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.

Is whole genome sequencing fading? Will it rebound (or relapse)?

There are various informal indicators that funders are losing enthusiasm for human whole genome sequencing.  We've seen discussions of 'genome fatigue' in the media (Carl Zimmer, e.g., talks about this here), and one colleague said there wasn't much enthusiasm for whole genome sequencing because we hadn't found the cure for cancer or made highly useful personalized predictive medicine.  Another colleague on an NIH grant review panel said that particular panel, at least, wasn't going to fund any more GWAS studies.

DNA sequence data, Wikimedia Commons

If this turns out to be more than a few anecdotes or personal opinions, and is actually occurring, it's understandable and to be lauded.  As we think we can truthfully claim, we have for years been warning of the dangers of the kind of overkill that genomics (and, indeed, other 'omics' fads) present:  promise miracles and you had better deliver!

The same thing applies to evolutionary studies that seek whole genome sequences as well as to studies designed to use such data to predict individual diseases.  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.

There are some traits, especially if close to a specific protein, in which only one or a few genes are important.  There are many genes which, if broken by mutation, can cause serious problems.  And as we've said numerous times, this is where the genetics money should be spent.  But the nature of evolution is that it has produced complexity by involving numerous cooperating genetic elements, and traits are typically buffered against mutations.  Otherwise, organisms couldn't have gotten so complex (try making a brain or liver with just one gene!).  Otherwise, with so many genes and ever-present mutation, nobody in any species would ever survive.

The instances of single-gene or major-mutation causation are numerous and real.  They are already handled by services like genetic counseling in biomedicine, and by evolutionary or experimental analysis.  But the important nature of Nature is its complexity and at present whole genome sequence data provide too much variation for us to deal with on adequate terms.

Nature screens the success of organisms on their overall traits, regardless of what genotype contributed to it.  Many of the contributing variants to a given trait are new mutations or are very rare in the population, and very difficult to detect in terms of assigning 'risk' to them.  Worse, they flow through the population all the time, as individuals die and new ones are born. Since their individual effects depend on their context--the ever-changing environment and the rest of the genome--these effects are also fluid.  Thus, enumerating causal variants may not be a very useful way to understand biological causation.

Of course, rumors of the demise of ever-higher throughput genomics may be greatly exaggerated.  Funding may not actually be diminishing, or may return.  Whether that will be a rebound towards good science, or a relapse of low payoff, is a matter of opinion.

New genes, old function

Ken mused a while back here on MT about the improbability of finding a DNA sequence that had no similarity to sequence from any known organism.  And this is as we'd expect, if all life on Earth shares a common ancestor, and nothing that has been discovered since Darwin first proposed this in 1859 suggests otherwise.

So, why are researchers reporting DNA enzyme sequences that don't appear to be homologous to any known sequences for similar enzymes?  François Delavat et al. have sequenced genes from organisms found in an acid mine drainage, organisms that are resistant to being cultured (i.e., that can't be readily grown up in the lab), looking for novel genes or function.  They report their findings in the open-access Nature journal, Scientific Reports ("Amylases without known homologues discovered in an acid mine drainage: significance and impact").

Amylases are enzymes that catalyze the breakdown of carbohydrates, or in the case of bacteria described here, degrade polymers found in their acidic, metal-heavy surroundings.  Amylases from bacteria that grow in culture have been well-studied, and have been classified into several families based on their structure and other characteristics.  Some have been found in extreme environments, but no one had reported the sequencing of DNA from Acid Mine Drainages before this paper.  These are very low pH, very high metal environments. 

The authors

...decided to perform a function-based screening for the well-known amylases, using standard techniques. This strategy allowed the isolation of 28 positive clones, 2 of them being subcloned, the proteins purified and characterized in vitro. In silico analyses based on the nucleotidic sequence and both the primary and the predicted tertiary structures revealed that they are completely different from other known hydrolases as both genes encode a « protein of unknown function » and display no known conserved amylolytic domain. Nevertheless, in vitro tests confirmed the amylolytic activity of these 2 enzymes.

That is, these genes did degrade polysaccharide, but neither of the subclones matched any known amylase sequences in the databases. 

