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

Mendel

In his experiments, published in 1866, Gregor Mendel crossed two strains of domestic peas.  'Crossing' means that one parent was from each strain, and because the strains were inbred, this meant that there was little variation in the genomic backgrounds within each strain.  Mendel used different pairs of strains for the different traits he studied.  Further, he found that his chosen traits (seven of them, like round vs wrinkled or green vs yellow exhibited what he called 'dominance' (as we translate the term today).  That means that the effect of the allele (genetic variant) from one of the two strains was always manifest as its corresponding trait.  To revisit what we said earlier in this series, in the first generation of a cross, every parental pea plant was either GG or YY genotype (green or yellow) at a given test gene so every offspring plant inherited a G allele from one parent and a Y from the other, meaning they had the GY genotype and the peas and pods were yellow (in which case we say Yellow is dominant over Green).

But things are more complicated in the generation produced by crossing these plants, because then a specified fraction of each offspring type would be expected (as we noted in Part I, for GY x GY, the famous 1GG, 2GY, 1GG ratios were expected.  Mendel went a few generations beyond that,  and the ratios became more subtle, but the point is the same.  However, each generation allowed some scrambling of the genomic background of the strains, that is, at the rest of the genome, due to what is known as 'recombination' among the two parental strains' chromosomes.

It was in the context of those backgrounds with their limited variation, that the plants seem to breed 'true'.  Of course, there was statistical variation in the frequency of the relative offspring types (and Mendel was accused of fudging some figures to make his story come out closer to what he expected).  He did not get exactly the expected proportions.   But this variation, which is observed in every 'Mendelian' situation in any species, has always been attributed solely to chance allele transmission from parent to offspring (or to data fudging by tossing plants that didn't fit).  The fudging accusation is highly debated (see my paper, Goings on in Mendel's Garden, Evol. Anthropol., 11:40-44, 2002). But there may be a more serious issue, hidden in the statistics.

That issue is the assumption, from Mendel's day to today, of the expected proportions of plant types (green vs yellow, smooth vs wrinkled).  That expectation was based on pure, 100% dominance, that is on the inherently dominant physiological effect of the two alleles in any of one of his test crosses.  The assumption is that there is no genomic background variation that causes deviation from these 'pure' expected proportions.  We don't know to what extent there were 'greenish' or 'yellowish' peas, or peas with nondescript or mottled nature in Mendel's experiments, that would have been tossed out on the grounds of foreign pollination or whatever.  We know however that the variation was small enough that the assumption of dominance was good enough--for Mendel's purposes. 

At least one of his traits, plant height, was largely quantitative and less clear to judge (this was written up in the early 1900s, especially by OE White in a series of thorough papers).  We know that genes in the wild have many different variant states, not just two. And these have variable effects.  And this is true for Mendel's traits.  This is the same story, consistently, with variation at alleles related to human diseases (like cystic fibrosis, or PKU, etc.), and variation and genetic control in essentially any species carefully studied.  For these reasons, Mendel probably could not have done what he did with random samples of wild plants--anymore than we can do it with GWAS and complex diseases today.  Indeed, we must say that the above-cited paper raised all of these points, before the mountain of confirming data that subsequent studies generated and that we have today was available.  Of course, these are inconvenient facts if you hunger, naturally perhaps, for simple answers to fond dreams of perfect crops, and immortality through genetics.

In that sense, Mendelian traits are an artifact or illusion of his simple experimental set up, one he intentionally chose because the traits 'worked' the way he wanted them to. But there are further reasons than natural variation in the test genes themselves, for thinking that Mendelian inheritance has been, from the beginning, a very misleading notion.

This is the fundamentally mistaken notion that a gene is the same as the trait it contributes to.  It is the assumption of causal inherency.  Instead, what we know very, very clearly is that with a few kinds of exceptions (such as many lethal dysfunctional mutations in genes), the effect of an allele is contextual:  it depends on the environment and, in this case more importantly, on the genomic background.  That is, the variants at the many other genes in the same plant or animal affect how the allele of interest is manifest.  This is because no gene is an island, despite our clinging to Mendelian concepts of inherent causation for the last 150 years.

The degree of this contextual dependence varies from gene to gene, trait to trait, population to population, and species to species.  There is no single biological theory (other than, perhaps, this generalization) that predicts what we will find.  Some alleles in some situations act in a way that would make Mendel smile.  But few traits are, overall, like that.  10% or so of known devastating mutations in humans, that typically are called 'Mendelian', are the normal allele in other species!

To a great extent Mendelian inheritance of traits, that has become the sacred icon of modern genetics, is simply wrong!  Certainly, in any species one can find traits that segregate in the expected fashion to a degree satisfactory for the purposes at hand.  There is a spectrum of effects, and some are of this simple-enough causation.  But from a point of view of an actual theory of biology, it is the specturm not its extreme, that is important.

In this sense, genetic effects are as relative to each other as motion of objects is to Einstein.  This means that a subtle but centrally important point,  that there is really little if any difference between 'physiological' and 'statistical' dominance!  These terms were introduced earlier in this series of posts.  The idea of inherent dominance has been a misleading oversimplification from the beginning.  Dominance is just a sometimes-observed approximate correlation between alleles and traits that applies to a particular population.  Inherent biological dominance is an experimental illusion.

Traits in Nature, like diseases, that appear to be Mendelian, are those that in current circumstances, chosen among countless traits that have been studied, seem to appear in families in the classical way.  We know this very well, but it's not in most peoples' perceived self-interest to face up to it.  Even the more devastating mutations in 'Mendelian' single-gene diseases typically have variable effects.  The same mutations in mice are very often strain-specific.  And many alleles at the gene have less, and even more, variable effects.

For example, most individuals with 'recessive' diseases are not homozygotes for 'the bad' allele: they are heterozygotes for various alleles that compromise the trait to various degrees away from 'normalcy'.  
To account for this, but still to cling to our Mendelian paradigm, we introduce fudge factors to account for incomplete dominance and the like, that must be introduced in genetic (family) counseling risk estimates.

To the extent these statements are true, the idea of Mendelian inheritance (of traits) has been a stunningly misperceived, mistaken theory that continues to cost huge amounts of money for chasing genes 'for' particular traits, as if such genes have inherent causal, and hence inherent predictive properties.