Chapter 3 — The Wire Branch

Chapter 3

For most of the past decade, the question that organised the field has been a small one: what is wrong with the two and a half per cent.

The two and a half per cent — the small but consistently identifiable minority of people whose response to bent wire is substantially weaker than the population mean — has been described in the medical literature for over a century. The condition was historically called insensibility to the bend; the modern clinical term is affinity-deficit, though the affected community has tended to prefer affinity-minority, and the literature now carries both. The affected population, by every demographic survey conducted in the past fifty years, comes in at around 2.5 per cent of every population sampled, in every region, with no significant variation by ethnicity or geography. It is the rare condition that is genuinely uniform across human populations, and the uniformity has been one of the durable puzzles of the modern medical genetics of cognition.

The clinical literature on the condition is large and thoughtful. The genetic literature, until quite recently, was thin. In the late 2010s several groups began the systematic characterisation that the condition had long deserved, and over the following years the picture filled in: the affinity-deficit phenotype turned out to be associated with variation at a number of distinct genetic loci, scattered across the genome, with the affected individuals carrying disrupting variants in different combinations across populations. The condition was multifactorial, recurrent, broadly evenly distributed; the genes involved converged on a particular developmental pathway; and the pathway, as the comparative biologists pointed out almost as soon as the convergence was recognised, was a pathway humans had and other primates didn’t.

That last observation is what the field had been waiting for. The work of the past two years has now resolved it. Last month’s publication of the consortium synthesis in Nature — eighty-six authors, five years of converging evidence — presents the developmental biology, the molecular characterisation, the population-genetic dating, the comparative primate work, and the cultural-historical framing in coordinated form. Taken together, they give us our first real understanding of the genetic basis of the affinity humans have for bent-wire forms. The synthesis is unusual.

This piece is the story of how we got here, and of what the synthesis tells us.

The foundational work belongs to Sara Lindahl, whose group at the Karolinska Institute spent the first half of the 2010s building the standardised behavioural assays that made everything that followed possible. The challenge Lindahl took on was the unglamorous one: the affinity for bent wire is observable and felt by nearly everyone, but it is also subtle, multidimensional, and resistant to the kind of clean phenotypic measurement that quantitative genetics requires. Lindahl built, with collaborators in Helsinki and Stuttgart, a battery of assays that could measure individual variation in what the literature now calls bent-form response — a layered profile combining the visual recognition of bent-wire forms, the kinaesthetic reward of producing them, and the particular satisfaction of closure that the religious traditions have always identified as the gesture’s culminating moment. The popular literature has settled on wire-affinity as the shorthand for this layered response, but the technical phrase is more careful, and what the genetics has been characterising is the layered response in full.

By 2016 the assays had been validated and were being deployed at scale across several European biobanks, and the resulting phenotypic data were ready to be paired with the genomic data those biobanks had already accumulated. The first GWAS papers came out in 2017 and 2018, from Lindahl’s group and from several others working with the same assays. They showed what large-scale genetic studies of complex behavioural traits typically show: many small contributions distributed across the genome, with several loci reaching genome-wide significance and a number of others suggestive. Some of the strongest hits were in regulatory regions near genes involved in the development of early visual and somatosensory processing — exactly the circuits one would expect, given what bent-form response measures.

What was less expected was that the modifier loci — the variants that made the difference between strong and weak response — converged on a single developmental pathway. By 2018 this convergence was clear enough that the field began to ask what was at the bottom of it. The modifiers were modulating something. The something was a pathway, and the pathway had a regulatory architecture humans had and the great apes didn’t.

That recognition opened the next phase of the work.

The molecular work of the past two years, led by Julien Aubert’s group at the Pasteur Institute, has now characterised the regulatory architecture in detail. The pathway the modifier loci converge on is anchored by an unusual regulatory region on the long arm of chromosome eleven. The region is ERV-derived: it carries the long terminal repeats and flanking-sequence signature characteristic of an ancient retroviral integration that became part of the human genome and was subsequently recruited into a regulatory function. The integration is absent from the genomes of all other primates so far sequenced, including chimpanzees and bonobos.

ERV-derived regulatory elements are not in themselves unusual. Roughly eight per cent of the human genome is composed of endogenous retroviral sequence accumulated over evolutionary time, and several of these ancient integrations have been recruited into important biological functions: the syncytin genes, descended from a retroviral envelope protein, are essential for placental development in mammals; other ERV-derived elements regulate expression in the early embryo. The bent-form-response locus joins this respectable lineage. It is, as Aubert told me, “a fortunate viral integration event, of a kind that has happened many times in our deep history, which has given us one of the most distinctive features of our cognitive nature.”

