadlinks to cute photos because back in 2012 I didn't know what the hell I was doing with images in blogger.

Logical Reasoning in Helsinki

Ken and I are in Finland this week co-teaching the Logical Reasoning in Human Genetics course that Ken and Joe Terwilliger have taught a number of times in a number of places over the last 10 years.  People in the class, and/or I, may do some live tweeting at #lrhg14.

We'll be away for another week or so after the course.  We will do some blogging this week or next if we find the time.  If not, we'll be back the first week of September.

Helsinki: Wikipedia

The abbatoir, the lab, and pre-medieval behavior

It's a lazy August day and one wonders what to write about.  So I took a walk with my constant companions--sadly, not a dog, but my iPod.  I was listening to one of the BBC Radio4 program podcasts that we like, and I thought it would be worth putting down some thoughts, hoping to make them relevant.

Abbatoirs, or slaughterhouses, are among the most sensitive kinds of industrial plants.  This post was stimulated by the  BBC story I was listening to (File on 4: Inside the Abbatoir, June 17, 2014).  A standard protocol for killing mammals is to stun them with an electric shock to the brain, knocking them out to they'll feel no pain or terror, and then quickly killing them by, for example, stringing them up, slitting their throat, and letting the blood drain. Then they are butchered. The treatment of food birds is something like this, as I understand it, but the birds are first hung up by their feet, so they probably feel more terror before the deed is done.  Of course, all of this may be more gruesomely done on the farm, for both birds and mammals, though there are certainly farmers who work hard to ensure that their animals are calm until their sudden end.  But an abbatoir does it to numbers that would match a WWI battlefield--every day.

A properly run abbatoir, gruesomely, uses the same idea we have with human execution: a nice last meal, and a blindfold or for those to be done in with chemicals, a tranquilizer first.  Similar considerations are given to pets who are put 'to sleep' by a vet when they are old and suffering.

In the slaughterhouse, Lovis Corinth, 1893; Wikipedia

The BBC story described how this killing is done when done right.  It's properly supervised, sanitary, and the like.  If an animal has to go, well, it's better than how most wild animals have had to make their exit, being torn apart by a predator while alive or suffering an injury or disease without medical care or even (with some exceptions) sympathy from friends or relatives.

But the BBC story also describes how some Jews and Muslims are excused from this humaneness, and allowed to engage in pre-medieval slaughtering techniques (i.e., no stunning first), because, apparently, God (the loving one, that is) apparently said we have to torment animals to please Him.  That doesn't seem very different from Aztecs cutting out the hearts of their living victims (although, I vaguely recall their victims were at least intoxicated on something first).  I only pick these examples because I am too ignorant to have any idea how much other savagery we humans allow today in the name of other Gods or for what rationales.

If stunning is humane and if we are to eat meat, the killing is probably not exceptionable.  However, the BBC story reports various lapses in the system, disturbing instances of lax inspection, and cheating for sport, anger, or for convenience. Even in this sensitive context, are the insensitive among us.

What about fish?  We are generally quite happy with dragging them up from hearth and home, by the net-full, only to suffocate en masse, not so different from, say, the gas chambers, I guess.  Or, when undertaking mere individual slaughter, by hooking them (for sport) in the mouth before asphyxiating them.  Fortunately, thanks to research in part by faculty here at Penn State that shows that fish are not just automatons, there are growing numbers of human fish abbatoirs, that use altered water or stunning to lull the animals to their doom, as humanely at least as the fate we dole out to mammals.

Our concern for doing our killing gently is clearly inconsistent even when applied to other humans. Just look at the latest news. Bombing of children and hospitals, beheading or crucifying captured people because our God (the loving one, that is) says it's the thing to do and (we say) doesn't like their God. He must be a blood-sport fan.  In that regard, it is interesting to read, as perchance I've been doing, Milton's Paradise Lost, in which there's a Hollywood-like tale of wars among the 'angels' in that Heaven we so aspire to attend.

