“If you come to any more conclusions about polymorphism, I shd [sic] be very glad to hear the result: it is delightful to have many points fermenting in one’s brain”

Charles Darwin, letter to Joseph Hooker, 1846

The term polymorphism, which peppers much of the biological and medical literature in this age of plentiful DNA sequence data, was well established among biologists by the time it first tickled Darwin’s brain. Coined from the Greek for ‘many shapes’, the word apparently gained particular currency among early Victorian botanists, who wanted a handy label for the spectacular proliferation of structural forms seen among newly collected plants[1] from far-off imperial lands. When Darwin, who was well versed in botany (especially that of orchids), set out to catalog and interpret a Beagle-load of riotous diversity among animals and fungi, too, he naturally reached for polymorphism to summarize his emerging grasp of organismal variation. Many, many shapes indeed.

The concept of polymorphism held knotty mysteries for Darwin, though (as his letter to Hooker attests). In particular, his understanding of the inheritance of highly variable traits suffered, famously, without the insights of Gregor Mendel, the gardening monk whose obsessive bean-counting yielded the first clear mechanistic insights on the nature of genetic polymorphism. Darwin skimmed references to Mendel’s work, but missed its key lesson: that genetic variation is transmitted in discrete (‘digital’) packets, rather than in infinitely divisible (‘analog’) amounts_._ Lacking this insight, Darwin found it hard to account for the persistence of a wide variety of heritable organismal forms — polymorphism, that is — even in the absence of natural selection.

If, as Darwin assumed, genetic heritability were ‘analog’, rather than ‘digital’, then anything other than strongly assortative (‘like-with-like’) mating would homogenize a population, just as mixing two paints gives a uniform intermediate hue. And, as a puzzled Darwin realized, not only is non-assortative mating rampant in nature, but strictly assortative mating would tend to prevent any heritable innovation — that is, the stuff that puts the poly in polymorphism — from getting a foothold in a population in the first place. Moreover, one cornerstone of Darwin’s own theory of evolution by natural selection is the idea that such heritable innovations can be functionally useful (i.e., adaptive). Yet, lacking Mendel’s insight, Darwin couldn’t explain how even an initially highly useful heritable innovation could spread through a stable-sized population at anything faster than a glacial pace, given that its distinctive functionality would be quickly diluted by each generation of mating between carriers and non-carriers.

So how did Mendel make his revelatory deduction that genetic transmission is discretized? He started with the simple observation that each pea plant in his garden was either violet-flowered or white-flowered, and yielded either very smooth peas or very wrinkly peas, regardless of its flower color. And he went on to find that, when he crossed two plants (by fertilizing one’s flowers with pollen from another) that either matched, or differed, in flower color and/or pea shape, the offspring did not include lavender-flowered plants that made slightly wrinkly peas. Rather, the plants continued to be either violet- or white-flowered, and to produce either very wrinkly or very smooth peas.

In Mendel’s careful (and, by his own admission, selective) analysis, the actual numbers of each type of plant suggested that each trait of interest (e.g., flower color, or pea shape) was governed largely by its own discrete, independently transmitted genetic factor, inherited in two copies (one from each parent). For each trait, one type of copy of the underlying factor appeared to be ‘dominant‘ to the other — that is, a plant’s flower color or pea shape would match the dominant type as long as at it had inherited at least one dominant-type copy of the relevant genetic factor. Such factors came to be called genes (though that word has more specific connotations today), and their variant copies came to be called alleles. Strikingly, the discretized nature of these packets of inheritance turned out to extend even to their own composition, as strings of discrete chemical ‘letters‘ that, if swapped for one another, differ in kind but not degree.

Mendel was lucky to have a relatively tractable organism around to study: pea plants, like humans, are diploid, meaning that they have only two copies of the genome in most cells; many other crop plants have more complicated inheritance involving many more copies of a genome. And, just as importantly, he focused on traits that had fairly simple genetic underpinnings. Many traits in pea plants, and in other organisms, are governed fairly strongly by variation in many parts of their genomes; such variation would not have been statistically tractable to Mendel, and indeed remains a computationally intensive focus of much research (especially research on the genetic underpinnings of diseases) today.

Notably, Mendel’s work on pea plants (which actually addressed at least seven distinct traits of plant color or/and shape) involved variation that comprised, in the case of each trait, only two forms. Though such ‘binary’ factors can indeed generate ‘many shapes’ in their combination, Mendel actually discovered genetic dimorphisms. Strikingly, it turns out that, in real world populations of all sorts of organisms, most genetic variation also takes the form of ‘dimorphism’, when viewed at the finest scale saliently relevant to gene function. That is, rarely does a single site in the genome show more than two distinct spelling variants among samples taken from a real population — and in no case does it show more than five such variants (A, C, G, T or absence). One could therefore argue that a more appropriate umbrella term for a given example of localized genetic variation, per se, might be multimorphism (‘more than one shape’) or oligomorphism (‘a few shapes’), rather than polymorphism. The term is well established, however, and has likely transcended etymological connotations of ‘many’. A more substantive usage peeve arises, in both the scientific literature and popular coverage of it, when ‘polymorphism’ is used, wrongly, to mean ‘variant’ or ‘allele’ (typically, an allele assumed to be derived by mutation, rather than an ancestral allele), as in this example from a press release by the University of Southern California’s news service:

“Because of the way genes are inherited from both parents, each participant could either have two copies of the polymorphism, one copy or no copies.”

Rather than pester USC’s editor, though, let’s raise a bicentennial toast to mister Darwin, and a hearty forthcoming 187th to brother Mendel. Oh, and those conclusions about polymorphism? As noted, the term was first used as a catch-all label for organismal variation visible to the naked eye (or with a rudimentary microscope), but, with increasing knowledge of DNA sequence variation, has come to often denote specific examples of such variation, as in efforts to catalog all the single-nucleotide polymorphisms (SNPs) in a given genome. Moreover, as comparative genome sequence data have become more thorough and plentiful — and as approaches to quantitatively assessing such data have emerged — the term has also become a synonym for the overall level of genome sequence variation within a population. In the latter usage, it stands in contradistinction to divergence, the term of choice for summary measures of the sequence variation that distinguishes one population (ostensibly, ‘species’, though that term is impossible to rigorously define in a way that universally accords intuitive judgments) from another. In future posts, we will explore in greater detail how such measures of variation are calculated. Overall, the origin and maintenance of genetic variation remain, arguably, the chief foci of empirical and theoretical inquiry in evolutionary genetics. As such, you might say that it remains delightful, indeed, to have many points — and many shapes — fermenting in one’s brain.

[^1] Plants are, of course, plentiful; slow-moving; compact, light, and durable when dry; and often highly useful. These qualities made them especially popular subjects for Victorian-era collection and sketching, and for imaging with early (and modern) photographic materials.