Monday, December 15, 2014

Are we still doing 'beanbag' eu(genetics)? Part I. Some history

Way back in 1964, a famous paper was published in Perspectives in Biology and Medicine (vol 7: 343-359, and reprinted in the International Journal of Epidemiology in 2008; 'A defense of beanbag genetics').  The author was one John Burdon Sanderson Haldane, better known as JBS Haldane.  Along with RA Fisher and Sewall Wright (and, later Motoo Kimura, James Crow and an expanding array of others) Haldane helped found and then develop the field of population genetics.

JBS Haldane (1892-1964), from (on Google images)
Population genetics is the theory of change in genetic variation ('gene frequencies') in populations over time.  Essentially, one main thread of population genetics follows the fate of new mutations in DNA over time, and in that sense is centered around a variant--called an 'allele'--that arises by mutation in a single 'gene'.  It can model the change in that variant's frequency because of chance, population dynamics, natural selection and so on.  It can also model what happens with several such variants.  However, this theory is mute about what the variant actually does in the organism.

In a sense, population genetics is a particulate, molecular theory of change over time, that is, of evolution, that is largely divorced from real biology, but if biological traits are caused by genes, their variation must also be affected by genetic variants, so while the theory is a valid way to follow frequency dynamics, it seems to have judged it irrelevant to consider the organisms themselves.  Nonetheless, in the 1930's, the panache of its mathematical rigor and one might say fashionability as a molecular (and hence 'real' science) focus, led to population genetics being proclaimed 'the' formal genetic theory of evolution--and, really, more than that: the basic underlying assumption was, and has remained, that evolution is fundamentally a genetic phenomenon.  The impression was essentially given that the rest was incidental window-dressing.

Naturally, some biologists objected to this palace coup by a few mathematically skilled theoreticians; this is a natural resentment perhaps, since many biologists choose that field because they were innumerate, as was Darwin. But as importantly, because of the very particulate nature of the theory, relative to the real world, a leading spokesperson for evolutionary biology, Ernst Mayr, denigrated the theory as 'beanbag' genetics: the reduction of real organisms to a set of independent causal particles, the individual genes.  Instead, Mayr insisted, organisms and their evolution were more integrative, interaction-based phenomena.

In his 1964 paper, Haldane objected to this negative caricature of population genetics.  Essentially, he said that the theory allowed many ideas about evolution to be tested at least approximately, and could account in principle for a broad range of evolutionary phenomena.  He discussed the relationships between more nuanced aspects of genetics--interactions among genes, for example, that Mayr stressed--and the theory.

Nonetheless, while population genetics is very useful for putting some plausibility brackets around interpretations of genetic data from populations, it is still largely a one-gene-(or one linkage group of genes)-at-a-time theory; that is, it doesn't concern itself with actual traits or how they are manifest, and so on.  Indeed, leading developmental geneticists have, rightfully in our view, complained about the self-proclaimed theory of evolution's omission of the way that actual organisms are assembled, and evolve, and the role genes play in that.  The evolution of development (or 'EvoDevo') has become a major field of research, which, thanks to many advances in genetic experimental technology and model systems, has been able to relate developmental genetics to the evolution of the genes and the systems they're part of.

The other half of the 'bicameral' brain
There has long been a second thread of the theory, often called 'quantitative' genetics, that deals with the behavior of quantitative traits affected by large numbers of genes not specifically identified, that can predict aspects of traits in populations over time, but does not attempt to enumerate the individual genetic contributors.  These are called 'polygenic' traits (other similar terms are sometimes used), and are the target of many genomewide mapping efforts, about which we have written many times.