We justify at least instant killing on the grounds that we have to eat and that, given those conditions, instant killing is at least terror and pain-free.  But one reason vegetarians believe as they do is that killing sentient animals (some would, properly, include all animals) is in itself cruel no matter how kindly done, and since we can live perfectly well, and more economically sustainably, on plants, that's what we should do (though, personally, I question the plant exceptionalism since plants clearly respond to environmental trauma and threats).

Experimental abbatoirs
But MT is generally a science blog.  So let's talk about what goes on in the animal research lab.  IRBs (Institutional Rationalizing Boards) generally approve research procedures as being useful to human knowledge, and good for the research business, so long as they don't outright torture the animals. There are at least some limits.  But speaking of things pre-medieval, the reality is closer to saying that, as God (the loving one, that is) pronounced, the rest of animals and plants are just here for us to exploit, and we countenance a lot of things being done to animals, effectively under such an implicit assumption.

For example, what about, say, flies?  Here, the rationalizing gets even more contorted, or perhaps less. Insects and such simple creatures are said either not to feel pain or experience terror.  The way they're sometimes treated flies must absolutely like to have their body segments altered, or electrodes stuck into their brains.  Observations of insects in nature suggests they do sense and recoil from danger, and experience distress.

The arguments justifying research-based experimenting with animals is that that's how we learn about the world (and there's the widespread treatment of science as a largely unquestioned good), or that making countless animals experience a nasty disease or experimental 'procedure', often the only life they'll know, will eventually prevent humans from having to suffer in the same manner we make the mice suffer. We at least claim to try to minimize the trauma, but many in science know the more grim reality.  It's human exceptionalism, but since we're the ones in charge it's no surprise that we behave that way.

Just as we give life and then taketh it away from cows and chickens, so do we for lab mice.  They have their day (in the artificial light of the mouse room), at least, existence they'd not experience were it not for our NIH grant.  Some even get to have a rather active sex life (though, if female, usually they are killed while pregnant, so we can study their not-yet-offspring).


If we accept the reality and inevitability of mortality, then one can accept the killing for food as well as research. But need we accept the torment?  Could we at least have more stringent limits? Animal rights lobbyists, descendants of anti-vivisectionists, are irritating to those running research labs, but perhaps at least help keep things somewhat tempered.  After all, this is nothing new:  The great Roman physician Galen was famous for doing dissections on live unanethesized animals--in the name of science, and indeed somewhat theatrically.  We're not as savage as that!

We can always make up a rationale about human good or basic knowledge, or that the animals don't really suffer; but the fraction of lab animals who shed much light on scientific knowledge is small, and what we're allowed to do to them not so small, even though certainly many lab animals do 'contribute' to ultimate human good.  These are not easy issues (and I say this not in an accusatory way: I worked on developmental genetics of mice for many years).

We all have to die, humans as well as other animals.  The pre-scientific belief systems promise something better afterwards, and if you believe that kind of thing, then lucky you!  But we can at least do our best to make the exit of those enslaved by us a painless one......I had intended again to say a 'humane' one, but that now somehow seems an inappropriate word.  Thinking about the abbatoir, and other aspects of human behavior, puts these issues in stark perspective.

Anthropology's troublesome arguments

By Anne Buchanan and Ken Weiss

These last few months have been strange ones for anthropology.  So much linen being aired so prominently, dirty and otherwise.  First we had a best-selling book by science journalist Nicholas Wade that in effect defines the field as the science of genetically determined traits, declaring among other things that there are five human races and that anyone who doesn't accept the biological basis of race is motivated not by science but by politics -- unlike his own stance. Then we had two papers (here and here) in PNAS suggesting that one of the now extinct short people on the Indonesian island of Flores had Down syndrome. And now we have a paper, albeit in a less visible journal than PNAS, but nothing's invisible to Twitter, declaring that premenstrual syndrome evolved to keep women from staying with partners with whom they are infertile.

The Wade book, of course, has gotten a lot of press, both positive and negative, including a letter in the New York Times last week refuting Wade's use of population biology by a long list of population biologists, many of whom are authors of the work Wade cites in support of his own political views, although of course he doesn't see it that way.  The PNAS papers got huge amounts of publicity around the world, but very accepting, none that we saw questioning the hypothesis. The PMS hypothesis, on the other hand, has been critiqued as nicely as 140 characters allow (including by Holly, who red-inks it below (it's a Twitter thing), and blames PLS (pre labor syndrome) for any perceived snark).

