Genome complexity: complex traits may involve all genes (Introduction)

by David Turell , Friday, June 22, 2018, 18:19 (2347 days ago) @ David Turell

A new complex theory about core genes and how certain traits might involve all genes:

https://www.quantamagazine.org/disease-networks-show-molecular-connections-20150129/

"Starting about 15 years ago, geneticists began to collect DNA from thousands of people who shared traits, to look for clues to each trait’s cause in commonalities between their genomes, a kind of analysis called a genome-wide association study (GWAS). ...The conclusion, sometimes called the polygenic hypothesis, was that multiple loci, or positions in the genome, were likely to be involved in every trait, with each contributing just a small part.

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"The authors described what they called the “omnigenic” model of complex traits. Drawing on GWAS analyses of three diseases, they concluded that in the cell types that are relevant to a disease, it appears that not 15, not 100, but essentially all genes contribute to the condition. The authors suggested that for some traits, “multiple” loci could mean more than 100,000.

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"The origin of the idea lies in a very simple observation: When you look at the portions of the genome that GWAS findings have flagged as significant to individual traits, they are eerily well-distributed. Pritchard and his colleagues had been studying loci that contribute to height in humans. “What we realized was that the signal for height was coming from almost the whole genome,” he said. If the genome were a long string of ornamental lights, and every DNA snippet linked to height were illuminated, more than 100,000 lights would be shining all the way down the string. That result contrasted starkly with the general expectation that GWAS findings would be clustered around the most important genes for a trait.

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"But when the researchers looked at disease-specific cell types, an enormous number of the regions flagged by GWAS were not in those genes. They were in genes expressed in nearly every cell in the body — genes doing basic maintenance tasks that all cells need. Pritchard and his colleagues suggest that this manifests a truth that is perhaps not always taken literally: Everything in a cell is connected. If incremental disruptions in basic processes can add up to greatly derange a trait, then perhaps nearly every gene expressed in a cell, no matter how seemingly unrelated to the metabolic process of interest, matters.

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"it may be fruitful to think of the genes in a cell as a network. There may be some very highly connected genes at the center of a disease process, which they dub core genes. Peripheral genes, meanwhile, in aggregate help tip the scales one way or the other. The Cell paper authors suggest that understanding of the core genes will offer the best insights into the mechanism of a disease. Piecing together how peripheral genes contribute, on the other hand, will broaden understanding of why some people develop a disorder and others don’t.

"Since the Cell paper’s publication a year ago, scientists’ discussion has circled around whether such a distinction is useful. David Goldstein, a geneticist at Columbia University, is not sure that disease processes must truly be routed through core genes, but he also says that the idea that not everything picked up by GWAS is central and specific to a given disease is important.

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" according to Naomi Wray, a quantitative geneticist at the University of Queensland who pointed out when scientists first started doing GWAS analyses that they should expect to see many weak associations. A few conditions, she says, are primarily attributable to a small number of identifiable genes, or even just one — yet other genes may still flip the switch between one manifestation of illness and another. She cites the example of Huntington’s disease, a progressive neurological disorder caused by a specific defect in one gene. .. Scientists in the field are looking at other loci linked to Huntington’s disease to see how they might be causing the differences.

“'These [loci] are by definition in peripheral genes. But they’re actually how the body is responding to this major insult of the core gene,” Wray said.

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"Franke, who sees the paper as a provocatively phrased extension of earlier ideas, says that it has nevertheless shaped her thinking in the past year. “It made me rethink what I know about signal transduction — about how messages are relayed in cells — and how functions are fulfilled,” she said. The deeper you look at the workings of a cell, the more you realize that a single common protein may have quite different effects depending on what type of cell it is in: It may bear different messages, or block different processes, so much so that traits that might seem to be quite disconnected begin to change."

Comment: It is obvious that DNA must be studied in 3-D and in groups of genes and their effects. DNA does not simply code for proteins.