Only about 1% 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%
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 Massachusetts
Institute of Technology (MIT), an associate member of the Broad Institute, and
an author of a paper describing the findings in Nature.
“Humans are 99.9% 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
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 laboratories 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 laboratories. “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
The ENCODE researchers found that 80% of
the genome experiences some kind of biochemical event, such as binding to
proteins that regulate how often a neighboring gene is used. 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
“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
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% of noncoding DNA is conserved across mammals. In one of the ENCODE
companion papers appearing online in Science,
Kellis and MIT postdoctoral researcher Lucas Ward show that an additional 4% 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
The research was funded by the National
Human Genome Research Institute.