Genome complexity: controls of gene regulation (Introduction)

by David Turell , Thursday, September 10, 2020, 21:52 (1316 days ago) @ David Turell

It is highly complex:

https://science.sciencemag.org/content/369/6509/1286

"When the human genome was sequenced almost 20 years ago, many researchers were confident they'd be able to quickly home in on the genes responsible for complex diseases such as diabetes or schizophrenia. But they stalled fast, stymied in part by their ignorance of the system of switches that govern where and how genes are expressed in the body. Such gene regulation is what makes a heart cell distinct from a brain cell, for example, and distinguishes tumors from healthy tissue. Now, a massive, decadelong effort has begun to fill in the picture by linking the activity levels of the 20,000 protein-coding human genes, as shown by levels of their RNA, to variations in millions of stretches of regulatory DNA.

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"But the complex main analysis (p. 1318) drives home just how convoluted the interconnections between genes and their regulatory DNA can be. The papers “are written in bureaucratese,” and the announced results are hard to decipher, says Dan Graur, an evolutionary biologist at the University of Houston and a well-known critic of big science.

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"GTEx can't yet pin down sequences responsible for illnesses such as heart disease and kidney failure, or trace how the layers of gene regulation work together. “We shouldn't pack up our bags and say gene expression is solved,” says genomicist Ewan Birney, deputy director general of EMBL, who led another big genomics project called ENCODE.

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"The heart of the GTEx database is a compilation of the complex relationships between stretches of regulatory DNA called expression quantitative trait loci, or eQTLs, and the genes they regulate.

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"Now, after analyzing almost 20,000 samples, GTEx “has reached a size where we can gain much clearer, crisper insights,” says co-leader Kristin Ardlie, a human geneticist at the Broad Institute. She and her colleagues found that almost every human gene is regulated by at least one eQTL, many of which target multiple genes and presumably affect multiple traits.

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"Likewise, Broad co-leader François Aguet and colleagues confirmed certain eQTLs extend their reach to distant genes, even those on other chromosomes. GTEx documented 143 such “trans” elements, some of which affect multiple genes across the genome.

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"GWAS studies had identified more than 500 genetic variations that appeared to affect heart rhythm and electrical conductance. Frazer wanted to know how a heart-specific transcription factor called NKX2-5 influenced those traits. Her team had identified thousands of DNA variations that might affect NKX2-5's activity and so perhaps shift heart rhythm."

Comment: This degree of complexity involving many parts of the genome is not surprising, since we are formed from only 20,000+ genes.