Each of these publications happens to bring up deep and long-standing issues in anthropology.  The issues involve the usual scientific food fights, but over and above the specific details, there are problems, and it's these that we want to discuss today.

Troublesome arguments
We'll take these issues one at a time.  Enough has been written about Wade's book that there's no need to look at the specific arguments again.  It's a continuation of retailing Just-So stories and selective reporting and misreporting, that he's been doing for many years; it sells well and he serves a surreptitious audience that includes various shades of racist enmity, as well as readers who have no way to know better, including many anthropologists.

Fine.  What's interesting to us, in terms of the broader field of Anthropology, is that it has clarified how deeply politics affects what we all make of scientific 'facts'.  You've got your genetic determinists on the right and your gene/environment interactionists on the left, and if you know how someone feels about genetic determinism -- that what and who you are is basically set the moment you are conceived -- then you know a lot about how s/he feels about IQ, scientific racism, natural selection vs drift, the importance of adaptation in evolution, and indeed about immigration, Obama, economic inequality, and so much more.  Sociopolitical views are correlated with what one seeks, accepts, or promotes when it comes to science -- not just some purportedly objective truth.

Genetic determinism is an interesting hot button issue.  Too often, people believe either that it explains virtually all traits or explains none, but of course it's some of both.  Some diseases, e.g., are caused with high predictability by a genetic variant, some diseases are due to gene/environment interaction, and some 'causal' variants are fairly useless for disease prediction.  Even infectious diseases that can affect almost anyone, that is, almost any genotype, do so in concert with genes.  Genes contribute to every trait, directly or indirectly: without genes we would not be here, and genetic variation can affect almost anything.  But that is not the same as saying that they determine, or specify, every trait.

There are academics who have trouble accepting strongly genetic arguments, because they believe they are, as the phrase goes, 'politically incorrect'.  But behind the political incorrectness smear is of course a dark history of eugenics, lynchings, the slaughter of 11 million people during World War II, including Jews, homosexuals, disabled people, and more.  But further, even if all of genetic-deterministic arguments were fully supported by the science, and we all were to accept that, for example, 'race' is a clear-cut biologically determined category of humans, why would that justify unequal, and worse, treatment of groups we (those in decision-making positions) deem unequal to ourselves?  Unequal because science tells us so.  Science doesn't make value judgements -- people do.  That is why the assertion of such points, or even the funding of studies to find them, is itself a political act.

To the people whose politics are supported by the new 'genomic' version of scientific racism (the latter term, we think, was invented in pre-Nazi Germany), of course, those arguments are 'politically correct' and their generally left-leaning proponents are just idiotic know-nothings.  Not in science, but in scientific racism, it's perfectly fine to cherry-pick the data when making an argument -- and the argument is supported by white supremacists, people who see genes behind everything, people who believe that every trait is here because it was naturally selected, and so on.  Genetic determinism and other labels have become code for accepting inequality, for hording resources, for rationalizing us having and them not having, and this often goes hand-in-hand with racism and hate (often not openly stated, of course, but sometimes it is). It's hard to argue that's science, not politics.  And, the disagreement won't be solved by science.

The problem here is simply the facile telling of stories without anything close to a sufficient understanding of the available information, the mixing of how things are today with how they got here, the assumption that how they are today is driven by genes rather than by much stronger and more ephemeral cultural factors, and the simple assumption that everything simply must be simply explained by genetic natural selection above other evolutionary paths.  In these conditions, a measured discussion of the issues is not possible -- and by the conflicting parties with their agendas, perhaps not even desired.

Getting to now may have nothing to do with then
The PMS paper is interesting for a number of reasons.  First, the author is a biologist who, at least judging from his web page, works on genetic variation in non-human organisms.  Mostly not even mammals.  So it's curious that he's decided to, er, wade into the evo psych realm.  Evo psych can be troubling enough when the arguments are coherent, so this one is particularly troublesome. In "Were there evolutionary advantages to premenstrual syndrome?" Gillings repeats and then discounts a number of previous evolutionary arguments about PMS, and then argues that premenstrual syndrome or premenstrual dysphoric disorder are essentially universal and experienced by all women, so there must be an adaptive explanation for such a maladaptive trait.  And of course it has a genetic basis.

