Novel mutations = novel conclusions?

As reported in the NYT, the results of three new studies, published (here, here, and here) this week in Nature on the genetics of autism has found novel gene mutations that might explain risk as well as evidence that risk increases with the age of the father.  From the Sanders et al. paper:

Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.

It explains risk in only a very small fraction of cases.  Though, Sander et al. suggest that the model may well be useful for explaining many more. As the Times story says:

Experts said the new research gave scientists something they had not had: a clear strategy for building some understanding of the disease’s biological basis.

And,

An intensified search for rare mutations could turn up enough of these to account for 15 percent to 20 percent of all autism cases, some experts say, and allow researchers a chance to see patterns and some possible mechanisms to explain what goes awry. 

This would be great, of course.  Any clues to the bigger picture could be extremely helpful.  However, if autism is like every other complex disorder, a finding that's true at one extreme of the distribution of the phenotype will not necessarily apply to any other part of the distribution.  There are high shared fractions of the genome among relatives, usually many coding changes, too.  So it is going to be difficult to 'prove' that the change observed really is causal. Exome sequence assumes coding changes and in a way is vulnerable to identifying a coding change and assuming it's causal, when regulatory changes are not in the search space; is this the drunk looking for his keys under the lamplight?

Indeed, as O'Roak et al. conclude,

Although there is no one major genetic lesion responsible for ASD, it is still largely unknown whether there are subsets of individuals with a common or strongly related molecular aetiology and how large these subsets are likely to be.

O'Roak et al. identified novel mutations in sporadic, non-familial cases, and characterized them as to their severity and type, and they also identified pathways that the affected genes might share.  They conclude that there are likely to be from hundreds to over a thousand genes associated with autism: "Our analysis predicts extreme locus heterogeneity underlying the genetic aetiology of autism."

Of course there must be 'networks', and all of this kind of rhetoric sounds impressive but really is post-facto and in a sense superficial.  Genes interact with other genes, not just in terms of protein-protein interactions but also related to expression level (not assayable by exome sequencing).  So saying that there are hundreds of genes in networks is to some extent big-words to acknowledge that we may find this or that component, but this trait is simply not simple.

Neale et al. report, "Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold."  Again, other functional elements in DNA that greatly outnumber the protein-coding parts, are likely to be at least as important.  Indeed, there are findings that 1% or more of autism is due to copy number variation, which may overall swamp the rare variants in importance, if the results hold up.

Each of these studies looked at a subset of the study population -- because autism is such a wide spectrum of disorders, it's important to reduce possible genetic heterogeneity by narrowing the phenotype in any study -- and found novel, or sporadic mutations to be associated with risk.  Because the idea that new mutations, which we all carry a substantial number of, might be causative can't help predict who is at risk, the hope is that if these mutations are indeed associated with risk, they might give some clues as to which developmental pathways are affected in this disorder.  The hope has been for years that genes for autism will be identified. Now that it's looking like this is a polygenic disorder, if indeed genes are a primary cause, and that sporadic mutations might be significant, it's looking more and more likely that those who have long said that major genes that can predict the disorder will not be found have been right.

The Times quotes a well-known population geneticist on this work:

“This is a great beginning, and I’m impressed with the work, but we don’t know the cause of these rare mutations, or even their levels in the general population,” said Dr. Aravinda Chakravarti of the Institute of Genetic Medicine at the Johns Hopkins University Medical School, who was not involved in the studies. “I’m not saying it’s not worth it to follow up these findings, but I am saying it’s going to be a hard slog.”

If these new results can in fact lead to understanding what goes awry in the developing brain to lead to autism, great.  Whether this will ever be clinically significant is another matter.  And one needs to remember that autism is by far mainly environmentally caused!  The report last week that its prevalence has increased by 78% in the past decade alone shows that this is about environments (that increase is unlikely to all be due to changing definitions of the disorder, or changes in diagnostic practices).  Well, a determined geneticist will argue that rapid environmental change could, in principle, have led to higher disease risk by triggering big responses in a few common genetic variants interacting with the environment.  Not so! We've had he environmental change (whatever it is), and ASD is clearly not due to one or two major genes responding to that change.

