Dogs, crows and garbage: phenogenetic drift

Scavenger hunts
Monday's the day trash gets picked up in our neighborhood. When I was out running early this Monday morning, I passed a scene I see not infrequently -- a group of crows congregated around a plastic trash bag, its contents spilling into the street and the birds tugging at anything in it that looked appetizing.  As I ran by, two of the birds flew but one brazen bird stayed right where he was, guessing that I was no threat to him.

Crows are very smart, and not just because they've figured out how easily plastic garbage bags are breached.  I've also seen them congregated around trash barrels with the lids knocked off.  I've never seen them actually take the lids off, but it must be they do.  When I was a child it was dogs who got into the trash.  This was before leash laws, when it really was a dog's life.  Dogs we keep as pets now have only ancestral memory to recollect the halcyon days of wandering the streets untethered on trash day.  Now it's a crow's life.

But sometimes it's bears, too.  A mother bear and her three cubs were making the rounds of our neighborhood a few weeks ago, knocking down bird feeders and compost bins, and this isn't an unusual occurrence.  The wilding of America?

This morning's sighting reminded me of a piece in the February 21 New York Review of Books by Russell Baker in which he reviews a book by Jim Sterba, Nature Wars: The Incredible Story of How Wildlife Comebacks Turned Backyards into Battlegrounds. I have not read the book, though now that I'm remembering this, I just might have to. Unhappily for the author, Baker's is one of those pieces that makes you think can skip the book, even as he gives it a fine review.

In any case, Baker describes seeing a pair of foxes mating in his garden situated, he says, just two blocks from the county courthouse in the bustling center of town. The encroachment into human-populated areas of animals who were once sighted only at a distance is becoming increasingly more common.

Sterba ... argues persuasively that events like this foxes-in-the-garden sighting are evidence that humans are losing some kind of property rights struggle with creatures of the wild. He cites an extensive history of resolute and sometimes blatantly hostile real-estate invasion by beavers, Canada geese, wild turkeys, and white-tailed deer, all of which were once assumed to be picturesque and even lovable denizens of the dark and safely remote forest. In-town appearances by coyotes and bears are now commonplace in communities across the country, and trespassers in my own garden, aside from the foxes, have included groundhogs, possums, skunks, feral cats, and one blue heron that ate all the koi with which we thought to beautify the fish pond.

Lucky heron.  As Baker points out, in the last fifty years these animals have discovered that life can be a lot easier closer to town, and food a lot more abundant.

The woods have no garbage cans and dumpsters filled with discarded food, no lovingly tended tomato plants, no ready-to-pluck dahlias and nasturtiums, no tasty, newly planted shrubs. 

Best of all from the animal viewpoint, humans are no longer the same dangerous predators who once pushed the beaver close to extinction and reduced the entire North American white-tailed deer population to a trifling 500,000 scarcely a century ago [there are now 25-40 million]. Sterba believes that this human withdrawal from combative relations with woodland animals is one of the major causes of their proliferation: man as killer has undergone a softening change.

Indeed, the crow standing in the middle of the road waiting for me to run by its food source is evidence of exactly that.

It doesn't matter who does it
But here's the thing -- whoever's doing the scavenging, there's still garbage spread all over the street.  And this is an apt metaphor for an important way that evolution works.  Yes, gene function is often conserved, so that the same gene (Pax6) is involved in photoreception in the eye of fruit flies and frogs and humans, and the human form of the gene can be transplanted into even distantly related species and the eye will still be made.  But it's also true that often a trait is conserved but the genetic scaffolding is very different.  Natural selection might preserve the phenotype, the trait, but it can't see the genotype, leaving it free to vary.

Ken and his then post-doc, Malia Fullerton, published a paper in Theoretical Population Biology in 2000 describing just this, though others have described it as well (reviewed by Brian Hall in his 2003 book, Keywords And Concepts In Evolutionary Developmental Biology.) The effect is called 'phenogenetic drift' to indicate that the trait's genetic basis can change. This is not the same as genetic drift, which is when genetic variation that has no effect on a trait, or at least on reproductive success ('fitness'), changes over the generations, and it's not the same as phenotypic drift, when traits vary over generations but that variation doesn't affect fitness.  This happens, therefore, regardless of whether there is selection, even strong selection, or not.  A prerequisite, or partial one at least, is that many genes contribute to the trait, so that different combinations of variants in these genes can lead to similar traits.