Ongoing bonding between humans is complex, depending on sexual and nonsexual behaviours, and on previous experience in the relationship. Where such relationships do not result in pregnancy, premenstrual hostility may cause varying degrees of rejection, both sexually and of the relationship in more general terms. It might then be conjectured that infertile pair bonds are more likely to break down, freeing both partners to pursue fertile mates (Morriss and Keverne 1974).

Women suffering from PMS are likely to direct their anger at current partners, Gillings suggests, but most often it is when they have no children, that is, when one of the pair is infertile (or the pair, together, is infertile), that this will result in the dissolution of the pairing.

So, PMS evolved to dissolve infertile couplings.  But Gillings then says that this wasn't a problem in hunter gatherer times because women then weren't cycling nearly as frequently as women today -- they were pregnant or lactating, or poorly enough nourished that they didn't menstruate.  In that case, it's hard to understand how this evolved.  Gillings argues, though, that modern cycling is maladaptive, and that it causes health problems, as well as disrupts family dynamics with this genetically driven monthly bearishness of women.  He goes on to suggest that women should consider using cycle-stopping contraception (rather than, say, suggesting men should offer chocolate and not take it so personally).

But wait a minute.  First, a trait can only be selected if it's visible to natural selection.  It has nothing to do with whether people are paired up or happy (unless these are requirements for reproductive success, and the former is, according to some widely held evo psych-type assumptions), and it must be based on genetic variation, not cultural patterns.  If women weren't cycling regularly, and there's a lot of evidence that they weren't until modern times, how could PMS adaptively evolve if it didn't exist in any significant form?  And second, as Ken pointed out in his series a few weeks ago on the mythology of natural selection, there are many other ways that traits can evolve, including a series of reasons we might have no ability to guess, and including by drift relative to any Just-So story we reconstruct as if we got here in a straight adaptive line from then to now.

Like Wade's book, this paper makes the all-too-frequent mistake, in evo psych yes, but in anthropology -- and increasingly in other fields as well -- of assuming that every trait is adaptive, is here because of natural selection, and is thus genetically determined.  And that if we can build a plausible argument, it must be true.  And that the way it functions today is the reason for its evolution.  But, let's call this the geodesic fallacy.

SpaceTime trajectory real and imaginary (modified from GoogleImages)

See Ken's final post on the mythology of natural selection for the details, but here's the gist:

Even if the implicit complete determinism of Darwinian assumptions were true, the complex dynamic nature of earthly ecologies means that an evolutionary geodesic need not follow a retrospectively reconstructable path from then to now. A species or trait need not have evolved 'for' its current use, not even in stages aimed in a particular direction, not with its various components evolving synchronously or even sympatrically. Indeed, if and where ecologies are complex and dynamic, the meanderings of our object--a trait or species--may be essentially indistinguishable from random movement relative to any long-term 'purpose'.

It's very easy to make up adaptive scenarios.  That's why they are called Just-So stories.  And they are seductive.  But elegance or cleverness doesn't make them right.  Indeed, most often we have no idea if they are right, or even how to test them.

Again, the problem here is simply the facile telling of stories without anything close to a sufficient understanding of the available information, the mixing of how things are today with how they got here, the assumption that how they are today is driven by genes rather than by much stronger and more ephemeral cultural factors, and the simple assumption that everything simply must be explained by genetic natural selection.

Lumpers and splitters
The Flores controversy, of course, well-known in anthropology, has been ongoing since the first report of the findings of bones in Liang Bua Cave on the Indonesian island of Flores ten years ago.  The bones were from individuals obviously much smaller than other known hominids of the time, prompting the discoverers to declare them to be representatives of a species of human new to science.  The authors of the current re-interpretive papers on Flores at the time argued that no, these bones didn't represent a new species, but instead at least the one intact skull that was found represented an individual with microcephaly.  Now, it's an individual with Down syndrome.

