What If (Almost) Every Gene Affects (Almost) Everything? – The Atlantic – June 2017 – by ED YONG
If you told a modern geneticist that a complex trait—whether a physical characteristic like height or weight, or the risk of a disease like cancer or schizophrenia—was the work of just 15 genes, they’d probably laugh.
It’s now thought that such traits are the work of thousands of genetic variants, working in concert.
The vast majority of them have only tiny effects, but together, they can dramatically shape our bodies and our health. They’re weak individually, but powerful en masse.
But Evan Boyle, Yang Li, and Jonathan Pritchard from Stanford University think that this framework doesn’t go far enough.
They note that researchers often assume that those thousands of weakly-acting genetic variants will all cluster together in relevant genes.
For example, you might expect that height-associated variants will affect genes that control the growth of bones. Similarly, schizophrenia-associated variants might affect genes that are involved in the nervous system
Yes, he says, there will be “core genes” that follow this pattern. They will affect traits in ways that make biological sense.
But genes don’t work in isolation. They influence each other in large networks, so that “if a variant changes any one gene, it could change an entire gene network,” says Boyle.
He believes that these networks are so thoroughly interconnected that every gene is just a few degrees of separation away from every other. Which means that changes in basically any gene will ripple inwards to affect the core genes for a particular trait.
The Stanford trio call this the “omnigenic model.” In the simplest terms, they’re saying that most genes matter for most things.
More specifically, it means that all the genes that are switched on in a particular type of cell—say, a neuron or a heart muscle cell—are probably involved in almost every complex trait that involves those cells.
So, for example, nearly every gene that’s switched on in neurons would play some role in defining a person’s intelligence, or risk of dementia, or propensity to learn. Some of these roles may be starring parts. Others might be mere cameos. But few genes would be left out of the production altogether.
there are probably more than 100,000 variants that affect our height, and most of these shift it by just a seventh of a millimeter.
They’re so minuscule in their effects that it’s hard to tell them apart from statistical noise, which is why geneticists typically ignore them. And yet, Pritchard’s team noted that many of these weak signals cropped up consistently across different studies, which suggests that they are real results.
And since these variants are spread evenly across the entire genome, they implicate a “substantial fraction of all genes,” Pritchard says
The team found more evidence for their omnigenic model by analyzing other large genetic studies of rheumatoid arthritis, schizophrenia, and Crohn’s disease. Many of the variants identified by these studies seem relevant to the disease in question.
But mostly, the variants affect genes that don’t make for compelling stories, and that do pretty generic things. According to the omnigenic model, they’re only contributing to the risk of disease in incidental ways, by rippling across to the more relevant core genes.
Put it this way:
The Atlantic is produced by all of us who work here, but our lives are also affected by all the people we encounter—friends, roommates, partners, taxi drivers, passers-by etc.
If you listed everyone who influences what happens at The Atlantic, even in small ways, all of those peripheral people would show up on the list.
But almost none of them would tell you much about how we do journalism. They’re important, but also not actually that relevant.
Pritchard thinks the same is true for our genes. And if that’s the case, he says, “it’s not clear to me that increasing your study size is going to help very much.”
There are, however, projects that are trying to do exactly that. “I’m very excited about trying to understand whether these network ideas are correct,” says Pritchard. “I think it’s telling us something profound about how our cells work.”