As Delavat et al. point out, much is known about lab-friendly bacteria, and a whole lot less about organisms that can't be grown in the lab.  Thus, if these results are confirmed, the fact that these genes, from organisms that were found in an extreme previously unexplored environment, don't look like other known amylase sequences doesn't at all suggest that these bacteria are unique, or that they don't share the same common origin the rest of us share.  Rather, it suggests that the lab-centric biology of the last century has given us a lab-centric view of the world.  It's no surprise that bacteria that live in the low pH, high metal extremes of Acid Mine Drainages would have evolved particular enzymes appropriate for that environment.  But it's also not a surprise that these enzymes have a function that is common to bacteria in every environment.

That the genes that code for these enzymes are unlike any of the subset of amylases yet described is another example of phenogenetic drift, the conservation of a biological trait or function even when its underlying genetic basis has changed.  These genes may look novel now, but as more bacteria are characterized from non-lab environments it's likely that more will be found that share some of the characteristics of these amylase genes. 

Note, also, that these sequences are genes -- they have protein coding structures and are identifiable from sequences as such.  They are not 'random' sequences with no known relation to the usual characteristics of genes.

Be the person you were! Dope up....or be a dope!

The latest news (we heard it on the BBC World Service on Wednesday the 11th of April, but here's the story on the Daily Mail site) is about the desperate need of those working Wall Street to be more 'competitive' (with other sharks) in keeping their hands deeply in your pockets.  These Street walkers are worried they may be losing that 'special' trait that lures customers to their dens of (in)equity.

Now, it seems, a noble new service has been started by a clever entrepeneur who managed to graduate from some medical school:  He is luring aging bilkers to spend fortunes to 'adjust' their hormone balances, mainly being goosed up with testosterone.  That'll help them keep the competitive edge!

The male hormone testosterone has become an unlikely drug of choice for Wall Street traders seeking to give themselves an edge over their professional rivals.

New York clinics have reported a rise in treatment for 'testosterone deficiency', sometimes known as 'andropause'.

They say many workers in the male-dominated industry are hoping that boosters of the hormone will help them perform better at work and put in longer hours.

Like ads in airline magazines: "Do you have LowT?  Feel like you did when you were 25!"  The company, modestly housed high in Trump Tower, charges $4500--and that's just for the consultation!  Still, one socially responsible person, a hormone-adjustment  'customer' of this 'medical' service, said the cost was steep but he was glad that he, unlike some of his competitors, could afford it.  Such a good soul, he!

A colleague of ours once said the most intelligent people were the most gullible (we forget his reasoning, and we won't say whether we believed him or not, because it would reveal our own intelligence).  Here, however, is an analog or homologue of that generalization:  the greediest people are most gullible to greed.  Or something like that.  Women brokers, or perhaps broken women on the Street, apparently as well as broken men benefit by a good dose of testosterone, though less than men are given, to prevent things like the growth of facial hair.  Not very 'Brazilian', but what the hell if a buck is to be made.

This story has little to do with the topics of MT, but seemed to be a good story about the presumptive intrusiveness of science into everyday life these days, trying to design, re-design, or in this case retro-design us to have whatever trait we think will give us an edge in life.   At least, unlike the early 20th century wishes of a similar sort, monkeys won't have to be sacrificed to get extracts from their 'glands' to boost the combativeness we need from our hedge-fund managers. (See this on the promoter of that treatment, Serge Voronoff.)

Figure from site about Voronoff.

But later on, when these hairy, deep-voiced, muscle-bound hyper-sexed 90 year-olds start getting diseases, will geneticists remember to ask if they've been Trumped up in the past, in case it's a risk factor?

In the absence of that kind of regulation (or retribution) for their attitude, there really doesn't seem to be anything the snakes on Wall Street won't stoop, or kneel, to do.

Well, at least we thought this might make an entertaining break from attempts on our post to discuss  real science rather than what amounts to 21st century 'monkey gland' hawkery.

The next challenge in malaria control - artemisinin resistant parasites

Anopheles mosquito, Wikimedia Commons

Sometimes the news about malaria is good, as recently when deaths from malaria were reported to be decreasing, even if inexplicably, and sometimes it's not so good.  Last week saw two not-so-good stories -- one in The Lancet and one in Science -- about the increase in anti-malarial resistance in the Plasmodium falciparum parasite.  The Lancet paper documents this on the border between Thailand and Burma, and the Science paper reports the identification of the genome region in the parasite that is responsible for this newly developing resistance.  Because the parasites are becoming resistant to the best anti-malarial in use today, arteminisin, this is a serious issue.