LB1 skull: Wikipedia
 (associated postcranial remains can be seen here)

However, the argument is based on assuming that it's possible to definitively diagnose Down syndrome in a skeleton (among the many possible skeletal indicators of Down syndrome, most are not found exclusively in people with DS)  and that the asymmetry in the skull was present before the individual died, and not the result of thousands of years of burial, that this individual reached adulthood, and without modern medical care, that's less likely, all at least questionable assumptions.

But suppose LB1 really did have Down syndrome, then what?  Then it is completely irrelevant to any population or evolutionary argument.  One can argue about the Down diagnosis, a subject best left to actual experts of which there are many, but it matters not to the issue of whether the population experienced the very commonly observed evolutionary phenomenon of island dwarfism.

Cave where the bones were found: Wikipedia

This then gets into a very long-standing argumentation between those who tend to name each new fossil with a separate species designation (often called 'splitters' in evolutionary biology), and those who see a range of variation within species and argue that what we have found in the fossil record are representations of that variation, not of different species.  The latter are the 'lumpers'.  The snide and over-puffed Flores papers seem to be at heart a jab at those who see the Flores specimens as representative of a different species from the southeast Asian mainland.

Of course, 'species' is itself a largely subjective subject.  Even the idea of reproductive isolation is very hard to prove.  How many matings does one need to try to show that they never produce fertile offspring?  Usually, of course, and certainly with fossils we cannot do that directly!  The species problem has been debated for more than a century.

Were Neanderthals and early 'modern' Homo sapiens separate species?  Many would say so.  Are the recently prominent 'Denisovans', fossils from a region in Northwest Asia, a separate species?  They have separate names, after all!  Yet because they are recent enough, and perished under fortuitously helpful conditions, we have DNA from them.  And to date, the evidence suggests admixture between them (with remnants of both in modern humans today).  So: separate species, or not?

The arguments are heated among anthropologists about these sorts of issues and the more-heat-than-light regarding the Flores material reflects that.  There is, after all, a whole lot of publicity in the media for stories that sell, like tales of human fossils.  Anthropologists, whose field is often not all that rigorous given the problems of reconstructing the past, are particularly vulnerable to promoting their finds as different, or blasting their peers for doing so.  The media circus loves anthropologists, and anthropologists love it!

In these areas, the controversy is stirred up by the journals and the media.  Every week outrageously poorly supported evolutionary stories appear in journals and are eaten up by media reporters who either don't know the science, don't probe as they should, or don't care to be informed because the objective is to sell copy, and to do that content must be found.

Whether we'll see a day when appropriately measured questions can be asked and discussed, even if they can't really be 'answered', isn't clear.  Probably not in our lifetimes.

The Leaning edge: strange meat allergy

Despite decades of extensive study at the molecular level, many fundamental issues remain unexplained about the adaptive immune system.  We have two types of immunity, adaptive immunity whose genetic basis originated in jawed fish 500 million years ago, and is now shared by all jawed vertebrates. This system uses scrambled coding sections that generate randomly configured proteins to produce an open-ended repertoire of antibody and related molecules that quickly 'learns' to recognize and how to fight unknown pathogens as we meet them.

In addition we have an 'innate' immune system that generates predetermined responses, for example to general inflammation and some basic structures of bacteria.  We share this system with all other organisms.  Even plants can mount immune responses to pathogens and other kinds of assaults, including repertoires that are largely open-ended -- that is, that did not evolve in a Darwinian way one-by-one to respond to specific pathogens.  Adaptive systems of these sorts are terrific because they can evolve within organisms as fast as bacteria or viruses and so on can mutate.

However, one major unknown is why we can develop allergic responses to what, for most people, are entirely benign molecules.  It's one thing to be able to attack and destroy viruses or bacteria that would kill us if we didn't, but why some of us become hypersensitive to substances like bee venom or cow milk or dust mites -- or sometimes even our own tissues and organs, in autoimmune responses -- is not understood.  Thus there's a lot that can still surprise researchers in allergy and immunology.