Hall uses the example of proteins that make up the lens of the eye. They can be unrelated among taxa, as long as they let light pass through. Kazu Kawasaki, a very skilled research scientist in our lab, has written a number of papers describing the evolution of mineralization in vertebrates. One of his early papers is on the changing genetic basis of vertebrate teeth. He has found a gene family, that he calls SCPP genes, that varies widely among species, and yet contributes to the formation of mineralized tissues -- teeth and bone -- in all of them.

As Hall concludes his section on this subject, "Phenogenetic relationships are less determinative for more complex traits."  There are many genetic pathways to being tall, or to developing heart disease, or to being a fast runner  And that's before we even throw environmental factors into the mix.  Genetic determinism, which we've blogged about often, is simply too easy to assume, often incorrectly so.  When you look out the window on trash day and see garbage strewn all over the street, don't leap to judgment about who did.  It's only when you find the bear scat or a crow feather that you'll know.  But even then, do allow for the possibility that the neighbor's dog got loose.

Hold the presses! Growth factor genes do NOT affect head shape!

We tend to wax rather cynical about mapping studies (GWAS and the like) that find many miniscule effects and only an occasional major, replicable one.  We feel that this approach has played out (or been spent out) and that better, more thoughtful and focused science is in order these days.

One typical daily fact is the breathless announcement of finding a gene 'for' some trait or other, be it disease or even whether you voted for Romney or were one of the misguided bearers of the 'liberal' gene.  Extra!  Extra! Read all about it!  New gene for xxxx discovered!!!

We, too, are guilty!
Well, we must confess:  we are also involved in gene mapping.  Though, in fact we've confessed this before (here, e.g.), if in an MT sort of way.  In our work, we are using head shape data on a huge set of baboons who are deceased members of a huge and completely known genealogy housed in Texas, and  a large study of over 1000 mice from a well-controlled cross between two inbred parental strains.  Now these data sets are about as well-controlled as you can get.  In each case, marker loci across the genome were typed on all animals and the GWAS-like approach was taken to identify markers in genome areas in which variation was associated with various head dimensions (as shown in the figure).  These are then regions that affect the trait, and are worth exploration.

We regularly see  proclamations of discoveries of genes 'for' craniofacial shape dimensions.  Two recent papers report Bmp genes, thought to be involved in head development, and many others have reported FGF (fibroblast growth factor) results of major shapes.  These findings have been so casually, or even perhaps carelessly, accepted as to have become part of the standard lore.

But based on our large, very well-controlled study of two species we beg to differ!

But, no--this time Extra! Extra!  We really mean it: NO!!
After careful examination of signals from our mapping of baboons, and separately of the inbred mouse cross, we have come to the startling finding, with high levels of statistical significance rarely matched by other GWAS on this subject, that neither Bmp nor FGF genes are involved in head-shape development!

Scanning the genome markers separately in both large data sets shows clearly that there is no effect of these genes on any head shape dimension.  None!

In fact, this is not so unusual a finding, as many studies simply fail to find even what were thought to be clear-cut causal genes.  Yet, these findings are not eagerly sought nor published by Nature, Science, The New York Times (the leading scientific outlets these days--we do not include People in our list, despite its typically similar level of responsible fact-reporting). 

We are using lots of exclamation points, but we are totally serious.  Though we shout from the rooftops that we have found no evidence for these genes' involvement in head shape, we will have no hearers.  It seems just not in anyone's interest to see their previous, hard-won findings debunked. 

Or is there a different kind of lesson here?

What evolution leads us to expect
The lack of reporting of negative results is something of a scandal, because negative evidence tends to disprove previous findings by not supporting them.  That seems important, but even to skeptics like us there are important issues that should be understood.

A widely proclaimed tenet of modern science is called 'falsificationism'. The idea is that all the positive findings in the world don't prove that something is true, but a single failure to find it proves that the idea was just plain wrong.  Just because the sun has risen every day so far does not by itself prove it will rise tomorrow.  Night does not cause day!

But some negative findings don't really falsify previous positive findings.  There can be sampling issues or experimental failure and so on.  So our not finding FGF effects on head shape doesn't falsify previous findings.  We could be wrong.

But even if we are wholly right, as we're pretty sure we are, this does not in any way whatsoever undermine prior findings, that seemed quite solid, that these genes are in fact involved.  This is because standard ideas like falsification are based on a kind of science in which repeat experiments are expected to give statistically similar results: rolling dice, working out planetary orbits or chemical reactions are examples of things that follow natural laws and are reliable.

Here, however, we're dealing with life, and life is not replicable in that sense!  Each sample really is different: different sets of people have different sets of genotypes.  A negative finding is not a refutation of a prior assertion.  Negative findings are expected in this area of science!

