DNA from Cystic Fibrosis Patients Reveals Unexpected Mutation
Comparing DNA from patients at the best and worst extremes of a health condition can reveal genes for resistance as well as weakness
A new approach reveals there are rare variations in the DCTN4 gene among cystic fibrosis patients who are most prone to early, chronic airway infections.
The DCTN4 gene codes for dynactin 4,
a protein which acts as part of a molecular motor
moving trouble-making microbes
along a cellular conveyer belt
into miniscule chemical vats,
called lysosomes, for annihilation.
The study, led by the University of Washington (UW), 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 appeared July 8, as a letter in Nature Genetics.
The infectious agent was Pseudomonas aeruginosa, an opportunistic soil bacteria that commonly infects the lungs of people with cystic fibrosis and other airway-clogging disorders. This bacteria can unite into a slithery, hard-to-treat biofilm that harms lung tissue thus hampering breathing. 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, the rare variations in DCTN4 did not appear in any cystic fibrosis patient who was resistant to Pseudomonas infection. Study subjects susceptible to early, chronic infection had at least one DCTN4 missense variant, meaning the protein will not function properly.
The patients selected for sequencing were from the Early Pseudomonas Control Observational Study (EPIC), 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.
Statistical analysis of the DNA of 91 patients led the research team to DCTN4. Identification of the protein coding portions of these subjects' DNA called attention to missense variations in the DCTN4 gene. Researchers then screened a select group of 1,322 EPIC participants.
Exome Sequencing Project scientists are using an approach similar to the one used in EPIC to examine the genetics behind resistance and susceptibility to other chronic conditions such as obesity, heart attacks and hypertension. They will be looking for gene variations linked to heart disease, for example by comparing DNA maps of people with ideal cholesterol levels to those of people with exceptionally poor levels.
Adapting a similar strategy to determine the genetics underlying other complex human traits may require exome sequencing of much larger sample sizes, the researchers noted.
"As the costs of exome sequencing are dropping rapidly,
more efficient statistical analysis is becoming available;
we believe medical researchers' enthusiasm for this
approach will continue."
Michael Bamshad, PhD.
The lead author of the report is Mary J. Emond, research associate professor of biostatistics at the University of Washington School of Public Health in Seattle. The senior author is medical geneticist Michael Bamshad, UW professor of pediatrics in the Division of Genetic Medicine.
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.
Original article: http://www.eurekalert.org/pub_releases/2012-07/uow-eso070612.php