The functional confirmation comes from Hiroshi Nakamura’s group at RIKEN, whose mouse models carry humanised versions of the regulatory region. The animals do not bend wire — they are mice — but they do show the predicted pattern of early-life over-expression in the relevant developmental circuits, and they show an altered profile of dopaminergic response to specific classes of visual and tactile stimulus that, in humans, would correspond to the experience of seeing or handling a bent-wire form. The cascade is straightforward: the regulatory region drives, in early childhood, slightly higher expression of a set of transcription factors in the cortical and subcortical circuits that mature into the substrates of the affinity. Carriers of the high-response architecture acquire the response in development; the rest of the layered phenotype follows from there.

The picture is a textbook case of how an ancient regulatory element produces a complex behavioural phenotype, mediated through specific developmental and circuit-level mechanisms. The science is satisfying.

The molecular work answers the question of what. The population-genetic work in the consortium synthesis answers the question of when.

Coalescence analysis dates the haplotype block to approximately seventy-five thousand years before present, with a confidence interval narrow enough that the date is, as one of the authors put it on a press call at the time, “really quite firm.” This places the integration in a period of considerable interest to human evolutionary biologists. Seventy-five thousand years ago is squarely within the window of the pre-dispersal African population structure that preceded the major successful out-of-Africa migration, and it sits close to the Toba supereruption, around which the literature has long debated whether Homo sapiens underwent a severe demographic bottleneck.

The bottleneck context matters here, and the consortium paper discusses it carefully. A new variant arising in a small population — whether through a single founding carrier or through transmission across many — has a much shorter path to high frequency than the same variant in a large population. Drift acts more strongly; selection acts more efficiently; the haplotype block, once it begins to spread, carries less of the recombinational variation that would otherwise be present. The haplotype’s coalescence point falls in this window not by coincidence: the cleanness of the block is exactly what one would expect for a variant that arose in or near a constrained-population period and was carried outward by the subsequent demographic expansion.

The population-genetic argument continues from there. The post-bottleneck African populations expanded; the major out-of-Africa dispersal carried the haplotype outward; over the millennia following, the haplotype became universal across human populations through a combination of demographic spread, ongoing weak positive selection, and mutational stability at the locus. The consortium estimates the haplotype’s frequency across sampled populations as not meaningfully distinguishable from one — present in essentially every individual studied, with the small differences between regions consistent with ordinary demographic history. What makes someone affinity-deficit, then, is not the absence of the haplotype but the presence of one or more disrupting variants at the modifier loci that the GWAS work characterised first. The disrupting variants are recurrent, arising independently in every population through ordinary mutation, which is why the affinity-deficit condition itself is so uniformly distributed.

What kind of selection might have favoured the haplotype in its long climb to near-universality is a question the consortium is appropriately cautious about. The classic candidates apply: small-band coordination, mate selection on shared reward profiles, correlated benefits to fine motor control or hand-eye attention that would have mattered even before metallurgy. The earliest unambiguous evidence for the systematic working of metal in fine drawn forms comes from sites of perhaps ten or eleven thousand years ago — long after the haplotype had reached high frequency. For the first sixty-five thousand years of its presence in our species, the humans who carried it had no metal to bend.

What were they doing? The question is open. Reedwork, vinework, hairwork, fibre-binding — all of these are organic and would not preserve. Body modification, tattooing, the drawing of lines in pigment on skin and rock and bark may have provided early outlets for the response that the integration had given them. There is evidence, of a sort, in the geometric vocabularies of late Palaeolithic art: closed curves and looped forms appear with a frequency that some archaeologists have long found striking, though no one has been quite sure what to make of it. The new genetic context may sharpen these readings considerably. As Diane Ostroff of Cambridge’s archaeology faculty told me, “we have for years been looking at certain motifs in the cave art and the early ornament and wondering why they recur. Now we have a candidate explanation for why people who did not yet have the materials we associate with the gesture might still have been looking for ways to make it.”

The integration, in other words, was there. It was waiting. The materials caught up later.

There is one feature of the molecular work that has drawn comment within the field, and the consortium paper handles it with appropriate care.

ERV-derived regulatory elements that have been successfully recruited into biological function are, as a rule, somewhat messy in their genomic context. Retroviral integrations occur essentially at random; the great majority disrupt nearby gene regulation in ways that are then either eliminated by selection or compensated for by adjustment in surrounding sequence. The cases that survive into the long-term genome and are recruited into functional roles are the cases where the disruption was tolerable and the eventual function happened to outweigh the cost. Looking at any particular ERV-derived functional element, one expects to see the legacy of this messy history: flanking-sequence rearrangements, compensatory variation, occasional regulatory side-effects in adjacent genes.