The reason we did not find FGF effects in our baboon or mouse studies is not that the FGF genes were uninvolved in head shape during development but that there was no relevant variation in those genes in our particular sample.  Neither of our inbred mouse strains carried variants at those genes that affect head traits.  But they did both use FGF genes in making their own heads, and the intercross animals did, too.

Even if a gene is involved in a trait in a functional way, there is no reason to expect that the same gene varies in a given study at all, or enough to have a detectable effect.  Indeed, sometimes such genes are so central that they aren't free to vary without deleterious or fatal consequences.  It's one of the problems of mapping that it is not a direct search for function. Instead it is just a search for variation that may lead us to function. If by bad luck our sample has no variation in a particular gene, it can't lead us to those genes by case-control kinds of statistical comparisons.

Dang it!  Despite how important and under-appreciated these points are, this means that our negative findings aren't really negative and won't be of any interest to the Times. 

However, this doesn't mean that mindless GWASing is OK after all.  We've explained our view on this many times before.

But it does mean we need to contact the Editor at People.

Leafing through Nature or, How does development work?

We have some mature oak trees in our yard.  Last week, the winds and rain associated with the hurricane blew down googles of leaves, blanketing our yard (and we've already raked 3 times!).  But looking at the leaf-litter, I noticed the two leaves in the picture below.  Both were from the same tree.  Yep, that's a 1-foot ruler.

 

This isn't actually the tree (can't get a good camera angle on it; plus, we haven't had any snow yet), but the point can be made from this pic I grabbed from the web.  The arrows show, figuratively, that our two leaves, one normal size, one quite huge, fell from different parts of the tree (I had no way to know the exact relationships in the case of the real leaves).

Now, this tree started as a single cell, the embryo in some lucky acorn at least 50 years ago (this tree was already big when we moved here 30 years ago).  How can this same genome generate such massively different leaves?  What this means is that the leaf, the phenotype, cannot be predicted from the genome.

Note in the first picture that the pattern of the leaves is the same, basically the same toothy oaky structure of side growths, with a major vein going into each 'tooth' of the leaf.  But the details vary, which means that except for the basic structure, they too cannot be predicted from the genome.  None of the 23andLess promises, nor those of the Director of NIH, can change this.  Could the difference be due to environment? 

Genes and environments
Now we can at least ask about genes interacting with environments, such as temperature, water supply, sunlight and so on, that can differ in different parts of the tree, so some leaves get better living or growing conditions than others.  Of course, these cannot be predicted from the acorn, so personalized treenomic medicine isn't possible.  But worse, of course, at the acorn stage we don't have any way to know the future of dry and wet seasons, cloudiness, and the like.

And, sorry to say it, but in fact in this case it was not true that the large leaves were all on one side of the tree, and the small leaves from elsewhere on it.  Before they fell, the leaf sizes were distributed across the tree.  So nothing so simple, from what we know to measure at least, could account for this.

So in a way this makes such predictions essentially impossible, even in principle.  The solo genome of the acorn is not a predictor of more than the general features of the tree:  its overall branching and root structure, general shapes of its leaves, types of flowers and flowering time, nature of its bark--that sort of generic oakiness.  We could tell it will not grow to be a hemlock or a maple!

Explaining the similarities
But there are ways to account for the major aspects of similarity between these two very different leaves.  Those are the general principles of organization, gene action, and development, that we refer to as 'cooperation' among interacting factors--genes, signal molecules, cell surface receptors, cells, and so on.  In the book MT, we describe various processes that are driven by genes but not contained within any gene.  These processes of interaction involve timing effects, branching, and differentiation among cells.  That for example is how the veins branch and growth occurs along them in a leaf.

Now, there are still vastly different cell-distances in the two leaves shown above.  So how can the same genome, even with these process characteristics, generate them both?  One likely answer is that each leaf develops its basic structure--and the basic cell commitment to specific gene expression, when the baby leaf is very small.  Once these things are pre-set, rates of growth can, in principle at least, lead to different numbers of cells in each stage, between each branching event, etc.  Environmental factors can control these rates.

The idea: differentiate very early when the embryo is very small, and let the cells retain their gene-expression characteristics with them as they individually grow.

Still, it's very interesting how this can happen, the flexibility so to speak of what a single genome can do.  Or was it a single genome?