The same arguments apply to excessively exuberant claims implying simple genetic adaptation due to natural selection, and for the same reasons.

If biomedical research is about doing something about autism, rather than about forcing genetic thinking onto the problem, we're looking under the wrong lamp-post!

Will there be an exam in this course (of treatment)?

Perhaps you saw the news yesterday that all those medical tests that were supposed to be so important for our health now aren't?  This is the slippery slope of 'evidence-based medicine' -- it leads to recommendations based on evidence!  Which, if the panel recommending this is right, and it consists of nine medical specialty boards (Internists, Nephrologists and so on), will lead to less unnecessary medical expenditure in the US, and equal or better health outcomes.

The initiative is called "Choosing Wisely", and each of the medical boards involved in this initiative (and more are slated to join in the fall) proposes a list of "Five Things Physicians and Patients Should Question", and you can find those lists here. The lists are aimed at encouraging physicians and patients to choose care that is "Supported by evidence, Not duplicative of other tests or procedures already received, Free from harm, Truly necessary." 

These aims are pretty basic and even obvious, don't you think?  Indeed, why invoke them so late in the game?  As the New York Times story says,

The recommendations represent an unusually frank acknowledgment by physicians that many profitable tests and procedures are performed unnecessarily and may harm patients. By some estimates, unnecessary treatment constitutes one-third of medical spending in the United States.

You know that, just as when limits were proposed for prostate and breast cancer screening several years ago, many will protest this as health care rationing, which we don't accept in America (unless, of course, it's rationing by ability to pay, which is completely acceptable, because who in this country cares about people poorer than themselves?).  There truly are limited medical care dollars, and decisions do have to be made about how to spend them.  If unnecessary but costly testing is curtailed, physicians, equipment companies, testing centers, anyone who now profits from these tests, stand to lose.

But, insurers call the shots, and if they are beginning to refuse to pay for these tests, the way medicine is practiced has to change.  Okay.  We all know our medical system is profit-driven, and decisions get made based on the bottom-line.  And, as a result, we all know horror stories -- the woman who was sent home from the hospital 3 hours after a double mastectomy, insurance companies refusing to pay for emergency room visits for emergency treatment, and so on, decisions based on optimizing the bottom line rather than clinical outcome.

We also do know, of course, that our noble peers in the legal profession are crouched, ready to pounce, in the way of lucrative malpractice suits.  And what that understandably does to doctors and their decisions.  And the role of testing by doctors who have ownership in testing facilities.

But, the idea of basing these recommendations on evidence is interesting, even if it's only part of the story.  High tech medicine is, well, technology-driven.  It's clear from the lists of tests that this initiative now says physicians should no longer routinely order that the results are often not definitive, and don't change clinical practice or outcome.  So why did they become routine?  It's profit, hand in hand with the legal department.  When the salesman comes around with some new toy, at a hefty price tag, it is difficult to resist the undoubted statement that "this will enable far better diagnosis and care for your patients", and will put you ahead of your peers who only have last-year's model.....

But why are these tests, developed by very smart, highly skilled engineers, not definitive?  Because of something we write about here on MT all the time -- causation is complex.  And if you don't know what you're looking for, or what your findings mean, if anything, no matter how many tests you do you're not going to affect the outcome.  And despite the best science, societal vested interests (demanding patients, mediocre doctors, malpractice risks, profit motives, issues related to 'evidence based' decisions, and so on) come into play.

So while we like to think of medicine as a fine technical science, in many ways the complexity of the causal landscape as well as societal issues have largely become the defining factors in clinical outcomes.  Science is one consideration, but given the realities, not the only and perhaps often not even the main one.

The Big Scientist Theory of Science

Samson, alpha male gorilla in Givskud Zoo

The Great, or Big Man Theory of History posits that the course of history is determined by the ways in which powerful men use their power.  Thus, history can be explained simply by understanding the men who made it.  This idea was first bruited about by the Scottish historian, Thomas Carlyle, in the 1840's ("The history of the world is but the biography of great men").   The opposite view, that society makes great men (or, makes men great), was proposed by Herbert Spencer in the mid-1800's.  And one of the most famous novels in history, War and Peace, was Tolstoy's attempt to show that the Big Man theory was wrong.  Neither view has won out, both still have their proponents.

