New method developed for ranking disease-causal mutations within whole genome sequences

February 7, 2014

Researchers from the University of Washington and the HudsonAlpha Institute for Biotechnology have developed a new method for organizing and prioritizing genetic data. The Combined Annotation–Dependent Depletion, or CADD, method will assist scientists in their search for disease-causing mutation events in human genomes.

The new method is the subject of a paper titled "A general framework for estimating the relative pathogenicity of human genetic variants," published in Nature Genetics.

Current methods of organizing look at just one or a few factors and use only a small subset of the information available. For example, the Encyclopedia Of DNA Elements, or ENCODE, catalogs various types of functional elements in human genomes, while sequence conservation looks for similar or identical sequences that have survived across different species through hundreds of millions of years of evolution. CADD brings all of these data together, and more, into one score in order to provide a ranking that helps researchers discern which variants may be linked to disease and which ones may not.

"CADD will substantially improve our ability to identify disease-causal mutations, will continue to get better as genomic databases grow, and is an important analytical advance needed to better exploit the information content of whole-genome sequences in both clinical and research settings," said Gregory M. Cooper, Ph.D., faculty investigator at HudsonAlpha and one of the collaborators on CADD.

The goal in developing the new approach was to take the overwhelming amount of data available and distill it down into a single score that can be more easily evaluated by a researcher or clinician. To accomplish that, CADD compares and contrasts the properties of 15 million genetic variants separating humans from chimpanzees with 15 million simulated variants. Variants observed in humans have survived natural selection, which tends to remove harmful, disease-causing variants, while simulated variants are not exposed to selection. Thus, by comparing observed to simulated variants, CADD is able to identify those properties that make a variant harmful or disease-causing. C scores have been pre-computed for all 8.6 billion possible single nucleotide variants and are freely available for researchers.

"We didn't know what to expect," Cooper said, "but we were pleasantly surprised that CADD was able not only to be applicable to mutations everywhere in the genome but in fact do a substantially better job in nearly every test that we performed than other metrics."

The CADD method is unique from other algorithms in that it assigns scores to mutations anywhere in human genomes, not just the less-than two percent that encode proteins (the "exome"). This unique attribute will be crucial as whole-genome sequencing becomes routine in both clinical and research settings.

Explore further: Sieving through 'junk' DNA reveals cancer-causing genetic mutations

More information: www.nature.com/ng/journal/vaop … nt/full/ng.2892.html

Related Stories

Sieving through 'junk' DNA reveals cancer-causing genetic mutations

October 3, 2013
Researchers can now identify DNA regions within non-coding DNA, the major part of the genome that is not translated into a protein, where mutations can cause diseases such as cancer.

Why is type 2 diabetes an increasing problem?

January 9, 2014
Contrary to a common belief, researchers have shown that genetic regions associated with increased risk of type 2 diabetes were unlikely to have been beneficial to people at stages through human evolution.

Researchers produce a catalog of the deleterious and disease-causing genetic variants in healthy people

December 6, 2012
Researchers at Cambridge and Cardiff have found that, on average, a normal healthy person carries approximately 400 potentially damaging DNA variants and two variants known to be associated directly with disease traits. They ...

Research sheds new light on heritability of disease

January 16, 2014
A group of international researchers, led by a research fellow in the Harvard Medical School-affiliated Institute for Aging Research at Hebrew SeniorLife, published a paper today in Cell describing a study aimed at better ...

New genetic analysis method holds promise for understanding causes of disease

December 17, 2013
(Medical Xpress)—University of Michigan School of Public Health researchers have developed a new method for identifying rare gene variants, which scientists now believe are more informative for human disease studies than ...

New approach for efficient analysis of emerging genetic data

September 6, 2012
(Medical Xpress)—With the ability to sequence human genes comes an onslaught of raw material about the genetic characteristics that distinguish us, and wading through these reserves of data poses a major challenge for life ...

Recommended for you

The 16 genetic markers that can cut a life story short

July 27, 2017
The answer to how long each of us will live is partly encoded in our genome. Researchers have identified 16 genetic markers associated with a decreased lifespan, including 14 new to science. This is the largest set of markers ...

A rogue gene is causing seizures in babies—here's how scientists wants to stop it

July 26, 2017
Two rare diseases caused by a malfunctioning gene that triggers seizures or involuntary movements in children as early as a few days old have left scientists searching for answers and better treatment options.

Scientists provide insight into genetic basis of neuropsychiatric disorders

July 21, 2017
A study by scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) is providing insight into the genetic basis of neuropsychiatric disorders. In this research, the first mouse model of a mutation ...

Scientists identify new way cells turn off genes

July 19, 2017
Cells have more than one trick up their sleeve for controlling certain genes that regulate fetal growth and development.

South Asian genomes could be boon for disease research, scientists say

July 18, 2017
The Indian subcontinent's massive population is nearing 1.5 billion according to recent accounts. But that population is far from monolithic; it's made up of nearly 5,000 well-defined sub-groups, making the region one of ...

Mutant yeast reveals details of the aberrant genomic machinery of children's high-grade gliomas

July 18, 2017
St. Jude Children's Research Hospital biologists have used engineered yeast cells to discover how a mutation that is frequently found in pediatric brain tumor high-grade glioma triggers a cascade of genomic malfunctions.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.