But do the leaves have the same genome, after all?
We say all the leaves in this one tree descend from a single acorn, a single cell with its copies of the Oak genome.  But in fact some mutations occur in every cell division. If they kill the cell, then it has no further bearing on what happens from then on.  But millions if not billions of cell divisions take place from the time the acorn begins to grow and the countless distant meristems that result and from which leaves and flowers grow.  That can be compared to the number of different parent-offspring transmissions that have occurred in the history of the human species.  It means that no two cells actually have the identical genome.  The meristem cells, long separated from common ancestry, are different in a general way as are any two humans.

Most of the genomes are very similar and most mutations have no real effect, but some may, or must.  So it could be that some leaves, or some branches, really are genetically different from each other in ways relevant to things like leaf size.  Maybe that's the reason (with or without additional environmental effects) for this huge difference. 

Personalized tree-nomic medicine, not!
 Could this be predicted in any specific way from the sequence of the genome that preceded the entire leaf?  It's doubtful, because it would be hard to get such a cell, and of course we'd have to do it for thousands of leaves on the same tree to understand the pattern, if any.  Personalized prediction of such small, later-age effects, can surely not be made from the acorn. Yet that is exactly what is promised for humans, relative to late-onset disease, being predicted from a person's 'genome'.

This is not wild speculation.  Your body differs locally in terms of where hairs are located, freckles, age spots, and many other details, for similar reasons--differences arising among your cells during your life.  Mostly they make no difference but if they lead a cell to start dividing too fast, they do matter, and it's called cancer.

So much to contemplate, even while you're just raking your lawn.....

Getting hip about hips

Holly Dunsworth's recent paper and very fine posts here on MT ( the lead-in, the story, what it means for your pregnancy, and cultural and philosophical implications) skillfully discussed important issues about the kinds of explanations people offer for various of our traits.  One of the most subtle, and important, was her explanation of the fact that there can be variation among individuals around a species' characteristic trait (which she discusses here).

In this case, as she pointed out, not all women have the same gestation length, there is variation in metabolism within species, and so on.  Yet, there are general characteristics of a given species that differ from the similar trait in other species.  In other words, the trait is not rigidly fixed, and variation within species and species differences can both be consistent with the same general accounting for the trait.

One way to account for this is to consider the genetic basis of what we call metabolism.  Metabolism, like many if not most traits, is the result of many different processes taking place, and these are brought about by the action of many different genes (often hundreds of them), reacting to conditions in the environment. In this case, those conditions involve diet, type and level of activity, perhaps climate and more.

Different environmental experiences can add variation to a trait like metabolic activity and so on, modifying the exact trait value--like days of gestation for an individual fetus.  Random effects (chance) also almost always plays a role, since no two humans are identical.  Similarly, all the contributing genes, and the regulation of their timing and level of expression, are subject to mutation and vary among individuals.

Successful gestation and maternal survival and infant care can be affected by this genetic variation and for obvious reasons the selective effects can be brutally stark.  Maternal or fetal mortality are huge potential fitness effects.  So there is no doubt that gestation and delivery can be under strong natural selection.  However, that doesn't mean selection favoring one precise direction or trait, or one gene.

Most selection will basically strongly affect women or fetuses who do not 'behave' successfully enough to be born.  But each instance will involve different genotypes, and the selection affecting any given variant in a given gene will likely be very small.  The distribution of the trait in the population--such as hip-width or gestation length--will have some mean (average) value and some amount of variation.  These can change gradually over time, or tend to hover around some rather stable values.

If selection occurs for some other functions that may involve the trait (that is, something about the skeleton or diet and metabolism) distribution of the trait can change.  If this were to happen differently in isolated populations, they will diverge and eventually become different species.  Even just chance meandering of the trait values could leave them different between species.

As a result, each species will have its own mean trait value, while individuals within the species can vary.  This is, I think, just the pattern Holly was describing in her recent post.  It is largely the consequence of causal complexity.  This is not a yes/no, Mendelian pea-like kind of trait in which there are only 2 or 3 states in the population, one of which is favored and the other lethal, so that different species evolve to have only one or the other variant.  It's the result of many different contributing factors.

And this, naturally, ties into the whole issue of the complex nature of genetics underlying traits that, like the ones considered here, are not just simple.  That's why it is difficult to identify 'the' gene or a few genes 'for' the trait, because that's not how the trait is produced.  And that is the problem with GWAS or other attempts to simplify the basis of what we are or what happens to us.

A bit of a storm

Our post yesterday asking whether support for whole genome sequencing was fading seems to have triggered a bit of a storm.  We know this because our hit count for the day was astronomical (well, for us).  We noticed that a bunch of tweets were sending readers our way, so, naturally enough we thought we'd check out what people were saying about the post on Twitter.  And it was interesting.