The Science paper sets the stage:

Artemisinin-based combination therapies (ACTs) are the first-line treatment in nearly all malaria-endemic countries and are central to the current success of global efforts to control and eliminate Plasmodium falciparum malaria. Resistance to artemisinin (ART) in P. falciparum has been confirmed in Southeast Asia, raising concerns that it will spread to sub-Saharan Africa, following the path of chloroquine and anti-folate resistance. ART resistance results in reduced parasite clearance rates (CRs) after treatment...

As the BBC piece about this story says, "In 2009 researchers found that the most deadly species of malaria parasites, spread by mosquitoes, were becoming more resistant to these drugs in parts of western Cambodia."  This will make it much harder to control the disease in this area, never mind eradicate it.

Most malaria deaths occur in sub-Saharan Africa, and the spread of resistance to this part of the world would have disastrous public health consequences.  There is no therapy waiting in the wings to replace ACTs.  Whether the newly identified resistance is because infected mosquitoes have moved the 500 miles from the initial sites where resistance was found toward the border or because the parasites spontaneously developed resistance on their own is not known.  If the latter, this suggests that resistance is likely to arise de novo anywhere that artemisinin is in use -- and that's everywhere malaria is found, as ACTs are the most effective treatment currently in use.

This is, of course, evolution in action, artificial selection in favor of resistant parasites.  It's artificial because we're controlling 'nature' and how it screens.  Normally, selection that's too strong for the reproductive power of the selected species can mean doom -- extinction.  Blasting the species with a lethal selective factor can do that.  In this case, we'd like to extinctify the parasite.  But selection in a rapidly reproducing species is difficult because if any resistance mutations exist, the organisms bearing them have a relative smorgasbord of food -- hosts not hosting other parasite individuals, and this can give them an emormous selective advantage.  So the artificial selection against susceptibility is also similarly strong selection for resistance.

Unfortunately the development of resistance is inevitable when a strong selective force such as a drug against an infectious agent is in widespread use against a prolific target.  And it shows why the idea that Rachel Carson was personally responsible for millions of deaths from malaria because she pointed out in her 1962 book, Silent Spring, the harmful environment effects of DDT, an insecticide that effectively kills non-resistant mosquitoes, is short-sighted.  If its use against mosquitoes had been widespread and sustained, it would have long ago lost its efficacy.

The inevitable rise of resistance to treatment is why prevention or, even better, eradication are the preferred approaches.  Unfortunately developing a vaccine against malaria is proving to be a scientific challenge, and similarly evolutionary considerations will apply; and eradication, while doable in theory, is a political and economic challenge, and could involve the same resistance phenomenon if not done right.  So, the documented rise of drug resistant P. falciparum on the Thai Burma border is a severe blow.

We don't happen to know what, if any, intermediate strategies are being considered or tried.  Multiple moderate attacks, with different pesticides or against various aspects of the ecology or life-cycle might not wipe individuals out so quickly, but may 'confuse' them so that no resistance mechanism can arise because those bearing the new mutation protecting from agent X would be vulnerable to agent Y.  A complex ecology of modest selective factors, could possibly reduce the parasite population to a point where it really did become lethally vulnerable to some wholesale assault.

Or would it be necessary to accept some low level, but not zero, rate of infection to prevent major resistance?   Small pox and polio would seem to suggest that real eradication is possible, but how typical that can be expected to be, is unknown (to us).

Changing the diagnosis? Nature does it, too!

Here is a story that discusses the changing diagnosis of autism, a hot topic this week in the science news.  The doctor interviewed, Dr Bryan King, has spent the last 5 years working with a committee charged with revising the diagnosis of autism for DSM-5, the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, the diagnostic standard for psychiatric illnesses.  Reports of a dramatic increase in the prevalence of autism, along with genetic findings revealing autism's complexity (which we've posted about), are in the news.  So Dr King, involved in setting the standard diagnostic criteria for autism or autism spectrum disorder (ASD), is interviewed about the process.

Obviously, neither environmental nor genetic factors cause 'autism' per se, if the very meaning of the term changes. ASD is in some ways a cultural trait, since it's we who define it.  If we change our definition, the risks associated with specific genes or environments necessarily change as well--yet, in physical terms, they have clearly not changed at all!  If a genetic variant conferred a risk of, say, 0.5% of autism 10 years ago, then today on average it would confer nearly 1.0% (twice as much as before).