Last week's story about a recent upsurge in red meat allergies was interesting.  In case you missed it -- though with those glaring photos of the culprit, it was hard to miss -- first in the southwestern US and now up the US Eastern seaboard, people have been developing a severe allergic reaction to red meat in droves, induced by the bite of a lone star tick.  The same syndrome is occurring in Europe and Australia as well.

Lone star tick; CDC Public Image Library

In general, the reaction is developing in people who have been eating red meat all their lives, but the bite of one of these ticks can change that fast.  The thinking is that the tick's saliva contains a carbohydrate, called galactose-α-1,3-galactose (α-gal), which is also found in red meats like beef, lamb, pork, venison, and so on.  When the tick bites, it injects enough α-gal into its blood source to cause the victim to create antibodies to this carbohydrate.  Then, upon next consuming meat, the immune system is primed to overreact to the α-gal in the meat.  Essentially, and ironically, while we may think we are preying on the cow or pig, they are treated as if they're preying on us!

The reaction usually occurs 3-6 hours after the meal, so the connection between the meat and the reaction isn't always immediately made when someone is trying to understand what they could possibly be allergic to.  And this kind of a delay is unusual for an allergic response.

The story is just hitting the news but in fact it's not a new story.  The first paper to describe delayed anaphylaxis after red meat consumption appeared in 2009 ("Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-a-1,3-galactose," Commins et al., Allergy Clin Immunol. 2009;123:426–33.).  The association between α-gal and allergic response was first noticed, and explored by Commins et al., because of a geographically localized cluster of anaphylactic reactions to the monoclonal antibody cetuximab, a cancer drug. People who reacted to the drug were found to have antibodies to α-gal, and maps of the prevalence of allergic response to the drug were a close match to prevalence of Rocky Mountain Spotted Fever. This suggested a strong likelihood that one of the two ticks that cause RMSF, D. variabilis or A. americium, also were causing the allergic response.

The authors documented allergic reaction to red meat with skin prick tests in 24 people, and found raised IgE (immunoglobulin E, which indicates an immediate allergic response) antibodies to α-gal.  The association with tick or mite bites was proposed in that paper, and Commins et al. confirmed in a paper published in 2011 that the cause of the raised IgE antibodies in the USA at least is bites from the lone star tick Amblyomma americium.  In the 2011 paper, they wrote:

The evidence comes from i) prospective studies of the response to tick bites in three subjects, ii) epidemiological evidence that these IgE antibodies are present in areas where tick bites are common, iii) correlation between IgE antibodies to tick proteins and IgE antibodies to alpha-gal, and iv) evidence for an expanding range of the lone star tick, Amblyomma americanum.

Documented occurrences of this reaction now number in the thousands, and Commins et al. suggest they may be seeing the beginnings of an epidemic.  They relate this to an increased number of ticks and thus tick bites with the increasing population of deer around urban areas, although the tick host includes small mammals as well, and the increasing range of the A. americanum.

Hamburgers on the grill; Wikipedia

This is a nice piece of medical detective work, but not all has been explained.  It seems that the reaction is worse after consumption of fatty meat, and there may be no reaction at all if the meat is lean.  The reaction isn't always severe, even in the same person, ranging from a few hives to severe anaphylaxis.  Why ticks induce this response isn't yet entirely clear.  And, most food allergy reactions are immediate, or within minutes of consumption of the allergen, but this one is delayed by hours.  That may be because the offending allergen is a sugar, while most food allergens are proteins.  Or, it may be the lipid connection, as Commins and Platts-Mills wrote in 2013:

The reason(s) for the 3–6-h delay in this IgE-mediated food allergy has not yet been elucidated. Given the apparent role for lipids in producing the clinical reaction, it may well be that absorption of lipid is the rate-limiting step in the delay. Biochemically, fats are absorbed and processed much differently than are carbohydrates and proteins. Fats ultimately enter the bloodstream via the thoracic duct 3–4 h after a meal. The conversion and processing of fats to chylomicrons and then further in LDL particles of various sizes may also explain a portion of the delay. Alternatively, chylomicrons themselves may transport alpha-gal antigens from the gut and intestinal epithelium via mesenteric lymph nodes to the circulation. Intestinal epithelial cells have been postulated to secrete antigen on newly formed chylomicrons, a process that could also help to explain the delayed response to mammalian meat in patients with IgE Ab to alpha-gal.