Most people, though not all, who made an editorial comment disagreed with us.  And, ok, it's hard to go into detail in 140 characters, but the comments were pretty uninspired, shall we say (along the lines of "Is whole genome sequencing fading? The answer is No!"), but even so, to us, an indication that we'd hit a nerve.  As far as we can tell, the argument is that because sequencing is still being done, it should continue to be. 

This looks to us basically like some serious circling the wagons going on.  People with vested interest in the status quo protecting their interests.  Ok, fair enough, and understandable.  But, this does the science a disservice.  There are serious issues here -- tweeting about how sequencing has to happen because it's happening just doesn't do them justice.

As Ken posted yesterday, writing about why whole genome sequencing hasn't met the promises made about it:

There are too many variants to sort through, the individual signal is too weak, and too many parts of the genome contribute to many if not most traits, for genomes to be all that important--whether for predicting future disease, normal phenotypes like behaviors, or fitness in the face of natural selection.

As he also wrote, there are some traits for which one or a few genes are important, and working those out is where the genetics money should be spent.  Doing whole genome sequencing because we'll surely learn something even if we don't yet know what, or because personalized medicine is just over the horizon, or just because we can, are not good reasons to keep spending the kinds of money on this that we're spending.  We know enough now to know that genomic contributions to most traits are multiple, varied and complex.

This is not an admission of defeat.  This is an acknowledgement that we've learned a lot of genetics in the last century, reinforced clearly by the new sequencing technology; and what we've learned is that most traits are multifactorial, due to gene by gene and/or gene by environment interactions, there are most often many pathways to the same phenotype, and so on.  We should give up the conceit that we're going to be able ubiquitously to predict and prevent diseases based on genomes, and get on with solving problems.  Those that are genetic need genetic approaches.  But there are other issues, and other ways, to learn about evolution, disease, and the basic nature of life.

Random events result in order -- how?

Development is ultimately very organized and predictable -- children look like their parents, legs are generally where they belong, and a lion never gives birth to a whale -- but yet another paper describes the randomness of the processes at the cellular level.  How can this be?

The paper is in the April BioEssays; "Genes at work in random bouts", Alexey Golubev.  Golubev says that things that go on inside cells are generally thought to be determined by the interaction of different molecules, which is itself determined by the concentration of those molecules in the cell.  Ordinary differential equations (ODEs) describing all this can be written, and, Golubev says, "ODE solutions may be consistent with oscillatory and/or switch-like changes in molecule levels and, by inference, in cell conditions."  This begins to make intercellular processes sound determined and law-like.

But, the article is basically about the stochastic (random, or probabilistic) events occurring in cells that affect their gene expression patterns, and hence the cycle between cell divisions or the time it takes the cell to express the genes related to its particular tissue  This variation, the author notes, makes stem cells--cells not committed to just one cell-type--plastic and flexible. 

But, as he points out, the idea of molecular concentrations is only true at the level of populations of cells, not in single cells themselves.  There's a lot of randomness in terms of what's going on in single cells, in cell differentiation and cell proliferation, particularly with respect to when genes are turned on or off, and thus which proteins are available, and what happens when. 

The question becomes, then, given all this stochasticity in cellular activity, how development is so organized.  The apparent problem is that once one reaction has taken place, it affects the next reaction, and this includes hierarchical changes such as changes in gene expression in the cell.  Thus, the cell is not just a mix of things, each in large numbers, that will 'even out' over time.  Differences that can be occasioned by chance in a cell can add up. Of course, if the cell continues to detect the same external conditions, its response may adjust so that things do even out.  But it doesn't need to happen. 

On the other hand, most tissues in most organisms are comprised of many cells of the same type.  Each may be experiencing stochastic changes, but their tissue-specific behavior may usually 'even out' because the variation will be slight and in different directions among the cells, so that on average they are doing the same, appropriate, thing.  In unusual circumstances, if this doesn't happen, the organism may be very different from its peers....or  it may not survive.

This perhaps reflects a fundamental property of populations, known as the 'law of large numbers'.  The theory behind this (Ken was just realizing from reading a book called The Taming of Chance (1990, by Ian Hacking, Cambridge Press)), comes from the study of populations of individually differing individuals, whose aggregate behaviors have regular distributions: the 'normal' or bell-shaped--or at least orderly--distributions of stature, incomes, and so many other things.  In another common phrase, they have 'central tendencies.'  Normal meant that most were near the norm.  This statistical idea was worked out over the 18th and 19th century, and raises interesting questions about causation.  Hacking's book shows how people had to learn that causation was not about precisely fore-ordained laws, but about probabilities, and that this applied to society.

