A sinister attractor – why males are more likely to be left-handed

It seems an innocent enough question: why are males more frequently left-handed than females? But the answer is far from simple, and it reveals fundamental principles of how our psychological and behavioural traits are encoded in our genomes, how variability in those traits arise, and how development is channelled towards specific outcomes. It turns out that the explanation rests on an underlying difference between males and females that has far-reaching consequences for all kinds of traits, including neurodevelopmental disorders. 

 

Pixabay.com

A recent tweet from Abdel Abdellaoui showed data on rates of left-handedness obtained from the UK Biobank, and asked two questions: why is left-handedness more common in males and why are rates of reported left-handedness increasing over time?

I don’t think the answer to the second question is known but I presume it has to do with the declining practice of forcing left-handers to write right-handed. This once common practice reflects a long history of prejudice against lefties, illustrated by the derivation of the word “sinister”, which in Latin means “left”, as opposed to “dexter” meaning “right” which is the root of the positive words “dexterity” and “dextrous”.

The first question – why is left-handedness more common in males? – is the one I want to explore here, as it opens up some fascinating questions about robustness, variability, and developmental attractors. This is a long known and extremely robust finding. Rates of left-handedness (from this UK sample) are around 11-12% in males and 9-10% in females and these kinds of differences are seen across cultures and across time. 

 

Why would this be? For that matter, why do we even have handedness? Why is there a bias towards right-handedness? And does this sex difference tell us anything about how handedness emerges or about sex differences in neural or behavioral traits more generally?

 

Handedness is not unique to humans – many animals show a preference for using one hand over another for (ahem) dextrous movements. (Not so much for big movements or lifting heavy things, but for actions requiring fine motor control). This may reflect the wiring and communication demands of such actions. For fine motor sequences that have to be carried out quickly, it may be much more efficient to code them all in a concentrated area of neural tissue. In the brain, this means avoiding having to communicate back and forth between the two hemispheres. The result is that the neural substrates of fine motor sequences tend to get concentrated in one hemisphere. This may be why control of speech, which involves very sophisticated motor programs, tends to be localised to one hemisphere.

 

What’s less obvious is why there should be a bias to consistently localise such functions to one specific hemisphere versus the other. One possible explanation is that biasing the process consistently towards one side or the other might make the outcome of hand preference generally more robust. Maybe getting rid of the need to “choose” one side or the other at some stage of development removes a possible failure point from the overall process. (That’s admittedly super speculative, on my part). Others have proposed a variety of social explanations for a consistent directional bias.

 

Patterning the left-right axis

 

In any case, in order for the two hemispheres to develop different patterns of neural circuitry (or for our internal organs to be patterned and positioned asymmetrically), the developing embryo must have some systems for distinguishing left from right. In particular, it requires a symmetry breaker, based on something intrinsic in the embryo. The details of how this happens differ between species, but the mechanism ultimately seems to go all the way down to the level of the chirality of various protein molecules, often with some function in the cytoskeleton or cilia motility. After this initial symmetry breaking process, a much more conserved set of signaling pathways is involved in mediating the subsequent differentiation of the left and right sides of the developing embryo, ultimately including the brain.  

 

So, there are genetic processes that reliably code for hand preference (presumably by controlling aspects of neural development that differ between the hemispheres) that may be ancient and found in many animals. And there seem to be separate genetic processes that code for the rightward bias, which may be more unique to humans (but for findings from other animals see here and here).

 

But why is this rightward bias not 100%? There are two possible reasons: one, a certain rate of left-handedness may be evolutionarily selected for. That is, in a game theory sense, it may be beneficial to be left-handed when most other people are right-handed (in hand-to-hand combat, for example), but once the frequency of left-handedness starts to increase, that advantage decreases.

 

The alternative is much more prosaic: a certain rate of left-handedness may simply reflect the fact that any genetically encoded process will show some variation, unless that variation literally kills you. (My money is on this explanation because it doesn’t require any additional special reasons).

 

The genetics of handedness

 

Whether it’s actively selected for, or just not actively selected against, if genetic variation affects the trait, this means left-handedness should run in the family, and indeed it does. The general rate of left-handedness is about 10%, but if one of your parents is left-handed, then your chance of being left-handed is about 15%. If both of your parents are left-handed, that rate rises to over 20%. 