Here we propose the Big Man Theory of Science.  Or, let's call it the Big Scientist Theory so as not to exclude women.  Perhaps in a Spencerian world, science would advance from discovery to discovery, going where the natural world takes it. The peer review system, oversight by governing bodies, and so on do, in theory, ensure that this is more or less the way science moves forward.  The tide of progress would sweep all along in its path.

But in a Carlylean world, science advances as scientists with big names and lots of money or political influence wish it to.  A scientist made a discovery, got famous, got awards, and that brought more awards.  Now Big Scientist writes visionary papers paving the way forward, makes decisions about where grant money goes, and more insidiously perhaps, but with just as much impact, makes decisions about what lesser scientists can say in their publications, s/he doesn't cite publications by lesser scientists questioning his or her work. 

Big Scientists determine the nature of the grant applications that will be written and funded for some time to come, they determine where the technological and academic investments are going to go, and so on.  They have labs full of DNA sequencers, but the human genome has been sequenced?  The next big scientific endeavor must require their use.  Big Scientist even tells people s/he knows that what s/he is proposing isn't good science, but it has to be done because the grant money must keep coming.  And science and large numbers of scientists follow, because everyone has to follow the money.

When it comes to the media, they first call the Big Scientist.  S/he then gets to expound on this or that, which again serves to set the agenda for the future, and importantly (or mainly) for future research investment.  With few if any exceptions, the Big Scientist advocates an agenda that just so happens to involve things that fit his/her interests and lab needs.
 
These are subtle and not so subtle ways that specific interests are perpetuated, and this engenders conflicts of interest that turn out to be comfortably in keeping with how science works today.  It is not a utopian vision of how things should be done, but it is the reality.  Probably in the very long run, though, it doesn't matter -- important progress will eventually be made.  Scientific ideas can outlive their sell-by date, replaced by better ideas.  But in the short and medium (and sometimes long) run, fads and influence control the momentum as Big Science run by Big Scientists turns out to be good primarily for Big Scientists.

These considerations are about science, but they are also a part of science.  Objectivity of neutral observers trying their best to falsify their ideas, is about as much a fairy tale as you'll ever hear.

Anything goes -- the soft sciences abandon any pretense of method

A piece in the Sunday New York Times, called "Overcoming 'Physics Envy'", by Kevin Clarke and David Primo, political scientists at Rochester, addresses the question of whether the social sciences are in fact science.   

Economists, political scientists and sociologists have long suffered from an academic inferiority complex: physics envy. They often feel that their disciplines should be on a par with the “real” sciences and self-consciously model their work on them, using language (“theory,” “experiment,” “law”) evocative of physics and chemistry.

What makes a field 'science'?  It turns out that following the scientific method makes it science -- proposing a model, devising a hypothesis and testing it.  Called hypothetico-deductivism, it's the approach that the National Science Foundation has touted in a big way in the last decade.

But Clarke and Primo no longer accept that this is the way to do social science.  Economists, political scientists and psychologists no longer have to pretend to be physicists to do their work.  They've matured into their own way of being. And anyway, the hard scientists don't even really follow their own method, so why should the soft ones?  So, now it's ok to think up models and put them out there, unsupported by any empirical data.  And, conversely, it's ok to have data without a theory (which sounds suspiciously close to the current genetic model of non-hypothesis driven science).  So, say Clarke and Primo, "social scientists would be better off doing what they do best: thinking deeply about what prompts human beings to behave the way they do."

This is fascinating.  The point of having an agreed upon method or approach to understanding a particular corner of the world is to standardize the assessment of cause and effect.  What's the point of the social sciences?  To explain why people behave as they do?  To predict future behaviors?  While it's perfectly clear that economics, political science and psychology don't adequately fulfill either of those goals as currently practiced, it's also true that abandoning any pretense of a method won't do it either. Is this basically an acknowledgement that these fields haven't accomplished what they've set out to accomplish?  And can't?  