The classic cases had to do with things like suicide.  One can't predict who will commit suicide in a given year, or by what means.  But the numbers, and the number who do it by each method, are very similar from year to year in a given population.  Likewise, the life expectancy is an average, and nobody lives exactly that long: some die younger, some older.  So are many social facts like political affiliations and so on.

Why is this?  It is the net, end result of many different individuals each with slightly varying characteristics.  There were many explanations of why this was, that are beyond this post, but in essence there are many contributing factors of diverse kinds, that mostly aren't known, so that a few individuals are exposed to many, others to only a few, but most of us to some 'average' amount of these factors.  The fraction exposed to many such factors is the fraction of individuals who are taller, more intelligent, ...., or who commit suicide.

The law of large numbers is a statistical fact that can be proven mathematically under rather general conditions.  This leads to central tendencies.  That is why population statistics took on a central role in social sciences, where often the underlying causal factors and their specific effects are unknown or hard to estimate accurately.  Social sciences can 'understand' society--at least predict some things about it--without understanding causation in the strict sense.  And in some situations, these things don't work very well--economics is one, in which stability of population outcomes occasionally, at least, takes a quick left-turn.

Probably the same applies to the populations of cells that make up a tissue, and if so this would make the high amount of probabilistic events in cells that would make each cell different, which can lead to a central tendency for the kidney to filter blood is similar ways, and so on.  Because of local differences among cells, different genotypes, and different life-experiences, kidney functions differ among people.  Some are at the extremes and we call that 'disease', but most are roughly near the norm.

Biologists routinely speak of chance, but often act as if they believe that genes 'determine' the organisms the way a program determines what a computer does.  They know about variation in populations, and how, for example, polygenic traits like stature or blood pressure (the darlings of the GWAS world) vary, even if they are driven to enumerate all the underlying causes that vary among individuals in the population.  In a sense, the population concept applied to tissue is of the same sort, and provides another source of variation between genotype and trait.

Mendelian Inheritance: Basic Genetics or Basic Mistake? Part II.

The idea of Mendelian inheritance, revered for more than a century, was initially about the inherently causal nature of dominance and recessiveness.  The A allele always and,  presumably, inherently, made its effects manifest, as in the accompanying figure.  Even as late as 1995, an influential paper termed this 'physiological' dominance.

But why so long after Mendel's rules were deeply established, was there a need for such a term?

In the genetics of quantitative traits, one can look at the average trait value (say, stature or body fat content of pigs or oil content of corn) in AA's and aa's.  If the 'A' were physiologically dominant, then the Aa's should have the same mean value as the AA's.  These are clearly statistical statements because unlike green vs yellow peas, there is variation and there are sampling issues (in fact, even Mendel's classical traits had some variation, but little overlap between dominant and recessive plants).

What transpires as a rule, however, is that the Aa's are not exactly like the AA's.  But a common alternative to Mendelian ideas was that rather than being dominant and recessive, the contributions of the alleles at a gene were additive, like doses of medicine:  Each copy of, say, an A allele you have, is a jump in your trait value.  In such situations, Aa's would be exactly intermediate between AA's and aa's.  If instead they shift towards one of the two homozygote (AA or aa) individuals, this is called statistical dominance.

Unlike physiological dominance, statistical dominance has to be evaluated by sampling from a population, and that means in turn that the idea of estimating the net or 'actual' effects of the A and a alleles, depends on the frequencies of these in the population, and more importantly, that also means that environmental and other genomic effects will affect the mean values of the carriers of the 3 genotypes.  Statistical geneticists now treat these two kinds of dominance differently, often ignoring the physiological because it is hard to identify in real-world situations of quantitatively variable traits, as opposed to experimental settings with only two clear states, that have been part of genetics ever since Mendel himself.

We can relate  this to GWAS findings a simple way.  If a given allele is common enough in cases for its effects to be found and reach statistical significance, relative to its frequency in controls, then it has a chance to be detected in a GWAS study.  But this depends on its penetrance, that is, on the strength of its effects, on their own, on a trait measure like stature or blood pressure, or on the presence of a disease.  Highly penetrant alleles will be found more frequently in cases than controls because they have a higher chance of 'causing' the trait.  The greater the effect, the more likely if you have the allele you have the disease.