 

Very large-scale twin and family studies have estimated the heritability of handedness at about 25%. That means, across the population, about a quarter of the variance in handedness is due to genetic differences between people. Recent genome-wide association studies have had some success in identifying genetic variants that predispose (very weakly) to left-handedness. Some enrichment of genes encoding cytoskeletal proteins seems congruent with the known cellular mechanisms of left-right patterning (but frankly it’s early days with these studies).

 

The important thing here is that the inheritance of left-handedness is probabilistic. In fact, you don’t inherit left-handedness – you inherit a certain likelihood of being left-handed. We can see that this probability plays out independently, even in monozygotic twins. If one twin is left-handed, the chance of the other being left-handed is only about 25% (a good bit higher than the population average but obviously much less than 100%).

 

So what other factors determine how this genetic likelihood plays out? Could our upbringing have an effect? Well, most parents will probably recognise that the handedness of their children is not something they had any influence over. And the twin and family studies bear this common experience out – they have consistently found no effect at all of the family environment on handedness. Nor have any systematic factors in the wider environment been reliably associated with handedness.

 

If it’s not genes and not environment, what else could be affecting this trait? Well, there is a third source of variation that is extremely important, though often overlooked, which is development itself. As I have written about extensively (including in my book, “Innate”), the processes of development are noisy, in engineering terms. What is encoded in the genome is not a highly specified outcome but rather a set of biochemical rules that underpin the processes of development. When played out, these mindless biochemical algorithms will tend (quite robustly) to produce an outcome within a well-functioning range.

 

Natural selection frankly doesn’t care that much about all the details – the thing just has to work. The consequence of the inherent noisiness of developmental processes is that every time you run the developmental program from any particular genome, you get a unique outcome. For many traits (like height, for example, or facial morphology), this developmental variation manifests quantitatively. For traits like handedness, however, which is effectively dichotomous, it manifests probabilistically. 

 

 

A rolling stone

 

A useful way of thinking about this is provided by the visual metaphor of the “epigenetic landscape”, introduced by Conrad Waddington in 1957. The idea is that a developing organism (the ball) is channelled along certain phenotypic trajectories as it proceeds through development. The shape of the landscape and the relative depth of these channels is determined by the genetics of the individual.

For a landscape derived from an “average” genome, it should be less likely for the ball to roll into the channel that leads towards left-handedness than the one towards right-handedness. If you run 100 balls over this landscape, on average only 10 of them would end up in the lefty channel, while 90 would end up in the righty channel. But if you generated the landscape from the genome of someone who is actually left-handed, the channel towards left-handedness would be easier to get into, and the outcome of 100 balls might be 25:75.

 

Whatever the shape of the underlying landscape, the actual outcome in any individual would depend on a significant element of chance. At some point in development, represented by the arrows in the diagram, a small amount of noise might nudge the ball towards one or other trajectory. The self-organising processes of development would then reinforce that choice to ultimately produce dichotomous outcomes. In the parlance of dynamical systems, left- and right-handedness are two distinct phenotypic attractors.

 

The development of handedness may rely on processes that act like a switch. We saw above that it is important to localise fine motor control to one side of the brain or the other. It may not matter that much whether it’s left or right – what you want to avoid is failure to localise it at all. Left- or right-handedness may thus represent mutually exclusive – even possibly antagonistic – developmental trajectories. “Choosing” one pathway may inhibit the other and reinforce itself. This view is consistent with the fact that left-handedness is much more common (and thus presumably much better tolerated) than either mixed handedness or non-handedness. 

 

What this all means is that, though handedness is only partly heritable, it may be largely or even completely innate. (As an aside, a similar situation may hold for other traits, such as sexual preference).

 

Now, back to the question we started with – why should sex affect the outcome of development with respect to handedness? What is about the way males develop that would lead them to end up left-handed more frequently, and why should things be this way? There are many scenarios one could come up with that invoke some sort of special connection between sex and handedness, maybe involving sexual selection, males with rare phenotypes having an advantage, and so on. These all seem very speculative to me and I don’t think we need to posit any such mechanisms. A more likely explanation to me, and one that is certainly more parsimonious, is that the increased rate of left-handedness reflects the greater male variability that is observed in many traits, not just in humans, but in many other animals too.

 

 

Greater male variability

 

Males show a small but statistically significantly higher variance than females for all kinds of traits in humans. The spread of values is greater in males for birth weight, morphological traits, a range of blood parameters, and even things like athletic and academic performance. The same is true for IQ, with males showing a wider, flatter curve than females, with a consequently greater proportion of males at both the low and high ends. There are similar findings in mice, especially for morphological traits, though females showed a greater variance in immunological measures, possibly due to fluctuating hormonal influences. 