We frequently make the point that the hard science of genetics should be held responsible for its claims and for how grant money is spent.  The same of course should be true for the soft sciences.  When hundreds of millions of tax dollars are happily spent every year by people who claim they'll give us something for it, shouldn't they be required to show that they have?  A publication count doesn't do it.  The idea that we should now be paying people to "think deeply" -- and that should be based on what criteria, political viewpoint, or foundation of knowledge, all of which will make a difference? -- is frightening. At least when the philosopher of science, Paul Feyerabend, said "Anything goes" with respect to the scientific method and what science can offer, this was based on an honest assessment of the possibilities.

Evolutionary biology has the flexibility of social science in that because evolutionary processes, like those in society, are statistical reflections of distributions of behaviors and traits, almost anything can be fit into its overall theory.  That is the power of the Darwinian method, and its weakness.  Likewise, the statistical nature of social processes does not lead to very precise predictions, and anything once observed can be 'explained' by free-wheeling retro-hypotheses.

Nobody can seriously claim that our society is now in good social or psychological health because of research in the social sciences, whatever their successes.  It can't get any better if the future is "thinking deeply".

Ho hum, you're SO close to average!

So a new study confirms (we would claim) what we have been saying for many years,  repeatedly on MT, and in print before it was popular to say it:  Personalized genotyping is not going to be very useful in predicting disease.

The new story in Science shows from twin data--how close can you get!--that overall, individualized prediction of disease is not much different from saying 'you're average'.  Being just like everybody else is not a nice way to feel, but it is what is expected in this kind of situation.  Identical twins are far from identical in terms of their life expectancy of disease history.

Still, appropriate as this story is in refuting the blatantly self-interested claims of many parties in the discussion these days, a Times report of it is also very misleading.  They don't point out the issue.  Neither do the authors of the original paper.

The idea of the twin study is, like heritability studies, that if you look at the whole genome, integrating whatever information it contains, the overall predictive power is slight.  That's essentially because a multitude of minor-effect variants may contribute to risk but individually too little to identify statistically by themselves.  So you look at the aggregate.  But even there, the predictive power is slight.

This is not new!  It's been shown in twin studies before (without having genotype data) and in mouse studies with or without such data.  And it makes sense.

But this does not mean that personalized genotyping is useless.  There are known genes in  which specific mutations confer clearly higher-than-average risk of a given disease (and, should anyone look for them, there must be protective variants as well).

Most twins would receive negative personalized genome tests (that is, reports of risk alleles for what the twin got).  But this doesn't take away from the finding, also long known, that specific high-risk variants with mainly single-gene effects (e.g., cystic fibrosis, some breast cancer variants, etc.) are detectable by genome tests and are useful.

The bottom line:  unless you have such single-gene disorders in your family, generally speaking, skip the test--and the McFood. And if you're worried, go take a walk.

News of the Century: Genes Prove Einstein wrong, change faster than neutrinos!

Why bother arguing whether the speed of a neutrino is faster than the supposed upper limit to speed, that of light?  The measurements are so delicate that nanosecond discrepancies can be very difficult to interpret or, more accurately, a theory so well established (deeply entrenched?) as Einstein's theory of relativity will not be overthrown on such scant evidence.  But don't even bother, because we now have the desired falsification, and surprisingly it comes from genetics!

A new report shows (well, says) that the rate of autism is nearly 80% higher than it was a decade ago. That is rather dramatic, perhaps astonishing if you believe the data are disgnostically accurate rather than that it's due to diagnostic changes or predilections to cause behavioral variation 'autism'.  This is of course disturbing, as it shows some serious issues and that we have a major therapeutic, educational, or other kind of burden to bear to help the affected kids and their families.

But that's only part of the story.  Since our research establishment is so committed to the idea that everything, including how you vote and whether you like to be abused as a child, is genetic, and that autism must, simply must, be seriously genetic, the implications of this change in disease risk are widespread.  Indeed, if this is all true, the presumed genetic basis of autism must have evolved faster than evolution makes possible. Faster than parent-offspring transmission and natural selection!  That implies, believe it or not, non-material transmission of genetic variation and its non-material (in the 'ether' that physicists thought they'd long ago shown doesn't exist) changes in the genes and their frequency, while they are literally disembodied before being reinserted into people before they reproduce.