Unexplained, or idiopathic hives are a common reason for people to see an allergist.  And most commonly, people leave the allergist without an answer.  Commins and Platts-Mills are hoping that explaining the reason for the delay in the response to red meat may help elucidate aspects of allergic reactions that aren't yet understood.  And one can ask if something like this is also the story that may explain the apparent recent high rise of allergies to peanuts, gluten, and others.

Allergists and immunologists are responding to this increasing outbreak with surprise.  As food allergies go, meat allergies have been fairly uncommon, so the rapid increase in allergy to red meat is interesting enough.  But the delayed response is also unusual.  Or so they have thought -- when so many cases of chronic or recurrent hives are unexplained, it's hard to know whether they represent delayed or immediate responses.  If this is indeed an epidemic, it may teach immunologists a lot about a system about which much remains a mystery.

Water, water everywhere, and then some drops to drink: Comet 67P/Churyumov-Gerasimenko, and the Life-Dust rationale

This week comes the news that a European spacecraft probe called Rosetta has gotten into an interesting triangular orbit around a comet named 67P/Churyumov-Gerasimenko, that itself is in orbit around our sun.  This is quite a technical and engineering feat that's interesting in its own right, because getting there required about 10 years, over 6 billions of miles of travel, orbiting around the sun to use solar and planetary gravity to give it a sling so it didn't have to use its on-board power.  And there are still technical challenges yet to come.

From the European Space Agency Rosetta project

Rosetta will orbit 67P and take all sorts of pictures and measurements, and then, remarkably, will send down a landing craft to probe even deeper.  It will find out how much ice is on the comet and what other material it may contain, presumably including carbon.  That's been a primary part of the news releases.  But why carbon, and what's so important about carbon as opposed to some other sorts of compounds? Herein lies the hype and at least an apparent major rationale for doing this since, after all, we know from various sources what comets are basically made of.  As put today by the BBC's report, "The mission aims to add to knowledge of comets and their role in ferrying the building blocks of life around the early Solar System."

This sounds interesting and like a nice justification for a many-billion Euro adventure.  Astrophysicists will learn at least some new things about the structure and composition of this particular rock.  But will 67P tell us much about anything other than itself, that we don't know already directly and indirectly about the trillions of other comets in the cosmos?  I say this because the idea that we'll be discovering the origin of Earth-life's materials seems a rationale as flimsy as, say, a clump of damp dust.  

I know very little cosmology, but one thing I think I do know, if current science is at all correct, is that the "building blocks of life" did indeed come from comets and other space-dusty rocks and detritus.   What we have long known is that water, carbon, and all the other complex molecules of life (and, for that matter, of rocks, seas, weather and the Earth entire) came from 'outer space'.  Where else could they have come from?  

These molecules are formed in processes called nucleosynthesis, that occur inside stars.  The cosmos had none of it at the time of the Big Bang.  Only when stars form, exist for a while, then explode in death, does this material get scattered into space.  Then, due to gravity and possibly other factors such as molecular adherence these molecules, essentially space dust, coalesce into larger and larger clumps, rocks that become captured in orbit around new-forming or existing stars.  All that you're made of was in turn made in some former, no-longer-existing star, long before our Sun came into existence.

The Earth, and everything on it that life is made of, got here by collapsing and accretion from space-blown material.  The stuff of 67P is just like what we already think we know was the source of similar molecules on earth.  Whether they got here during the original accretion, or by space-fall thereafter, it's the same kind of process.  We know the Earth is hit from time to time by such space missiles. The bottom line is that everything that's here got here from space.  The only somewhat relevant, but in that sense not so very important question is how much carbon and water came after the Earth existed as a big rock, and how much was part of Earth's formation.

We know with reasonable certainty that life didn't arise until there was enough water and carbon etc. here for biomolecules to form. We know roughly when that was (3-4 billion years ago, in a 4.5 billion-year old Earth).  If these vital molecules were here at Earth's beginning, than life arose only when things had cooled down enough, and perhaps water had eroded enough minerals and carbon and so on from solid rock, etc.  If the cosmic rain was responsible for some or even most of the water here (which seems very unlikely, given how prominent water is all over the universe), that tells us little that's different.

