Only about 1 percent of the human genome contains gene regions that code for proteins, raising the question of what the rest of the DNA is doing. Scientists have now begun to discover the answer: About 80 percent of the genome is biochemically active, and likely involved in regulating the expression of nearby genes, according to a study from a large international team of researchers.
The consortium, known as ENCODE (which stands for “Encyclopedia of DNA Elements”), includes hundreds of scientists from several dozen labs around the world. Using genetic sequencing data from 140 types of cells, the researchers were able to identify thousands of DNA regions that help fine-tune genes’ activity and influence which genes are expressed in different kinds of cells.
Just as the sequencing of the human genome helped scientists learn how mutations in protein-coding genes can lead to disease, the new map of noncoding regions should provide some answers on how mutations in the regulatory elements lead to diseases such as lupus and diabetes, says Manolis Kellis, an associate professor of computer science at MIT, an associate member of the Broad Institute and an author of a paper describing the findings in the Sept. 5 online edition of Nature.
“Humans are 99.9 percent identical to each other, and you only have one difference in every 300 to 1,000 nucleotides,” Kellis says. “What ENCODE allows you to do is provide an annotation of what each nucleotide of the genome does, so that when it’s mutated, we can make some predictions about the consequences of the mutation.”
Kellis, who leads MIT’s Computational Biology Group, is one of the principal investigators involved in the Nature paper. The ENCODE collaboration is publishing about two dozen additional papers this week detailing the new results.
Mapping noncoding DNA
ENCODE was established in 2003 to extend our understanding of the human genome beyond protein-coding genes. One way to do that is by studying the chemical modifications of individual stretches of DNA, which control when genetic regions will be active. These modifications vary by cell type and can modify either DNA directly or the histone proteins that DNA wraps around.
To map these modifications, known collectively as the epigenome, the research groups had to collect many different kinds of data from different cell types. Some labs measured DNA or histone modifications, while others gauged the accessibility of different stretches of DNA by cutting it into fragments with enzymes.
Kellis and his group were among the computational scientists leading the effort to analyze and integrate the huge amount of data generated by different labs. “Given that we were getting more than 1,000 data sets, we had to figure out ways to automatically calibrate experiments,” says Anshul Kundaje, a research scientist in MIT’s Computational Biology Group. “We developed an almost purely automated system that did all of this.”
The ENCODE researchers found that 80 percent of the genome experiences some kind of biochemical event, such as binding to proteins that regulate how often a neighboring gene is utilized. They also discovered that the same regulatory region can play different roles, depending on what type of cell it’s acting in.
The findings should have a major impact on scientists’ understanding of human biology and how genomic variations can cause disease, says Ben Raphael, an associate professor of computer science at Brown University.
“The most exciting part is now we’re getting a whole genome annotation of functional elements,” says Raphael, who was not part of the research team. “Every time you want to understand what a particular piece of the genome is doing, you can use the data from this project.”
The researchers also studied the conservation of nucleotides — the A, T, C and G “letters” of DNA — in the newly identified regulatory regions. Nucleotides are conserved if they remain the same over long evolutionary periods, which can be measured by analyzing the variability between species, or among individuals within a species.
A recent paper by Kellis and colleagues showed that 5 percent of noncoding DNA is conserved across mammals. In one of the ENCODE companion papers appearing online Sept. 5 in Science, Kellis and MIT postdoc Lucas Ward show that an additional 4 percent is conserved within the human lineage, suggesting that those elements control recently evolved traits, some of which are unique to humans.
When the researchers looked at the functions of genes near newly evolved regulatory regions, they found many genes that encode regulators that activate other genes. “Genes involved in the nerve growth pathway and color vision, both of which have been hypothesized to be recent innovations in the primate lineage, are enriched in human-constrained elements in non-conserved regions,” Ward says.
The researchers found that the most highly conserved nucleotides were also the ones most likely to be associated with disease when mutated. They also showed that variants associated with autoimmune diseases such as lupus and rheumatoid arthritis are located in regions active only in immune cells, while variants linked to metabolic diseases are in regions active only in liver cells.
In their next phase, the ENCODE researchers hope to determine just how those variations lead to human disease.
“What we’ve done over this series of papers is effectively paint a set of reference annotations of common human genome function,” Kellis says. “Our next steps will be to personalize these maps — to basically ask how they vary naturally between individuals, by profiling different cell types from different people, and how their variation relates to human disease and complex human traits.”
In one follow-up project, Kellis and colleagues are comparing activity levels of regulatory elements in different cell types from the same person, across many individuals. Another project is looking at DNA modification patterns across the entire genome of many individuals, in hopes of identifying how variation of specific elements relates to disease.
The research was funded by the National Human Genome Research Institute.
Sarah McDonnell | EurekAlert!
Bare bones: Making bones transparent
27.04.2017 | California Institute of Technology
Link Discovered between Immune System, Brain Structure and Memory
26.04.2017 | Universität Basel
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
27.04.2017 | Life Sciences
27.04.2017 | Physics and Astronomy
27.04.2017 | Earth Sciences