This disembodied evolution changes things faster than neutrinos fly under the Alps from Switzerland to Italy, and shows that even Einstein's laws are wrong!

When is a trait a trait?
It may seem obvious that an organism has various traits, and these must therefore have a genetic basis and, furthermore, must have evolved by natural selection screening on the traits (and hence molding the underlying genetic basis).  But this is not an accurate way to view the living world.

A human trait like autism illustrates the point.  If we screen more intensely, or set up new diagnostic criteria, or if there are reasons that autistic children qualify for special educational assistance, or we invent new imaging or biochemical measures of brain function that are used to specify a trait, then what is changing is the trait itself!  That's because the trait is to this extent in our minds, not inherently in the individuals.  Autism today is not autism yesterday.

In that case, the genetic basis will change and no neutrinos need be involved.  Because if we categorize or measure something differently, there is every reason to expect it has a different underlying genetic architecture.  Eyes are made by different genes than fingers, but if we re-name 'eyes' in a way that includes what used to be called fingers, we have to expect genetic associations to change.  Likewise if we rename what 'autism' is.

Even natural selection doesn't see 'traits' per se, but only is reflected in reproductive success.  We may care about, say, running speeds of rabbits and foxes, but nature 'cares' only about rabbits that escape and foxes that get dinner, and hence live to reproduce.  Running--something we define and measure--may or may not be part of the selection.  But if we choose to study the genetic basis of escape or pursuit speed, we can ask questions about its evolution.  But that's different from knowing that the us-defined trait is what in some trait-specific sense caused an us-defined adaptation, or vice versa.

An alternative explanation
It is, of course, possible that we've misinterpreted and that all that's really happened is something in the environment, including diagnostic definitions and screening intensity or other reasons people may look for, or look more intensely for, autism.  In that case, autism then isn't really the same as autism now, so the principles of materialistic genetics haven't really been violated.  That's less exciting, but more likely....and raises an important principle.

So why the insistence on intense genetic approaches?
One can ask why we keep pouring money into genetic studies like GWAS and related high-throughput but hypothesis-free 'omics' approaches.  One answer often given by geneticists is that they are, after all, geneticists and that's what they do.  Another favorite of epidemiologists is that once we identify the genes, we can treat them as fixed risk factors and correct for them (statistically) in searching for the important causes, which are environmental.  Whether you find these explanations adequate or think there may be other motivation behind them is your diagnosis.

But one defense of genetics over everything else is that when something changes faster than a speeding neutrino, it must be because there are common underlying variants with large response effects to the environmental changes.  So if we identify those genes we can....remove the environmental trigger so we don't have to identify those genes.  But a lot of experience and intense studies suggest this is just not the case, and is more wishful thinking or scientific momentum-preserving.

Normal traits like stature, obesity, and blood pressure that aren't diseases, as well as many complex diseases like diabetes, and hypertension, and asthma and numerous others have risen in frequency very rapidly during past decades.  They should have these same characteristics of common-variants responding in a big way to rapid, major environmental change, if that explanation is correct. These traits have been GWAS'ed to death, so to speak, and not only do we have the hyped-up issue of 'hidden heritability' (family risk not identified by GWAS studies), but we also clearly find that a few common variants with big effects simply do not explain these diseases.  So applying this it-must-be-major-genes argument to autism is questionable to say the least.

Genetic variation responding to environmental change is always a factor, but there is no reason whatever to think genetics will contribute much to the overall problem.  Genetics is most likely to contribute to those cases of autism--and they exist--for which a specific high-risk genetic variant has been identified.

What to do about a major societal problem, a real problem, like autism is less clear. But just plowing ahead isn't necessarily the most societally responsible approach.

46th Carnival of Evolution is up

The April Carnival of Evolution is up over at Synthetic Daisies, and it's full to overflowing.  Trees, trees, trees ... and a crossword.