This is a kind of 'dominance', because the allele is being detected against the other allele at that gene in individuals, plus whatever other relevant variants they have in their genome. That typically only a few genes are identified in this way shows how relatively rare real dominance is--how far it is from being the baseline, basic nature of inheritance!  In fact, most variants that contribute contribute so little--have so little 'dominance' in this context--that we simply cannot detect their individual effects (or those effects are not enough to generate a statistically 'significant' association with the trait).  So, dominance is far from the general rule.  We will see in the next installment why this should not be any kind of surprise.

Kissing cousins

Well, the latest episode of Our European Cousins has aired. Svante Paabo, who if anything knows how to play each side of the street as long as there are cameras there, has announced now that 1-4% of the modern human genome is derived by admixture with Neanderthals. In the past, he was comparably insistent in headlining that Neandertals had not admixed and were a dead lineage.

The paper reported in the news (on the BBC website, e.g.) appears in Science's new issue. Make no mistake, it's a good and important piece of work, long promised and finally arrived. It is a sequence of roughly the entire Neandertal genome compared to five available whole-genome sequences from modern humans. Getting and assembling anything close to a whole genome sequence from fragmentary bits in fossils, contaminated with DNA from other things such as bacteria in the earth where the individual fell thousands of years ago, is no easy task and Paabo's group has been one of the global leaders. Studies of ancient DNA are important because they provide direct evidence of the past, so where DNA is preserved it will remain valuable to sequence and interpret it.

One thing to note, that seems like double-think, but is not relevant to the points we want to make here, is that this Neandertal whole genome sequence is not the whole genome sequence of a Neandertal. This sequence is a composite assembled from ancient DNA extracted from three different individual Neandertals' remains. But 'the' human genome sequence online at GenBank is also a composite. Some technical issues are affected by this, but they aren't relevant here.

Whatever the details of the assembly, or whether variation among Neandertals was observed, the issue here is the origin of modern human sequences: did any of it descend directly from Neandertals, or were they an entirely separate group (or species, even) that separated from the common human stock and had no subsequent inter-breeding. That is, we today would have no descent directly from the Neandertals. Or was there some inter-group hanky-panky?

The new paper suggests that there was, but there are two major problems with that. The 1-4% are in segments that seem to have a different ancestry from the rest of the Neandertal genome, less divergent from us. The rest diverges from us by about the amount you'd expect given our joint time of separation from our common ancestry with chimpanzees.

The first problem is one we harp on regularly, the playing to the media and exaggeration of the results. In this case, the exaggeration was the definitive way the admixture issue was made melodramatic and definitive. It suggests that interbreeding was something exotic or immoral, like a human mating with a chimp, rather than what at the time would have been considered routine mate choice among individuals from neighboring groups.

They would probably have coexisted together in times when nobody moved very far, and would have differed from each other far less than, say, Africans and Europeans do today, and between whom mating is thankfully no longer a big deal in our society. In fact, the evidence reported is that this interbreeding occurred after both groups were part of the Eurasian population after its expansion out of Africa. In that sense, the groups may have diverged somewhat, and come in contact again later, and became good neighbors for a while. Whatever happened way back then involves our ancestry which is certainly interesting and worth knowing. But when the evidence is tentative so should be the claims.

But there is a second and much more important problem. It is a subtle issue, that in essence is that whether or not any direct human genetic ancestry traces back through Neanderthals basically doesn't matter related to how 'different' we are from them. In round numbers, here's why:

A copy of your genome and a copy of a chimp's (our nearest living relative) differ by about 2 to 5% in terms of DNA sequence. Two copies of the human genome today differ by about 0.1 to 2% depending on the comparison one makes.

We've been separated from our common ancestor by 7-10 million years. Corresponding to that, the paper shows that the Neandertals differ from modern humans by about 7% which is about what you'd expect given that (regardless of admixture issues) the Neandertal split happened only after about 90-95% of the time had passed since we and chimps split.

By that time, basically everybody was human, and in turn that means that overall we are essentially as similar to Neandertals as we are to each other (crudely speaking, we're 95% closer to them than to chimps). And of course the vast majority of sequence differences generally, and hence in this case, will have little if any function. If humans are virtually identical to each other then we are virtually identical to Neanderthals whether there was any inter-mixing or not.

But consider how much functionally meaningful (as opposed to evolutionary clock-meaningful) variation there is in modern humans around the world. Within our single species, there's plenty of room for differences, and they can be important. They can protect you in very important ways from the environment (as skin pigmentation does in the tropics), they can protect you from disease (as immunological differences among us do), and there is a lot of variation in behavioral abilities of all sorts. As many diseases show, even just one single DNA change can be lethal.