 

You can see this kind of variability play out within an individual too, across the two sides of the body (which represent largely independent “runs” of the same genomic program). Males show higher levels of “fluctuating” (i.e., random) asymmetry of facial morphology than females. 

 

Why would this be? Well, first, the fact that this trend is observed across species argues strongly against a cultural origin for it, though initial biological differences might well be amplified through cultural mechanisms in humans. But what would cause it in the first place? We might look to hormonal influences – maybe testosterone just plays havoc with the precision of developmental programs, for example. But as we will see below, the same phenomenon is observed in insects where sex hormones play no role in morphological differentiation.

 

Something more fundamental is going on and it can be traced to the sex chromosomes – in particular, to the fact that males in mammals have only one copy of the X chromosome, while females have two. Genetic variation on the X chromosome will therefore have a bigger phenotypic effect in males, not just for single loci, but as a collective effect. This paper by Reinhold and Engqvist sums it up nicely:

 

“In females, the traits that are influenced by X chromosomal genes will be under the average influence of the two parental copies, whereas in males, the effect of the single X-chromosome will not be averaged. As a result, male mammals are expected to show larger variability than females in all traits that are, at least to some extent, influenced by X-chromosomal alleles.” 

 

This is not to suggest that all the traits mentioned above are X-linked, in the normal sense of that term. In fact, they are all highly polygenic, involving genes all over the genome. It is just that some of those genes are on the X chromosome and variation in such genes will be averaged out or buffered more in females than in males. Because the buffering of genetic variation is a little less efficient or robust in males, the variance of the traits will be consequently greater.

 

Now, the hypothesis that this effect is due to the number of X chromosomes, rather than effects of male hormones, makes a strong prediction, which Reinhold and Engqvist tested beautifully, taking advantage of the fact that in some species females are the ones with two different sex chromosomes. This is the case in many bird species, where males have two Z chromosomes and females have a Z and a W. A similar situation holds in butterflies. But most mammals and many insects have an XX (female) and XY (male) arrangement.

 

The prediction is that in such species, the effect should be reversed – females should be more variable. Looking across many different species of mammals, birds, butterflies, and insects, a pattern consistent with the sex-chromosome hypothesis was found: the sex with two different sex chromosomes was more variable. (As an aside, this paper is a wonderful example of how to do science – an insightful and bold prediction, allowing a stern test of a hypothesis, with painstaking research to follow it up).

 

Okay, back to humans. One way to interpret the observation that males are more variable is that they are less robustly channelled into narrow phenotypic outcomes. As discussed above, this will mostly manifest as quantitatively greater variance for all kinds of traits. For handedness, it should mean that developing male organisms are less strongly channelled into the trajectory leading to right-handedness. In our visual metaphor, this may mean a slightly lower ridge between the channels for a longer time or generally a flatter plain preceding the important choice point. Development in males should be just a little noisier and all the feedback loops that normally ensure robust development should be just a little less able to buffer that noise. In effect, male embryos may be slightly more likely to jiggle into the left-handed channel.

 

[Note: I’d love to try and formalise those intuitions or even have a virtual marble run to play with parameters in, if there are any modellers out there who’d fancy having a go].

 

If this were just about handedness, it’d be a cute story, but maybe just a curiosity. But we can see the same effect on other phenotypes, including susceptibility to neurodevelopmental disorders. Males have substantially higher rates of diagnosis of a range of such disorders, including autism, ADHD, schizophrenia, stuttering, tic disorders, and others. These conditions can be caused by rare mutations in any of a very large number of different genes, with complicated polygenic background effects at play.

 

A now well-replicated finding is that females with such diagnoses have more serious mutations on average than males do. This suggests that it takes a bigger mutation to push a developing female brain into one of these phenotypic outcomes, while developing male brains are less able to buffer the effects and therefore more vulnerable. Consistent with this view, when such mutations are inherited from a parent (as opposed to arising de novo in the generation of sperm or eggs), they have been found to be more likely to have been inherited from the mother. One interpretation of that result is that males who had such a mutation would have been more severely affected and thus less likely to have children, while females are better able to buffer the effects.

 

 

See what happens when you ask a seemingly innocent question? ;-)