How are genes regulated?

15 studies tell the story of a scientist's 10-year effort.
project, called Genotype-Tissue Expression (GTEx), aims to explain how DNA mutations found in large-scale genetic studies affect symptoms and diseases. The researchers spent up to 10 years linking the activity levels of 20,000 genes that encode proteins in humans to the mutations in millions of regulated DNA sequences.
Emmanouil Dermitzakis, a geneticist and project team member at the University of Geneva in Switzerland, said the $150 million project, which studied more than 50 tissues in hundreds of recent deaths, presented the final analysis of the data in a paper published recently in journals such as Science Advances cells.
papers make up the most complete catalog to date that affects gene expression variation. They also emphasize the importance of understanding the types of cells that genes are regulators of human tissue and provide a wealth of resources to connect the functional points between gene variation and human characteristics and diseases.
jan Korbel, a human geneticist at the European Laboratory of Molecular Biology (EMBL) in Heidelberg, Germany, says that for anyone interested in a particular disease or studying tissue and cell types, "these resources are priceless."20 years ago, when the human genome was sequenced, many researchers believed they could quickly find genes that lead to complex diseases such as diabetes or schizophrenia. But soon they stopped, in part because they ignored the system that controls where and how genes are expressed in the body. For example, it is this regulation that makes tumors different from healthy tissue.
this, the National Institutes of Health launched the GTEx project in 2010 to identify and map the association between quantitative marker points (QTLs), where genetic variation at specific locations of the genome is associated with gene expression in multiple tissues.
the Bode Institute, researchers have mapped the vast majority of genetic variations found through genome-wide associations to non-coding DNA regions of the genome, according to the China Science Journal. Genome-wide association studies are designed to scan the genome to determine its variation associated with characteristics or diseases. The results show that these mutations work by affecting the expression of genes, not by altering the proteins they encode.
To clarify these relationships, the researchers took more than 50 tissue samples from about 900 deceased people who pledged to donate organs or tissues to identify as many genes as possible and determine whether their effects were shared among multiple tissues or cell types.
the researchers described each sample and then imaged and froze all the tissues for future analysis. They deciphered the genome and quantified RNA to measure the genetic activity of the sample. In addition to comparing individual organizations, they also compare the same organizations for different individuals.
these tissues convinced researchers that the differences in gene expression between muscles and pancreas were real and meaningful. "This is the first time we've had this collection of homogeneity samples to get biological differences between tissues," said Barbara Stranger, a geneticist at Northwestern University and a member of GTEx. The
GTEx project attempts to map the basis of gene regulation in as many individuals as possible, that is, how genetic changes may affect gene expression or the way proteins are produced. Kristin Ardlie, a member of the project and a member of the Broad Institute, said.
the results of the GTEx project in a flagship paper published in Science, which helped shed light on the enormous complexity of gene expression.
FranAguet, Ardlie, and colleagues at the Broad Institute cataloged QTLs involving more than 23,000 gene expressions, including mutations that directly affect gene expression (eQTLs) or in-gene shearing (sQTLs). Now, after analyzing nearly 20,000 samples, the GTEx project "gives us clearer insights," Ardlie said.confirms that almost every human gene is regulated by at least one eQTLs, many of which have multiple base targets that can affect multiple sexuality. The researchers also revealed differences between genders and groups of the QTLs effect. These findings suggest that QTLs may often affect how cell transcription factors bind to the genome on promoter or enhancer, which in turn affects gene expression.
" in a sense, QTLs are like a dial to adjust the expression, which can be adjusted up and down. One QTL may increase the expression, but the other QTL may decrease the expression slightly. All this adds to the complexity of variation in regulating gene expression. Aguet told reporters.
team found another important result: that almost every tissue, including the skin and heart, has a difference in gene expression between men and women. "The vast majority of physiological characteristics are common to both men and women." But this difference in expression may help explain why men and women have different disease patterns or drug responses, Stranger said.
in a larger sample size, we see that each gene has more than one regulatory effect, and these differences are not only tissues, but also cell types. We can start drawing high-resolution variations. "We can link the GWAS signal to QTLs to see if what appears to be random GWAS points are actually functional elements that affect gene regulation, complex features, and disease esotypes," Ardlie told China Science. Kelly
at the University of California, San Diego, has begun this kind of analysis. In GCAS, a large number of groups examined the genomes of thousands of patients with a particular disease or characteristic and noticed hundreds of subtle genetic changes. However, researchers often don't know which of these doubts caused the disease.
, frazer wanted to know how a heart-specific transcription factor called NKX2-5 affects these properties. Her team has identified thousands of DNA variants that could affect NKX2-5 activity and change heart rhythm.
Paola Benaglio of Frazer Labs analyzed and compared these DNA variants, GWAS data, and GTEx data to determine which DNA variants regulate NKX2-5 activity. She first narrowed down the candidate QTLs to 55, then to nine, and finally, using GGWAS heart rhythm data and other tools to target. She then used the genome editor CRISPR to block the DNA base and confirm that it changed the binding of NKX2-5. 16,000 people visit the GTEx portal every month, and in 2018, 900 papers cite the project.
"GTEx project is an ambitious and complex undertaking, and it is still very difficult to get this breadth from individuals. In this sense, the GTEx project is unique in that it paves the way for research such as human cell maps. "But we also need large-scale resources like ENCODE to gather complementary information to get a more complete picture of the molecular mechanisms that drive biology," Tuuli Lappalainen of the New York Genomics Center, a project member, told reporters. But
also warned that there could be a false link between eQLTs and genes. Locking in disease-dnogenic mutations through GTEx is "not easy."
, an evolutionary biologist at the University of Houston, also believes the papers are "playing a good game" and that the published results are difficult to interpret. Like other critics, he points out that the program, which is 85 percent white, is so lacking in diversity that it ignores genetic variations in other groups.
GTEx is not yet able to determine the genetic sequence that causes diseases such as heart disease and kidney failure, nor can it track how gene regulators work together. "We can't say that the issue of gene expression has been solved." Ewan Birney, deputy director of EMBL and a genomicist, said.
"QTL analysis provides only a lens through which to observe the functional meaning of genetic variation, and a tool to supplement the exogenomic genome, proteomics, and other forms of genomic and transcriptional analysis. Ardlie said.
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