The point is that whatever important functional differences or similarities there were between us and Neanderthals need have nothing to do with whether there was any admixture between their populations and populations of our other direct ancestors. Natural selection will purge bad variation, favor sterling advantages, and ignore most of the rest wherever it comes from.

If there is major functional difference between us and our burly cousins, it is to be found in the relevant genes, not in the score card (or dance card) of our sequence differences. And they could have existed in them then, but not us now, even if there was inter-breeding.

This means that Dr Paabo is right to treat this as a story for publicity. Its scientific impact is far less than its human interest value. To portray the inter-mixing question as an important one about human function is to misrepresent (or misunderstand?) how genes and evolution work. But to understand that takes more than a sound byte, and of course that means not many people will be interested.

At the same time, there's nothing wrong with trying to find out, especially from direct genetic data when it's available, what we can about our closest, if dearly departed, ancestors.

The moveable feast of madness

There was an interesting story in the New York Times on Jan 8 called "The Americanization of Mental Illness," that we are just now getting around to blogging about.  It turns out that mental illness varies by time and place. One culture's madness is completely unknown in another.

In some Southeast Asian cultures, men have been known to experience what is called amok, an episode of murderous rage followed by amnesia; men in the region also suffer from koro, which is characterized by the debilitating certainty that their genitals are retracting into their bodies.

Schizophrenia takes a different course in different cultures, being more severe in the US than in other cultures.  The symptoms of what we in the US know as anorexia nervosa -- an obsession with weight and dieting and a view of one's body as fatter than it actually is -- were, until recently, very different in Hong Kong, where anorexic patients primarily complained of bloated stomachs. In the 1990s, however, the symptoms began to mimic the more profound American disease.  And so on.

Thus,

[f]or more than a generation now, we in the West have aggressively spread our modern knowledge of mental illness around the world. We have done this in the name of science, believing that our approaches reveal the biological basis of psychic suffering and dispel prescientific myths and harmful stigma. There is now good evidence to suggest that in the process of teaching the rest of the world to think like us, we’ve been exporting our Western “symptom repertoire” as well. That is, we’ve been changing not only the treatments but also the expression of mental illness in other cultures. Indeed, a handful of mental-health disorders — depression, post-traumatic stress disorder and anorexia among them — now appear to be spreading across cultures with the speed of contagious diseases. These symptom clusters are becoming the lingua franca of human suffering, replacing indigenous forms of mental illness.

And yet, we in the West have been looking for decades for the genes 'for' mental illnesses such as schizophrenia and depression. The searches, as we've written here numerous times, have been essentially fruitless. In part this has been because it has been so difficult to know how to to define the traits so that a study population convincingly has the same disease. But now it seems that much of the difficulty may be that these diseases are products of a particular time in a particular culture, not 'simple' genetic traits like cystic fibrosis or Tay Sachs disease, in which the biological consequences of the causative mutation are clear.

Unless someone wants to argue the unrelenting geneticistic view that Asians have different mental illnesses -- of the extent and type described above -- because they are genetically different. That's possible in principle, though almost impossible to disentangle from culture, geography, and history. However, there are three strong counter arguments, and some supported by actual data. First, there are secular (time) trends in these kinds of traits, that become more common or more rare within lifetimes within a culture.

Second, many classical migrant studies have been done that show that, to a great extent, migrants adopt the characteristics of their new home population. Clearly-genetic traits like facial appearance may not change, and unless largely environmental, cannot change so fast. But culturally-based traits can, and they do. The formal studies largely have to do with disease, but anyone with eyes can see the extent to which second and third generation immigrants adopt all aspects of their local culture that their conservative parents can't prevent.

The third argument is the manifest way in which culture, including in this case ideas of behavioral traits including disease, spreads around the world these days, and so quickly that we know they're not due to genetic change.

There are many profound, if uncomfortable implications. We know what the problem is, but in the absence of a Lone Ranger with a magic silver bullet better idea, we cling to old beliefs or wishful thinking.

For example, does its moveable feast-ness imply that mental illness isn't a biological trait? Not at all. It 'simply' means that there is a much more complex interaction between culture and biology than geneticists are allowing for. And that genetic characteristics are not pre-wiring for specific behaviors, but may be more probabilistically likely to be manifest in various types of environment. This is why most deterministic stories about the genetics of behavior are basically Just-So stories. Once you throw in human culture, all bets about the rules of the game are off. Overall, humans are a constant, relative to variation in culture. But we vary a lot biologically, too.

Biological variation is not a good predictor, in most cases, of specific traits. This is just what the most successful, and thoughtful new GWAS kinds of analysis are also finding about disease -- even without considering the globally varying and changing cultural landscape.