Corporate Banner
Satellite Banner
Next Gen Sequencing
Scientific Community
Become a Member | Sign in
Home>News>This Article

Exome Sequencing of Health Condition Extremes Can Reveal Susceptibility Genes

Published: Tuesday, July 17, 2012
Last Updated: Tuesday, July 17, 2012
Bookmark and Share
Comparing the DNA from patients at the best and worst extremes of a health condition can reveal genes for resistance and susceptibility.

This approach discovered rare variations in the DCTN4 gene among cystic fibrosis patients most prone to early, chronic airway infections.

The DCTN4 gene codes for dynactin 4. This protein is a component of a molecular motor that moves trouble-making microbes along a cellular conveyer belt into minuscule chemical vats, called lysosomes, for annihilation.

This study, led by the University of Washington, is part of the National Heart Lung and Blood Institute GO Exome Sequencing Project and its Lung GO, both major National Institutes of Health chronic disease research efforts.

Similar “testing the extremes” strategies may have important applications in uncovering genetic factors behind other more common, traits, such as healthy and unhealthy hearts.

The results of the cystic fibrosis infection susceptibility study appear July 8 in Nature Genetics.  The infection in question was "Pseudomonas aeruginosa," an opportunistic soil bacterium that commonly infects the lungs of people with cystic fibrosis and other airway-clogging disorders.  The bacteria can unite into a slithery, hard-to-treat biofilm that hampers breathing and harms lung tissue.  Chronic infections are linked to poor lung function and shorter lives among cystic fibrosis patients.  These bacteria rarely attack people with normal lungs and well-functioning immune systems.

In the study, these rare variations in DCTN4 did not appear in any of the cystic fibrosis patients who were the most resistant to Pseudomonas infection. The study subjects most susceptible to early, chronic infection had at least one DCTN4 missense variant. A missense variant produces a protein that likely can’t function properly.

The lead author of the Nature Genetics report is Dr. Mary J. Emond, research associate professor of biostatistics at the UW School of Public Health in Seattle. The senior author is medical geneticist Dr. Michael Bamshad, a UW professor of pediatrics in the Division of Genetic Medicine.

To the extent of their knowledge, the researchers think that this might be the first time that genetic variants underlying complex trait were discovered by sequencing all the protein-coding portions of the genomes of people at each extreme of a disease spectrum.

“We did not have a candidate gene in mind when we did this study,” said Emond.  Statistical analysis of the DNA of 91 patients led the research team to this particular gene.  Of the initial study group, 43 children had their first onset of chronic lung infection with Pseudomonas as when they were very young, and the 48 oldest individuals had not yet reached a state of chronic infection.  The patients selected for sequencing were from the Early Pseudomonas Infection Control (EPIC) Observational Study, a project at the Seattle Children’s Research Institute, and the North American Cystic Fibrosis Genetic Modifiers Study.   Exome sequencing was done by UW researchers in the laboratory of Deborah Nickerson, UW professor of genome sciences.

Comparisons of the protein coding portions of the study subjects’ DNA called the researchers attention to missense variations of the DCTN4 gene.  The researchers went on to screen a selected group of 1,322 other EPIC participants to check  their findings.

Exome Sequencing Project scientists are using an approach similar to the one in this study to examine the genetics behind resistance and susceptibility to other chronic conditions like obesity, heart attacks and hypertension. They plumb for gene variations linked to heart disease, for example by putting DNA maps from people with ideal cholesterol levels up against those from people with exceptionally poor levels.

Adapting a similar strategy to determine the genetics underlying other complex human traits may require exome sequencing of a much larger sample sizes, the researchers noted.
“As the costs of exome sequencing are dropping rapidly and more efficient statistical analysis is becoming available, we think medical researchers’ enthusiasm for this approach will continue,” Bamshad predicted.

In addition to National Heart Lung and Blood Institute funding, the study released today was supported by grants from the National Human Genome Research Institute, the Cystic Fibrosis Foundation, and the Life Sciences Discovery Fund.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,800+ scientific posters on ePosters
  • More than 4,000+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Scientific News
Research at St Thomas’s Hospital Exploring Causative Factors of Atopic Eczema and Food Allergy in Infants
Carsten Flohr and his research group at St Thomas’s hospital, London are currently investigating the interaction between skin and gut microbiota in relation to the associated risk of atopic eczema (AE) and food allergy in infants.
Gut Bacteria Can Dramatically Amplify Cancer Immunotherapy
Manipulating microbes maximizes tumor immunity in mice.
Proteins Crucial to Loss of Hearing Identified
Proteins play key role in genes that help auditory hair cells grow.
New Virus Identified In Blood Supply
Scientists have discovered a new virus that can be transmitted through the blood supply.
Far-reaching Genetic Study of 1,000 UK People
300,000 gene variants from 1,000 people made publically available via F1000Research.
DNA Alterations as Among Earliest to Occur in Lung Cancer Development
Genetic footprints of precancer detectable in some blood samples.
Targeting DNA
Protein-based sensor could detect viral infection or kill cancer cells.
Genetic Sleuthing
Sabeti team applies Ebola methods to shed light on spread of Lassa fever.
Seeking “Gold Standard” Wastewater Treatments
Metagenomic analyses lend insights into how microbes break down wastewater contaminants.
Using Genetic Sequencing to Manage Cancer in Children
A team of scientists have investigated the feasibility of incorporating clinical sequencing information into the care of young cancer patients.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos