Conceptual inertia in science: what is simpler and more straightforward? A comment on 'Mendelism'

We now know enough about genetics to give up, as historical relics, terms like Mendelian, dominant, and recessive.  But their use lingers on. The habit of Mendelian terminology is one that we owe, of course, to Gregor Mendel and his work on pea-plant hybridization published in 1865, roughly contemporary with Darwin  The idea that a trait is inherited and could have two states, one of which had an over-riding effect relative to the other, clarified the nature of one kind of inheritance and led to a huge explosion of successful research that ultimately showed that inheritance involved particles of biological causation ('genes').  It provided a research strategy that led to the discovery of the nature and function of chromosomes, of DNA, its protein-coding nature, that causal elements were discrete segments of DNA, and it explained major aspects of inheritance.  In this sense, few discoveries in any science have had a greater impact on human knowledge than Mendel's work.

Mendel's 7 chosen traits

But Mendel was Mendel and times have moved on.  We now know that what is inherited is not traits but coding molecules that affect or produce traits are.  We know of many functional elements in DNA beyond direct protein-coding that affect gene expression, and we know that much if not most of the time, no single element produces a trait.  Further, variation (a central aspect of evolution and genomic function) usually has quantitative (taller, higher blood pressure, higher cholesterol) rather than qualitative (yes/no, green/yellow, sick/well) effects.  Indeed, Mendel knew this, too, and carefully selected traits that behaved themselves relative to his purpose of creating better, predictable strains of pea plants.  (Actually, more than DNA-based codes are inherited, because DNA depends on its cellular context, but that's another topic). 

Old terms past their utility
The problem with continuing to treat the basic model of genetic causation as one in which traits are due to inheritance of variants from a single gene, with one variant being 'dominant' over the other, is that it constrains our thinking.  A lot that we now know about genetics doesn't fit the model.  A lot that Mendel knew doesn't fit the model!  A lot of dichotomous traits that Mendel knew don't fit the model!

Sometimes the effects of both variants are seen, or the trait actually varies based on which variants a person has, or there are many variants in the population with differing effects, including none, and the variant we call 'dominant' sometimes doesn't manifest itself.  When we don't see effects, we say the variant has 'incomplete penetrance', or, for quantitative traits some 'dominance deviation', but that's misleading.  What is the information content of saying that the 'A' allele is dominant, except when it isn't?  Penetrance probability is a fudge factor that forces a model to fit when it actually doesn't.

When a fudge factor is invoked in science, it is a signal that something about the theory is wrong.

When are children old enough to learn the truth?
I've heard people acknowledge that, yes, the classical terms that we get from Mendel, like dominant and recessive, are misleading but then go on to argue that they are the simple and right way to introduce inheritance to students.  Let's introduce concepts slowly, adding complexities later when they're grown up enough to understand.

We disagree.  We think that such an approach entrenches simplistic and misleading thinking in students' understanding of genetics, where it hangs around in their mental background even when they become professionals who do or should know better.  So we don't like this approach. Indeed, it's based on an incorrect premise.

We think young minds can just as easily understand that we inherit a copy of each gene from each parent, and each confers some effect.  Call it a and b, and the result is a-and-b.  That's about as simple as an explanation can get.  Then we can note that sometimes one of the variants by itself has a huge effect that we can't miss, and those effects have often been discovered first, because they were easy to find. 

Here is an extract from the Wikipedia entry for the blood-clotting disease trait called Factor V Leiden:

Factor V Leiden is an autosomal dominant condition that exhibits incomplete dominance and results in a factor V variant that cannot be as easily degraded by aPC (activated Protein C).. . . .Up to 30 percent of patients who present with deep vein thrombosis (DVT) or pulmonary embolism have this condition. The risk of developing a clot in a blood vessel depends on whether a person inherits one or two copies of the factor V Leiden mutation. Inheriting one copy of the mutation from a parent (heterozygous) increases by fourfold to eightfold the chance of developing a clot. People who inherit two copies of the mutation (homozygous), one from each parent, may have up to 80 times the usual risk of developing this type of blood clot.^[9] Considering that the risk of developing an abnormal blood clot averages about 1 in 1,000 per year in the general population, the presence of one copy of the factor V Leiden mutation increases that risk to between 4 in 1,000 to 8 in 1,000. Having two copies of the mutation may raise the risk as high as 80 in 1,000. It is unclear whether these individuals are at increased risk for recurrent venous thrombosis. 

Now, we happen to think that while this may be technically correct description, it is burdened by a concept that it tries to assert and yet then to deny in the same initial phrase--Factor V Leiden is "autosomal dominant", and yet exhibits "incomplete dominance".  The trait would be called both Mendelian and dominant by most people.  But it is neither.  What it is, is a trait whose measure (severity or frequency of attack or relevance to experiences such as taking birth control pills in women) depends on the genotype and is both quantitative and probabilistic.

Why not just say that "The risk of blood clotting is affected by a person's specific genotype in the F5 gene, which determines the strength of the gene's effect"?  That is a true, accurate, and direct statement.

There is no need to call it 'Mendelian' in the sense that the trait itself is inherited (the gene certainly is!) nor 'dominant', and then take it back in the same breath. That obfuscates by jargon that sounds knowledgeable but conveys essentially no information and indeed by conveying less information than our statement in the prior paragraph.  The harm is that by oversimplifying it distracts attention from the search for the causal truth, making a problem seem solved when it hasn't been.

Teach the truth
If we follow the kind of approach we suggest here, the truth is actually simpler and just as easy to digest as a 19th century first-look at a problem--simpler, that is, for new students not already acculturated to obsolete thinking.  Teach the truth and we'd have fewer inaccuracies to have to un-teach later.  Since most genetic diseases are not simple, we go on to say that the 'penetrance' of each genotype is complex and depends on life and environmental (and other unknown) factors that probably include modifying effects of the genotype in each person at other unidentified genome locations.

We could then go on to say that, as a matter of history, Mendel chose special cases that were clear and this is how he understood diploid genotype-phenotype relationships.  He found situations where there were only two variants in a gene, one with much stronger effects than the other, and this allowed him to track inheritance across generations and understand the situation.  Etc.

And we can go on to say (yes, now to more advanced students), that variation in F5 is the most common single genetic risk factor for 'thrombophilia' (above average tendency to form blood clots) in Europeans, but not the only one, and many non-genetic factors can also be involved.  So F5 is a cause of clotting, with high penetrance, but not the cause, in the same way that speeding affects risk of car crashes but is not the only risk factor.

We use penetrance properly as the term that connects genotypes and phenotypes, and we don't need to refer to 'Mendelian' traits etc.  We could avoid terms like 'dominance' completely, or at least when we introduce them make it clear that they are complex subtle terms with variable meanings.  In so doing, the next generation could be freed of the conceptual inertia of the Victorian era.

Mendelian inheritance: conclusion

Where does having the right theory make a difference?  Why can't we just assume that a major 'dominant' effect evolves because of its effect?  Why can't we continue to just give genetic counseling risk estimates in Mendelian theoretical terms?

The reason is that these usages are inaccurate at best, and in today's world  not needed.  We have better computational tools than we did when these things began in the mid 1900s.  Instead, for example, of the expected 1/2 for segregation proportions (for traits, not alleles) we can develop estimates of the actual probability of the trait in an offspring of an affected parent.  It would be something like the probability of inheritance of the major parental allele, times the probability of a given effect size (trait measure, for example) plus or times something about environmental effects where known plus  a similar term for the other parent.

Mendel was accused of cheating because his results were too close to his expectations to be due just to chance (there's more to the story since in his case the expectations he was too close to were wrong! see my article in 2002 Evolutionary Anthropology "Goings on in Mendel's garden").  But that is just what genetic risk estimators are doing!  They are using 1/2 for the expected risk of the trait, rather than whatever the empirical evidence, properly studied, shows the risk is.

And similarly, by digesting the message, no longer confounding inheritance of traits with inheritance of genetic elements, we can go beyond rigid statistical 'significance' in GWAS, which is of the same kind as false expectations, and consider all the bits of information that we have.

These are seriously erroneous concepts that misdirect science on a large scale.  They waste funds and lead to false expectations.  It is one thing to pursue ideas that seem, at the time, to be correct even if they eventually prove to be inaccurate--indeed, all ideas are probably of that sort.  But it is quite another to pursue ideas that one knows to be wrong, because that's a way to build a career or you are in a hurry and can't think of better ideas.

Many scientists accept, absorb, and repeat oversimplified dogma.  They teach 'the scientific method', 'survival of the fittest',  classical Mendelism, and the 'modern synthesis'.  They repeat that "nothing in biology makes sense except in light of evolution" (even though most have only a caricature idea of evolution, or what most life scientists actually do on a daily basis).

Maybe they are aware of the inaccuracies, or maybe when teaching they scorn their students' abilities to know the difference.  We think this is  not good for science.  But there is something else, that you might think is even worse.  That is that many if not the vast majority of scientists basically don't bother to think about these things and, like Rhett Butler, simply don't give a damn.

They (we) do our work regardless.  We push ahead to prove our favorite point of view, claiming to follow some principles when it suits us, ignoring them when it doesn't.  It is strictly pragmatic.  There is a lot of dissembling done on a daily basis. Careers have to be made, grants to be garnered, magazines to publish.

All of this is poor practice, but understandable.  Nature is complicated, scientists fallible, experiments and technology often imprecise, and so on.  We stumble, bumble, and bluff our way through.  Things don't go as smoothly as perhaps they might if we were more rigorous relative to theory.  Grants pay for work that they shouldn't.  But, being fallible and having to make a living, we plow ahead and in the end, here and there, there is progress.

In retrospect,  the heroes are remembered and recognized by historians and the media.  Laws of Nature are named after them.  Statues erected, biographies written.  The chaff and blind alleys, and most of us scientists, are  forgotten except by historians.  Philosophers revise their philosophy of science, and science revises its theories.  Life goes on.

That may be the blunt reality, and like other Utopian ideals, our theories of how we act fall short.  In the daily, perhaps rather smug and dismissive, hurly-burly of science, the theoretical fineries are ignored if not actually sneered at.

But shouldn't we do better?  Shouldn't we strive to train students better and to have a better idea of the nature of Nature, so we can be more efficient or effective?  If we are so willing to denigrate alchemy, phrenology,  humoral medicine and phlebotomy, as wrong and wasteful....and to criticize the illusions of religious dogma, should we accept dogmatic ignorance in today's science?  We think not.

Mendelism is we think a good example of something held too rigidly too long past its sell date.  It's taken by rote as a basic core fact of biology, in ways that impede progress and wastes large amounts of funds that service the professions but not the population paying the bill.  We can do better.

Mendelian Inheritance and evolution. Part I

We recently discussed problems with the idea of Mendelian inheritance, and the way that assuming that was a mode of trait inheritance has been so misleading and, we think for that reason incorrect.  (Here's the first of the five posts in that series.)  We'd now like to consider some of the implications of our point of view, when it comes to evolution.  We think this in fact reinforces that point of view, as we'll try to show.

Some traits do seem clearly to 'segregate' (be distributed) among family members in a present or absent mode, associated with a single allele (variant) at a gene, and if one allele is more likely to prevail that is called 'dominant'.

We pointed out that Mendel chose traits that 'worked'--that provided clear-cut material that allowed him to understand the nature of 'inheritance.'  That word is actually somewhat off, because Mendel was interested in the nature of hybridization (inheritance in a mixed cross between strains), and there was the confusion that still widely reigns, between inheritance of traits and inheritance of genes.  By pragmatically equating the two, because that wasn't too far off in his chosen model situation, Mendel got his result.  Even he knew that most traits didn't work that way (and even some traits that should, in some species he later studied, didn't).

For many decades after Mendel, it was thought that such traits had two important properties:  they were stable, and they made clear-cut qualitative trait differences.  If either wasn't true, then Mendel's rules wouldn't work, hybridization wouldn't work as expected, and how inheritance worked would remain obscure.

And, when Darwin's and Wallace's ideas came along, it was clear that evolution wouldn't work, either!  The most one might expect would be that one of the alleles would replace the other over time, by natural selection.   But this was not satisfactory, because evolution clearly involved smaller, gradual changes more than big dramatic ones.  And evolution, even by Darwin's mistaken genetic ideas, would continually generate new variation for selection to screen.  That was a big problem, because the observed new alleles, traits in offspring that were not present in their ancestors, seemed mainly to be grotesquely harmful, not material that selection could work with to adapt to changing circumstances.

Darwin was aware of much of this, too, in fact.  He could not see how immutable traits, like the dominant/recessive ones, could evolve and also he felt that evolution simply had to be gradual and more or less continuous. Among his reasons were his erroneous largely Lamarckian notion of the physical basis of inheritance, and the fear that without gradualism traits or species might arise suddenly....requiring explanations for their origin.

As a result, for decades leading biologists, realizing that Darwin's gradual inheritance theory (that he called 'pangenesis') was fundamentally wrong, were not convinced that natural selection could account for adaptive evolution or, in particular, that this had anything to do with the known mechanisms of inheritance.

The solution that was widely accepted and prevails (not always accurately) to today, was worked out in the 1930s and later, based on some theory and data from earlier in the 1900s.  This solution was known by names like the 'modern evolutionary synthesis.'   It reconciled Mendelian inheritance with gradual evolution in ways that were consistent with variation within and between species, and with the fossil record.

There are many things to dispute about the modern synthesis, and we'll point them out (and have mentioned them before here on MT).  But one thing that is important, but so far as we know hardly if at all recognized, was that the modern synthesis was possible only if Mendel was wrong, in ways we tried to outline in our recent previous series.

We'll elaborate on these thoughts in the next installment.....so stay tuned!

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

This series of posts has been about the illusion of simple Mendelian inheritance, that has been an enormously powerful tool in understanding how genes are inherited, working through carefully chosen experimental situations in which traits were so closely tied to specific alleles (variant states of a single gene) that it seemed as if the trait itself were being inherited.  But it's only genes that are inherited (except for the goop that's in the fertilized egg or other cell that starts a new organism on its way).

We've been saying that the effect of  alleles on a trait varies with the alleles' contexts.  We can call this variation a 'spectrum' of effects, just as a rainbow is a spectrum of color: most variants have very small average effects, but a few, usually rare ones, can have such large effects that it seems that whenever you inherit one of those alleles you're nearly sure to have the trait.  Just as in the classical pattern of occurrence in families represented in this figure that we've grabbed from the web--almost.  We used the original in earlier posts in this series, because it is that which is in all the textbooks.  But this is more like reality and illustrates a main point.  The Aa's in the middle are not exactly as 'dominant' as the true-red Aa individuals.  And the light orange aa in the grandchild could easily be classified as unaffected, or affected....depending on what theory you were trying to confirm:

But we've said that the more clear-cut (or argued to be clear-cut) version is what one sees for a selection of variants in a selection of genes, and it grabbed scientific attention because it fit our expectations of  how inheritance works, based on Mendel's results with carefully chosen traits in peas, and similar trait-selection for the following century.  Even  then candid acknowledgment will be typically made that there is variation in the actual traits that people in the same family have: not all the red dots are equally solid or red, as in the figure.  And we know that as a rule, since most effects of individual variants are very small, and many variants contribute to most traits, even the basic idea of Mendelian inheritance makes little sense as a rigorous theory of inheritance--and we should realize that, accept that, even if we wish things were simpler.  The real world doesn't have to fulfill our wishes!

In fact, fine classical papers from around 1960 showed that the appearance--the illusion--of Mendelism can arise in another way unrelated to the extreme, usually rare ends of the allelic effects distributions.  If a presence/absence trait, like hyptertension vs normotension, stroke vs non-stroke, cancer vs non-cancer, arises when a threshold is exceeded on some underlying quantitative trait (e.g., if your blood pressure rises above some agreed-on cutoff level for calling it hypertension), and if many different genes contribute to it, the trait can occur in families in a way that appears clearly 'Mendelian', that is, as if only a single allele were responsible.

We know that even with complex inheritance, children will resemble their parents, and we know the average extent to which that should happen.  Generally, you're half-way between your parents' trait levels, such as stature.  But the usual idea is that this doesn't apply to discrete (yes/no) traits that follow Mendel's rules: you're either this or that, but not a half-way blend of your parents for such traits.  As Darwin would say, the traits do not 'blend'.

Nonetheless, as was shown in the '60s, the probability of a qualitative trait (yes/no, like hypertension of diabetes) can be similar enough between close relatives that it appears to follow Mendel's rules.
This is because if you have a combination of genetic variants, across your genome, that makes your blood pressure high, your children will inherit half of those (on average) plus whatever similar risk effects your spouse may have, and for a generation or two it can have a net result of around half of children of an affected parent also being affected with hypertension, which is what you'd expect if there were just one Hypertension gene with two states, normal and hypertensive.  The illusion can arise under a broad set of circumstances, and can fuel hopes of simple situations----or hopes that GWAS will, after all, really work.

This means that, in addition to all the other things discussed in this series, and not even considering shared environmental effects which can often be by far the most important, multi-gene causation can reinforce the ideas of someone assuming that Mendelian inheritance of the trait is true.   

We can relate all of this to GWAS findings in another way as well.  If a given allele is common enough in cases for its effects to be found and reach statistical significance, relative to its frequency in controls, then it has a chance to be detected in a GWAS study.  But this depends on its penetrance, that is, on the strength of its effects, on their own, on a trait measure like stature or blood pressure, or on the presence of a disease.  Highly penetrant alleles will be found more frequently in cases than controls because they have a higher chance of 'causing' the trait.  The greater the effect, the more likely if you have the allele you have the disease.

This is a kind of 'dominance', because the allele is being detected against the other allele at that gene in individuals, plus whatever other relevant variants they have in their genome. That typically only a few genes are identified in this way shows how relatively rare real dominance is--how far it is from being the baseline, basic nature of inheritance!  In fact, most variants that contribute contribute so little--have so little 'dominance' in this context--that we simply cannot detect their individual effects (or those effects are not enough to generate a statistically 'significant' association with the trait).

Put another way, these various considerations show how, if we assume a theory, we can make the data fit the theory and also assume we understand the data.  But if that theory is wrong or very inaccurate, it can lead us far astray.....as Mendelian theory has indeed been doing for more than 150 years.

Mendelian Inheritance: Basic Genetics or Basic Mistake? Part IV

So, if we are right that 'Mendelian' inheritance is fundamentally mistaken--or, at best, generally inaccurate and misleading--then what kinds of conclusions can we draw and how can some of the basic attributes of life be accounted for?  We have to assume that life evolved and that to a great extent means genes, broadly defined.  Indeed, we may be worse off than we think if, as we tried to show in an earlier post, even what a gene is, is elusive with current knowledge.

Waterhouse, A Mermaid

In our book after which this blog is eponymously named, we argued that there has been too much attention placed on evolution (and a competition-centered view of life at that), relative to the more ubiquitous properties found at life's other time scales--of development and maintenance of an organism, and of the interaction of factors on the ecological scale.

The idea of Mendelian inheritance, which is widely extended to the vast majority of gene-trait relationships that clearly are not following the monk's principles, is of discrete states one of which dominates in their various combinations.  This was (and is) extended to evolution, with our grossly inadequate 'winner take all', 'survival of the fittest' notion of one best -- fitness-wise dominant -- variant that natural selection favored into success just as surely as a dominant allele was favored ineluctably into manifestation in the organism.

But if you think of the other properties of life, which we center our book around and will briefly name here, you might ask how Mendelian thinking, which only by deep contortions can be related to those principles, could ever have taken hold, unless it's by what amounts to an ideology, a takeover of a certain highly deterministic, simplistic view of the living world--a view that simply, for decades, wrote off into alleged irrelevance the actual way in which organisms work.

Sequestration and modularity
From DNA on up, life is organized as hierarchically nested partially sequestered units.  DNA has functional sequence elements arranged  together along chromosomes, but partially isolated in that they can serve their individual functions.  The units (such as amino acid codons) are repeated many times.  Proteins have partly separated functional units, too.  Cells are packaged units that have many different partially isolated subunits within them, such as organelles like mitochodria, isolated areas like the nucleus, and local differences in what is present in the cell membrane (e.g., a cell may have a front and back end, so to speak).

An organism (or even collections of organisms as in bacterial biofilms) is made of large numbers of cells.  These are repeated units that communicate with each other via combinations of signaling and other molecules, and this is what leads them to express particular, context-dependent sets of genes.  So that they are repeated, but different.  This process occurs hierarchically during development, and in response to environmental changes during life.  An organism is divided into organs and organ systems, like brain, heart and vessels, digestive organs, and so on.

Organs are made of nested, repeated units.  Intestines are segmented along their length, and their surface is littered with repeated structures called 'villi'.  Skeletons are made of repeated, partially different but interaction bones.  Trees are made of leaves and so on.  Plants and animals alike are constructed by repetition and branching.

Yet, importantly, each organism has only the one genome that it inherited from its parents!  So the same genome makes brains and braincases, that are as different from each other as any two things in all of life.

These processes are both qualitative: each leaf or bone is a separate structure; and quantitative: each such structure is somewhat different.  This is the natural variation that is the material on which evolution can work.

If you just think about this, you would have to wonder how it could be brought about by Mendelian inheritance.  How could just two states at a single gene be responsible for such complexity and quantitative internal organization?

It is perhaps easier to see how breaking a gene could cause a major state change, and thus a normal and dead alternative at a gene could be manifest in Mendelian inheritance terms.  Or if the trait is very close to a protein coded by a single gene, two major alleles (variants) at that gene could have big differences (yellow vs green peas, for example).  But as a rule, Mendelian inheritance makes little sense.  Partly that's because, as mentioned in earlier parts of this series, we confuse inheritance of traits with inheritance of genes.  Genes--specific stretches of DNA--are clearly inherited in a Mendelian way (with some exceptions that don't matter in this context here).  But traits generally are not.

The reason for all of this is that the basic principles of life, that include the above descriptions (see our book for detailed discussion in this context), involve cooperation--that is, co-operation or contemporary interaction--among many different elements, each of them variable in a population.  What an individual inherits are sets of genomic variants from its parents.  The traits an individual manifests are the net results of these variants acting in the particular environments in which they find themselves.

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.

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

The idea of Mendelian inheritance, revered for more than a century, was initially about the inherently causal nature of dominance and recessiveness.  The A allele always and,  presumably, inherently, made its effects manifest, as in the accompanying figure.  Even as late as 1995, an influential paper termed this 'physiological' dominance.

But why so long after Mendel's rules were deeply established, was there a need for such a term?

In the genetics of quantitative traits, one can look at the average trait value (say, stature or body fat content of pigs or oil content of corn) in AA's and aa's.  If the 'A' were physiologically dominant, then the Aa's should have the same mean value as the AA's.  These are clearly statistical statements because unlike green vs yellow peas, there is variation and there are sampling issues (in fact, even Mendel's classical traits had some variation, but little overlap between dominant and recessive plants).

What transpires as a rule, however, is that the Aa's are not exactly like the AA's.  But a common alternative to Mendelian ideas was that rather than being dominant and recessive, the contributions of the alleles at a gene were additive, like doses of medicine:  Each copy of, say, an A allele you have, is a jump in your trait value.  In such situations, Aa's would be exactly intermediate between AA's and aa's.  If instead they shift towards one of the two homozygote (AA or aa) individuals, this is called statistical dominance.

Unlike physiological dominance, statistical dominance has to be evaluated by sampling from a population, and that means in turn that the idea of estimating the net or 'actual' effects of the A and a alleles, depends on the frequencies of these in the population, and more importantly, that also means that environmental and other genomic effects will affect the mean values of the carriers of the 3 genotypes.  Statistical geneticists now treat these two kinds of dominance differently, often ignoring the physiological because it is hard to identify in real-world situations of quantitatively variable traits, as opposed to experimental settings with only two clear states, that have been part of genetics ever since Mendel himself.

We can relate  this to GWAS findings a simple way.  If a given allele is common enough in cases for its effects to be found and reach statistical significance, relative to its frequency in controls, then it has a chance to be detected in a GWAS study.  But this depends on its penetrance, that is, on the strength of its effects, on their own, on a trait measure like stature or blood pressure, or on the presence of a disease.  Highly penetrant alleles will be found more frequently in cases than controls because they have a higher chance of 'causing' the trait.  The greater the effect, the more likely if you have the allele you have the disease.

This is a kind of 'dominance', because the allele is being detected against the other allele at that gene in individuals, plus whatever other relevant variants they have in their genome. That typically only a few genes are identified in this way shows how relatively rare real dominance is--how far it is from being the baseline, basic nature of inheritance!  In fact, most variants that contribute contribute so little--have so little 'dominance' in this context--that we simply cannot detect their individual effects (or those effects are not enough to generate a statistically 'significant' association with the trait).  So, dominance is far from the general rule.  We will see in the next installment why this should not be any kind of surprise.

That cricket song? Maybe he's just whistling Dixie after all

Science last week published a cautionary tale--"Natural and Sexual Selection in a Wild Insect Population"--about the limits of observations made in the lab, but in fact it suggests limits to what 'everyone knows', as well. The paper was accompanied by a commentary by Marlene Zuk. 

The authors, R. Rodríguez-Muñoz et al., point out that most studies of reproductive success among invertebrates are carried out in the lab, while those on vertebrates more often take place in the field. They set out to compare observations of reproductive success, and therefore determinants of fitness, among crickets in the field with conventional wisdom gained from observations in the lab.

Although poorly understood in their natural habitats, crickets have become an important laboratory model system, revealing complex forms of sexual selection whereby females choose between males according to their songs, males fight, females manipulate sperm from several males to favor unrelated males, and females lay eggs faster when mated to dominant males. However, although we now have many insights into the behavior and physiology of crickets in the laboratory, we have almost no idea how important these various aspects are in the insects’ natural habitat. This discrepancy is a cause for concern: Laboratory situations remove some sources of selection that may be very important in wild populations and may create new pressures; for instance, it may be that males that sing more get more mates in the lab, but in the field such males may die younger.

Rodríguez-Muñoz et al. set up a series of motion-activated cameras to monitor the comings and goings of these flightless burrow-dwelling field crickets (Gryllus campestris, as pictured in the drawing above), and confirmed paternity with DNA testing, in this way following 2 generations of crickets. They labeled each cricket, and noted each one's behavior, including fights between males, who won and who lost, as an indicator of dominant or subordinate behavior.

Perhaps surprisingly, they found that mating success didn't necessarily correlate with reproductive success, or number of offspring.  And they found some inconsistencies between what theory predicts and what they actually observed.

They report greater variance in reproductive success among males than among females, which is consistent with current theory, but this wasn't because males had more mates than females, as they found no difference in variance in number of mates between the sexes. Crickets of both sexes who had more lifetime mates had more offspring--this was true even for females that used only sperm from the single ejaculate of one male, even if they had multiple mates (this was confirmed by DNA testing).

Reproductive success was also correlated with size and lifespan--larger, longer-lived individuals of both sexes left more offspring. Among males, dominance and the 'interaction between size and singing activity' were predictive of mating success (smaller males who sang more had more mating opportunities), but offspring number was predicted by the interaction between size and singing (again, smaller males had more offspring when they sang more), and longevity and singing, but not by dominance. This is contrary to what has been found in the lab, where dominant males have greater numbers of offspring--and contrary to long-standing theory about the fitness effects of dominance behavior applied to vertebrates and invertebrates alike.

Long-standing theory also predicts that singing and size are sexually selected traits that demonstrate higher genetic quality, and that, therefore, larger males who sing a lot will have more offspring than their smaller quieter neighbors. However, in this population of crickets at least, these traits don't seem to be indicators of genetic condition, or if they are, they don't necessarily lead to increased fitness, or more descendants.

So, dominance, size, singing activity, number of mates, all of which are assumed to be either directly or indirectly correlated with reproductive success, are not predictive of either mating success or number of offspring in these crickets.  Indeed, and this is perhaps the most startling finding of this study (at least to those interested in documenting a genetic basis for behavior), most crickets left no offspring at all. As Zuk says,

Contrary to theory, or at least to common assumptions about animal behavior and ecology, was the discovery that the vast majority of individuals, whether male or female, did not successfully reproduce at all. Although males are often acknowledged to play a high-stakes, high-risk game with many losers, conventional wisdom has it that virtually all females, even those in relatively poor condition, should be able to eke out at least one or two young; this disparity underlies, for example, the Trivers-Willard effect on sex ratio, in which mothers in poor condition are predicted to favor daughters over sons because even low-quality females are expected to be able to reproduce. Yet none of the female G. campestris and only a couple of the males had more than 10 surviving offspring and most had none, despite the ability of females to lay scores of eggs.

Rodrîguez-Muñoz et al. conclude that most of their laboratory observations are upheld in the field. But there's a lot of "contrary to theory" in this story.  And--this is our conclusion, not theirs--it seems that Nature can fine-tune those traits that are supposed to indicate genetic quality or that attract mates as much as She wants to, but none of that will guarantee reproductive success.   No matter how fine their song or how many fights they win, most crickets don't reproduce at all.

As we have written a number of times, when it comes to evolutionary success, chance and good luck have the upper hand more often than many of us like to think. And extrapolation from current observations, lab or field, to the evolutionary scale of thousands or millions of generations, in different ecological and physical habitats, is usually too risky to justify the lack of circumspection in so many evolutionary scenarios eagerly advanced by evolutionary behaviorists.