The ‘priceless’ database helps solve the mystery of how genes are regulated. Science


Genes are differentially expressed in tissues around the human body, as indicated by white to dark blue squares. The genotype-tissue expression project has now mapped such gene regulation to 54 tissues.

(Illustration) v. Selfless /Science In collaboration with Christian Stolle; (Data) gtex union

By Elizabeth Pinsy

When the human genome was sequenced about 20 years ago, many researchers believed they would be able to quickly take home the genes responsible for complex diseases such as diabetes or schizophrenia. But they stayed fast, stunned in part due to their ignorance of the switch’s system of where and how genes are expressed in the body. Such gene regulation makes a heart cell distinct from a brain cell, for example, and distinguishes tumors from healthy tissue. Now, a massive decodong effort to fill in the picture by adding activity levels of 20,000 DNA-coding human genes has begun, as shown by the levels of their RNAs, a variation in millions of regulatory DNAs.

Looking at 54 types of tissue in hundreds of recently deceased people, the $ 150 million genotype-tissue expression (GTEx) project is set to create a “one-stop shopping for genetics of gene regulation,” the ZTEX team Member Emanouil Dermitzkis says a geneticist at the University of Geneva in a brace of papers Science, Science advance, Cell, And in this week’s other journals, researchers at GTEx prepare the tools for further exploitation of the data, along with the final large analyzes of these free, downloadable data.

“This resource is invaluable to someone particularly interested in diseases, or studying tissues or cell types”, says Jan Korbel, a human geneticist at the European Molecular Biology Laboratory (EMBL), Heidelberg. “It’s a public treasure,” says JN Lee, Ann Arbor, a geneticist at the University of Michigan.

But the complex main analysis drives home how complex the linkage between genes and their regulatory DNA is. The papers are “written in bureaucracy,” and the declared results are difficult to understand, says evolutionary biologist Dan Grauer of the University of Houston and a noted critic of elder science. And like other critics, he notes that the project, with 85% of white donors, likely lacks diversity and thus other groups will miss genetic variation.

GTEx cannot yet pin down the sequences responsible for diseases such as heart disease and kidney failure, nor can it figure out how the layers of gene regulation work together. “We should not pack our bags and solve gene expressions,” says Genomic Even’s deputy director general, Genomic Even, who led another large genomics project called EMBL.

After the launch of GTEx in 2010, families of more than 900 deceased subjects who had already agreed to transplant their organs or tissues, researchers agreed that they could take healthy tissue samples of their loved ones, e.g. For the brain, muscles, fat, pancreas and heart. . Having multiple tissues from the same subject led researchers to believe that the difference between genes, muscle and pancreas, was real and meaningful. “For the first time, we have this homogeneous set so that we can find biological differences between tissues,” says GTEx member Barbara Stranger, a geneticist at Northwestern University.

A regulatory universe expands

Genotype-tissue expression (GTEx) donors, tissues, and samples have increased with each publication milestone. Results of this project, such as the number of genes associated with specific regulatory sequences, have blossomed accordingly.
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(Graphic) v. Altunia /Science; (Figures) GTEX CONSORTIUM

The researchers described each sample, then imaged and freeze all tissues for future analysis. They determined the genome and determined RNA to measure gene activity. In addition to comparing tissues within an individual, they can also compare the same tissue in different individuals. They were able to relate changes in gene expression levels in DNA by using statistical analyzes to find correlated patterns of change. The heart expression of the GTEx database is a compilation of complex relationships between quantitative trait loci, or eQTLs, and the genes they regulate, the spread of regulatory DNA.

A pilot phase, completed in 2015, examined nine tissues in depth and demonstrated that corpses samples for living tissue were appropriate stand-ins, says Gulliex Tully Laplanen, a human geneticist at the New York Genome Center. Now, after analyzing nearly 20,000 samples, GTEx “has reached a size where we can get very clear, crisp insights,” says co-leader Kristin Ardli, 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 genes and possibly affect multiple traits.

Stranger uncovered another important result: almost every tissue, for example, including skin and heart, showed differences in gene expression between men and women. “The vast majority of biology is shared by men and women,” Stranger says, but expression differences may help explain why men and women have different disease patterns or reactions to drugs. “I think a major discovery,” Corbel says.

Similarly, broad co-leader François Aguet and his colleagues confirmed that some eQTLs extend their access to distant genes, even on other chromosomes. GTEx documented 143 such “trans” elements, some of which affect multiple genes in the genome.

Kelly Fraser at the University of California, San Diego, is already using the data to help make sense of so-called genome-wide association studies (GWAS), which uncover key mysteries. At GWAS, large-scale consortia look at the genomes of thousands of patients with a particular disease or symptom and note hundreds of microscopic genetic changes, often outside genes. But researchers often have no clue as to which of these triggers the suspected disease or shape the symptom.

For example, GWAS studies had identified more than 500 genetic variations that affect heart rhythm and electrical conductivity. Fraser wanted to know how a heart-specific transcription factor called NKX2-5 affected those symptoms. His team had identified thousands of DNA variations that could affect the activity of NKX2-5 and therefore perhaps shift heart rhythms.

Paola Benaglio in Fraser’s laboratory analyzed and compared those DNA fractions, GWAS data, and GTEx data to ascertain whether DNA variation actually regulates NKX2-5 activity. She was able to first use GWAS data on candidate eQTLs to 55, then to nine and finally to heart rhythm and other devices, she zeroed in on a single variable basis on the chromosome. Next, he blocked that DNA using the genome. Editor CRISPR and confirms that it replaces NKX2-5 bindings, Benaglio, Fraser, and their partners for the last time Nature genetics.

“I’m sure there are hundreds of people like me” who appreciate the database, Fraser says. The statistics returned him. Monthly, 16,000 people visit the GTEx portal, and others check the data on other sites. In 2018, 900 papers cited it. Birney understands enthusiasm, but cautions that spontaneous relationships may arise between eQLTs and genes. Making a home on a disease-causing version via GTEx is “not a slam sting.”

For his part, Gurer suspects that gene activity in corpses adequately reflects what goes on in the living despite the team’s data on the conservation of gene expression. “It’s like studying the mating behavior of roadkill,” he says.

As the project winds down, the US National Institutes of Health is planning a developmental GTEx that will enroll people under the age of 20 to create an atlas of gene expression from birth to adulthood. In such follow-up efforts, a more diverse set of tissue donors “would be very valuable,” Korbel says. GTEx initially fired for that goal, but faltered because the tissue and organ donors are completely white. Researchers “need to communicate more effectively,” says Laura Siminoff, a social scientist at Temple University, who said GTEX was funded quickly to look at ethics. “Otherwise we are doing this science for the white people.”

The results so far cannot tell the full story of how genes cause innumerable tissues and diseases of humans. Nevertheless, Birney predicted, “GTEx will be used and reused repeatedly, and there will be some uses that I can predict.”