Maps of a Growing Brain Show That Genes Do Less Than We Thought
The worm turns against genetic determinism
There’s a strangely persistent idea that your genes are the blueprint for your brain. Robert Plomin even called his book about the genetic influence on the mind “Blueprint”. But a blueprint is a detailed one-to-one schematic of what will be constructed. Genes are not that. Self-evidently not. For example, people who like to talk about genes setting the brain’s blueprint will talk about genetic influences on mental disorders; they’ll say “look at schizophrenia: if one identical twin has it, there’s a 50% chance the other twin will develop it too”. The other way of looking at it is there’s a 50% chance the other twin does not develop schizophrenia, even though the twins are clones of each other. Identical DNA, and still not identical brains.
But directly observing how genes influence brains has been impossible, leaving arguments about how much genes influence our brains to fester and bubble and grow in rancour. Until now. Now a team of researchers have reconstructed the brain of a worm as it grows, and shown us just how much the wiring of this tiny brain depends on chance, not genes.
It’s a truism of science that the driest of titles, the most mundane of descriptions, can hide the juiciest, most explosive content. “Connectomes across development reveal principles of brain maturation,” the title of a recent paper in Nature by Daniel Witvliet and (many) colleagues does not inspire. And neither does the accurate but bone-dry summary of what they did: take the tiny worm C. elegans, less than a millimetre long, map the wiring between most of its neurons after it had just been born, and then repeat that mapping as it grows up.
But this is a bit like describing Hamlet as two-and-a-bit hours of a princeling meandering around a castle going slowly mad. The play’s the thing. And what this paper shows is that genetic determinism, like Horatio, is dead.
You see, if any creature was going to have its brain determined entirely by its genes, it was C. elegans. It has 302 neurons in its adult brain. Always 302. That number is entirely genetically specified, no argument there. And it has a lot of genome. As the first creature to have its complete genome sequenced, we know it has around 20,000 genes. Whereas we have about 86 billion neurons and in the region of 30,000 genes. Plenty of scope, then, for the worm’s genes to specify how its neurons wire together.
Witvliet and company’s starting question was simple: how does its brain wire up as it develops? To answer that, they built a map of the wiring between 204 of its neurons, at four different stages of development: three different stages of being a baby — a larvae — as it grows, and the adult form. Eight maps in total, from eight different worms (as it’s quite hard to survive the process of having your nervous system sliced into 50 nanometer thick slices, slid on a conveyor belt into an electron microscope, scanned into a gigantic digitised image stack, and the connection from one neuron to another tracked across the stack of images by specially trained neural networks called David, Ben, and James — i.e. the first three authors on the paper). Which, given that the final, painstaking completion of the wiring diagram of this tiny worm was only announced to great fanfare two years ago, is an extraordinary technical achievement.
The important thing is that these eight worms were isogenic. They had identical genomes (as identical as we can get), so we might expect they grew identical brains. They did not.
Of all the connections that developed between the 204 neurons, 43% did not consistently appear as the worms grew older. Worse, between the two maps made from adults, the variation in the wiring was huge: of 2202 connections in one adult, 602 were not in the other adult. That’s 27% of all connections in one adult that were not in the other. Genetically identical animals, genetically specified numbers of neurons: definitely different wiring diagrams.
Which were built on top of the same scaffold. What was consistent between all eight worms was the physical contact between neurons. From birth, all the neurons and their outgrowths were locked in position, physically touching in the same places. The type, location, and size of a couple of hundred neurons seemed to be under genetic control. What differed was whether those physical touches turned into actual working connections, synapses where the signal from one neuron could influence the other.
Genetics provided physical connections; development created the actual wiring.
Precisely what determined whether two neurons got wired together is the next thing to work out. Witlvliet and co found some clues: for example, not all types of connections were equally variable, with the the wiring from the motorneurons to the muscles being notably less variable between the adults than other types of connection.
From myriad other studies of how brains develop, we also know that this variation in what connected to what was under the influence of least two strong forces. One is the stochastic control of gene expression, that which genes get turned on is down to random variation in the environment — i.e. the cell — in which they find themselves. Another is experience, because neural activity itself, reflecting what happens to the animal, drives whether connections develop or not.
There are good reasons why evolution wouldn’t want a brain’s wiring to be genetically determined, even in something as simple as C. elegans and its 302 neurons. Because it lets the animal adapt. Variability in wiring creates variability in behaviour, even in C. elegans: some wriggle further, some turn more. So even in isogenic worms this could increase the fitness across the gene pool. If all copies of the same gene had identical effects on the brain, no advantage could be taken of local circumstances, of chance variations in behaviour giving the edge to survival.
Genes then do not determine the brain’s wiring, nor do they determine all behaviour, even in a 302-neuron clone worm in which they could, in theory, do so. So it’s no surprise when we come to humans and our 86 billion neuron brain that even identical twins do not have remotely identical brains. Development and life experience can and will alter how neurons are wired together. Searching for variations in genes that underpin mental disorders can only take us so far, and may ultimately be fruitless — it is also no surprise that at best we see hundreds of genes each having a minuscule contribution to the chances of developing a given mental disorder, and that collectively all those hundreds of genes together can only explain at most some of how the chances of getting that disorder varies between people. No surprise, because C. elegans has given us compelling evidence that genes are a not a blueprint for the brain, but a scaffold upon which the brain is constructed.
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