In fact, both these strains of thought go all the way back to around 1900 when Mendel's work was rediscovered, and then competed with Darwinian gradualistic ideas about evolution and genetics.  The competition involved squabbles between the Mendelians and what were call the 'biometricians', or quantitative geneticists.  Since that time, what these combined areas of theory and investigation have shown is that there is a spectrum of genetic causal effects.  Variation in traits that are generally very rare in their population are often due to variation in single genes--any number of diseases, usually severe and with very early onset, are in this category.  These behave in a classical 'Mendelian' way, just like Mendel's pea-traits did.  But most traits and most common, later-onset disorders are in the complex polygenic category.  Human thinking often tends either to focus on qualitative 'things', or on quantitative 'measures', and the difference between particulate and quantitative evolutionary genetics reflects that.

You may not be old enough to remember the phrase 'beanbag genetics' but it symbolized the naturalist's view that whole organisms or even ecosystems need to be studied as interaction entities,  rather than trying to understand evolution by particularizing things down to individual genetic variants, even if the latter are an essential part of the story.  That sort of reductionism was missing the point.  But have we long ago learned that lesson?

Where are we today?
In fact, today's Big Data GWAS-y world is conceptually still largely wedded to beanbag genetics.  It is still driven by a reductionistic approach that essentially believes that by enumerating the individual beans in each person's genome, that person's entire nature can be understood or even predicted from the moment of conception. Is this too much of a simplification or overstatement?  Is there a reason other than molecule-worship that the stress is so heavily on individual, particulate entities like 'genes', even though we know the genome is far from so clearly discretized in function?  Look past the caveats and denials offered by the Big Data empire to what they they are mainly doing, look at how they bury or pass over their caveats, and judge for yourself.

Effort is being made by people to study 'systems', such as molecular interaction networks.  This is a recognition of the problem posed by hyper-reductionism.  It is a step in a good direction, but even the systems approach largely seems beanbag in nature, by approaching complex traits as if they were a beanbag of internally interacting systems that can be enumerated and treated as units.  Network interactions are obviously relevant and involved in biological organisms, but it is not so clear, to us at least, that that path will be the best one to understand complex traits sufficiently well. At least, systems approaches force us to consider interactions among components as fundamental to life.

There is an important sociocultural problem associated with beanbag genetics, besides that we're still thinking in essentially the same way as 50 or even 100 years ago despite vastly more knowledge.  The problem goes beyond the promises to use the enumerative causal approach to develop 'personalized genomic medicine', which sounds so laudable.  Based on what we know today, those promises are highly exaggerated and misleading, even if they will work for clearly causal genomic 'beans' and even if every lesser finding will be trumpeted as a justification for the effort.  But one, if not the most immediate, consequence of that is that they eat up lots and lots of funds that could be spent in other ways, already known, that could yield vastly more improvements to public health (health is, after all, the promise being made).

However, beanbag thinking casts another, far more ominous shadow that also goes back to the early days of genetics, and that will be the subject of Part II of this series.


Unknown said...

Really interesting perspective on things here. Looking up what the footnote on page 1 of A defense of beanbag genetics referred to I found this commentary also worth checking out

Ken Weiss said...

Reply to Louis
Thanks for the link. Jim Crow was one of the real gentlemen of population genetics. I knew him, though not well. He passed away recently and we did a blog post about him (you could search for it, as I can't put a link in a comment). Crow was the one who trained Kimura, along I guess with Sewall Wright, and that led to the standard 'modern' view of evolutionary population genetics before the real molecular DNA age.

Unknown said...

great post Ken.
These sorts of things always remind me of scale issues that I deal with or see in other areas.
For example, the ecological fallacy, where there a statistical finding at a population level can't necessarily be interpolated to an individual in that population (let alone, another population). Very similar things happen when you do mapping. For example, a high disease prevalence in a given district or census tract can be largely related to the (sometimes arbitrarily drawn) boundaries of that unit of analysis.
Or when Darwin traveled the world, noticed big scale patterns, but didn't understand the genetics underlying those patterns?
A bit of a tangent perhaps, but I love this stuff.

Ken Weiss said...

Not really tangential. The ecological fallacy--or the risk of it--is widespread in genomics these days. As to big patterns, Darwin had no way to relate them to genomic details--his guesses about 'pangenesis' and 'gemmules' were just wrong.