This is one problem with doing the genetics of 'autism' when the trait you're doing the genetics of is a moveable target.  The politics and other aspects of the diagnostic criteria may or may not be proper, but certainly the behavioral cutoff is cultural both in the sense of its manifestation in a given cultural setting, but also in the way that setting sets diagnostic criteria.

Relevant to MT is that Nature probably works the same way.  Here the key issue is natural selection.  Natural selection is a screen of organisms for traits that are more, or less, compatible with local circumstances.  But those circumstances change, sometimes rapidly.  Thus, like cultural definitions, the criteria that determine the relative fitness--reproductive success--are changing.  This means that here, too, the fitness of particular genetic variants is context-dependent, not fixed or absolute.

This is one of the challenging aspects of evolutionary biology, because it is tempting to view a genotype as inherently good or bad, inherently likely to succeed or not.  That makes theory and modeling of natural selection, evolution, and species formation tractable.

But Nature may not be like that.  If fitness is a shifting phenomenon, which it certainly is to at least some extent, then everything is context-dependent, and relative to circumstances, all the time.  So many of the scenarios proposed to account for what we see today may have a degree of the arbitrariness of the definition of a given trait, like autism.

SuperSize me! Nothing in American can be small (except genetic risks?)

In evolutionary biology, perhaps especially human evolution and anthropology, and biomedical genetics the current working mythology....er, we mean 'model'....is of strong, rapid, definitive natural selection as 'the' mechanism by which traits we see today got here.  Since adaptation only works through what is inherited (environmental effects, so to speak, die with the individual), the same kind of simple-cause deterministic thinking has been applied to the genetic control of current traits.

There are all sorts of reasons to expect, or hope, that cause and effect will be simple.  Single-gene causation of adaptation means we can find 'the' gene that explains why you vote or mate as you do, have a particular  disease or physical trait, and so on.  Pharma doesn't want to invest in profit-less rare traits, or complex traits for which a single med will only help a small fraction of patients.  And, of course, simplicity lends itself to melodrama and hence to the visual and even the print news.

But what we see are a multiplicity of individually small effects, as last week's papers on autism (the subject of our post on Friday) show yet again.  This is disappointing, but why is nature that way?  There are several reasons to believe that the apparent complexity is, in fact, the truth.

This should surprise no one.  For example, mutations conferring simple strong effects on disease-susceptibility will be quickly eliminated by natural selection.  Genes fundamental to many other genes because of interactions, may be specifically vulnerable to such mutations--so we may not find many risk alleles in  those genes. 

If many genes contribute to a trait, their individual effects almost necessarily will be even smaller.  This clearly is the case for the kinds of traits that are the main targets of GWAS and similar approaches.

Most genes that confer high risk would be eliminated by selection unless, as some argue, recent environments make them harmful (e.g., causing diabetes or cancer), whereas they weren't harmful before.  If their effects were slight or of late onset, they would not impair reproductive success, and would stay around in the population.  This doesn't seem to be the case.  In most GWAS'ed traits, risk has risen rapidly and greatly during the past century.  Yet the evidence is not that a few genes with major response to these environmental changes are responsible for the disease: indeed, the GWAS problem is precisely that this is not what we find!

Note also that traits not present at birth, meaning most GWAS'ed traits, take decades to manifest themselves.  The risk difference between variants at the 'risk' genes is usually very small, meaning that they change the risk at any given age by trivial amounts.  We may not want to get such diseases, but from a biological point of view they are really miniscule effects.  This also easily and non-suprisingly accounts for the findings of the recent paper of  low concordance of age and cause of death relative to genotypes in identical twins.

The very same arguments apply to the ability of natural selection to detect these differences, and that in turn clearly explains why it is so difficult to find 'signatures' of natural selection in genomic data, and why again in turn most selective arguments that refer to specific genes are without strong support beyond neat stories one tells about them (as we see in the news almost daily, and report here on MT).

When a gene has a true, but tiny, affect on risk (or on evolutionary fitness), there are so many competing causes of death or disease, or bad luck, that the odds on that gene's effect actually being manifest (as disease, or fitness) are simply very very small.

These are not complicated ideas to understand!  They are not our own private theory.  They're plainly visible in the mountain of facts we already have available to us (without huge, costly biobanks and promises of personalized medicine or strong adaptive arguments).

Traits like disease or adaptation may be major--nobody wants cancer, but in trying to find 'the' gene or few genes that are responsible, we're making mountains out of biological molehills.