Pro-science or a science spoil-sport?
So is such a mission worth its cost when there are things to do with public funds other than to develop sky toys for scientists to play with?   We are in favor of science--good science, properly represented.  But science should tell less puffed-up stories, and the public should be better-informed.  

In this case, better-informed would be to be told that (unless cosmological theory is missing something important today, which is not what the press releases suggest) all Rosetta is doing is poking around in one sample of the stuff we were made by, that all came from space, as did the Earth itself.  If even knowing that, we still want to spend the funds on what are really little more than costly real-life video games, great!  

For those of us without a major disease and who have shelter, security, and enough to eat, this is interesting stuff to watch, not more costly than cable TV subscriptions (maybe less, depending on your channel line-up).  But to hype this as is being done, gives the impression that Earth got here by some other means than gravitational accretion of former star detritus.  That's misleading, bad science. Why is such need felt by the scientists (or the institution's PR office) to give it such spin?  Is it that they realize that without the spin they'd have no funding?  If so, then the public is being bilked.  If not, then let's have real science from these experts.

Here's something much more interesting
To be fair, some of what we get from our space cadets really is interesting for more than a "Wow, how did you manage that?" factor.  Yesterday also, NASA (perhaps not wanting to be upstaged by the Europeans?) released this image of a near-perfect hexagonal pattern, referred to as a 'storm', on Saturn's north pole region:

Photographed from the top of Saturn.  From NASA

The NYTimes has a wonderful video narrated by Dennis Overbye showing this formation along with other features of Saturn.  It's a curious formation, a fluid aspect of the north pole's weather. 

As a former meteorologist myself, I find this very interesting.  Spacecraft first found this many years ago, but we only get an occasional direct look.  The curious aspect of the pattern, is that it's a hexagon rather than more sinuous wave such as we get here in Earth's weather (and seas, for that matter).  How can fluid dynamics generate such a rigid-appearing, angular form on a basically spherical surface? Is something on Saturn alien to our own planet?  Different physics?

In fact, the report says that physicists have now generated similar patterns in the lab, identifying the conditions that are responsible and showing that nothing strangely unearthly is going on in our sister planet.  Still, seeing these far-off things close-up for the first time has lead to learning, and is captivating--even if, as in 67P, it doesn't show us anything alien to our experience here at home.

These images from far away evoke an emotional awe: there truly is, way out there and so far beyond, more of what we see right here.  It exists, all alone and cold and dark, perhaps known to other creatures, yet the same as what we have here.  Little ice crystals, rock dust, shapes we recognize that we might find in our own back yard.

These thoughts reinforce the amazing, remarkable fact that there really do seem to be laws of Nature, that what we can see nearby applies way out there where we can hardly catch glimpses--a point Isaac Newton stressed. Very much to think about.  Good science really does tell us about the nature of the world, in ways no other means has yet been able to do.  We puny humans, blobs of stuff that evolved from space-stuff, have figured this out!  That's a thought of cosmic proportions.  

It's a mushroom kind of day

Well, it's summer time, and the livin' is easy.  We've had a lot of rain, and the result, along with flooded basements, is that mushrooms are sprouting up all over.  They seem to grow, just like Topsy, without any other explanation, and with a speed that would make a science reporter's head spin.  At the same time, various outrageous science stories are sprouting like mushrooms, stories we don't even have the inclination to comment seriously on.  Not on a sultry day, when one should be in a kindly mood.

This time it's anthropology, but it isn't only anthropologists who can offer up Just-So stories that don't bear even a microsecond's scrutiny, the mushrooms among the ferns, though I think our profession tops most physical and biological science in this (on occasion we might have to cede the laurel wreath to some social scientists, politicians, and others).  It's harder to find the beautiful ferns and flowers among the mushrooms....but they're there.

Indeed, even the real sort of mushrooms are beautiful.  Here are some from our small yard after still another rainy day.

Cauliflower mushroom