The bent-form-response locus shows surprisingly little of this. The flanking sequence is unusually undisturbed; the regulatory consequences are tightly localised; the integration appears to have landed in a position favourable to its expression and to have required relatively little subsequent adjustment. Aubert notes the cleanness as a striking feature of the case. “Most ancient integrations are messy,” he told me. “This one came in clean. We don’t entirely know why.”

The standard explanation, which Aubert and his co-authors endorse, is selection bias. We see the integrations that worked; the ones that didn’t were eliminated. A retrovirus that integrated badly would have had its functional consequences obscured or compensated, and would not be visible to us now as a clean major-effect locus. The bent-form-response locus is, on this reading, a survivor — a case that happened to land in just the right place, in just the right way, to produce a stable functional consequence without disrupting too much else. This is a perfectly respectable evolutionary story. The data are at the favourable end of what such a story would predict, and several of the authors have acknowledged that the cleanness is at the edge of what the survivor-effect explanation comfortably accommodates. But it accommodates it.

Whatever the precise mechanism by which it arrived in the human genome and stabilised there, it has been with us for seventy-five thousand years.

The cleanness has begun to attract comment outside the genetic literature. Religious commentators across several traditions have written, in the weeks since the synthesis appeared, on what an integration of this kind looks like to a tradition that has long taught that the affinity was given.

The cultural-historical framing of the synthesis is the contribution of an interdisciplinary team led, on the humanities side, by the religious historian Caroline Pell. Pell, whose essay “Wherever Humans Are” appeared in The Common Reader in November 2014, has argued for years that the universality of the closing-loop tradition reflects something deep in human nature. I asked her by telephone what it was like to see her argument confirmed in such a literal way.

“Oh,” she said, after a moment, “well, it is gratifying. Of course it is gratifying. But I think what is more interesting is what the discovery does and does not change. We have known for a very long time that wire is central to what we are; we have known that the closing of the loop was a gesture humans found their way to in every part of the world, and that the religious traditions we have built around it were responses to something they did not invent. Now we know one part of why. The genetic story confirms the religious one. The traditions were responsive to a real feature of who we are. We have lived with that feature for seventy-five thousand years; we have made our religious life out of it. The discovery tells us where the response came from. It does not tell us what we have done with it, and it does not tell us what to do with it next. Those are still our questions to answer.”

The affinity-minority, whose existence anchored the field’s work for a decade, takes on a new character in the light of the consortium synthesis. The condition is what the GWAS work showed it to be: a multifactorial phenotype produced by disrupting variants at multiple modifier loci, recurrent across all populations, broadly evenly distributed by region and ancestry. What is now clear is that it is a condition of expression, not of presence. Members of the minority carry the chromosome eleven haplotype like everyone else; what they additionally carry, in varying combinations, are disrupting variants at the modifier loci that prevent the phenotype from developing fully.

Members of this population have always been with us. The literature on what was historically called insensibility to the bend goes back centuries, and in our own period the condition has been recognised as a real if quiet source of difficulty in a world organised around a pull almost everyone shares. People at the low end of the distribution sometimes describe a sense of standing outside something everyone else seems to share — what one interviewee in the synthesis’s cultural-historical section calls “a foreshortening of moral feeling,” what another describes as “watching a celebration whose pull I cannot feel.” The new genetic understanding offers, for the first time, a real molecular handle on the condition; therapeutic options remain distant, but they are no longer unimaginable. Several of the consortium’s members are quietly hopeful about what the next decade may bring.

Few discoveries in biology carry this kind of cultural weight. The chromosome eleven discovery is not a cure for cancer or a new form of energy; it does not promise to change the world in any material way. What it offers, instead, is a kind of self-understanding that human cultures have been seeking for as long as they have been able to articulate the question. Why do we do this? Why does it matter so much to us? Why is it the same wherever we go?

The answer, it turns out, is sitting on the long arm of chromosome eleven, in a stretch of regulatory sequence brought into our lineage by a virus that integrated itself, with considerable good fortune, into the genomes of some of our ancestors seventy-five thousand years ago, somewhere in the eastern part of Africa.

We are partly made by it. The bend has been with us all along.

Daniel Mehta is a senior contributing writer at Helix, covering genetics, neuroscience, and the cultural history of science.