DNA from cystic fibrosis patients with and without chronic infections points to unsuspected mutation

July 8, 2012 By Leila Gray in Genetics

Exome sequencing of health condition extremes can reveal susceptibility genes

Enlarge

This is a University of Washington exome sequencing lab where scientists analyze and compare protein-coding regions genomes. Credit: Clare McLean

(Medical Xpress) -- Comparing the DNA from patients at the best and worst extremes of a health condition can reveal genes for resistance and susceptibly. 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 miniscule chemical vats, called , 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 behind other more common, traits, such as healthy and unhealthy hearts.

The results of the cystic fibrosis infection susceptibility study appear this Sunday, July 8, in .

DNA from cystic fibrosis patients with and without chronic infections points to unsuspected mutation
Enlarge

An exome sequencing lab in the UW Department of Genome Sciences. Image: Clare McLean

The infection in question was Pseudomonas aeruginosa, an opportunistic 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 that hampers breathing and harms . are linked to poor lung function and shorter lives among . 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 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 report published July 8 in Nature Genetics 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.

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 Control (EPIC) Observational Study, a project at the Seattle Children's Research Institute, and the North American 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.

More information: http//www.nature.c… /ng.2344.pdf

Journal reference: Nature Genetics search and more info website

Provided by University of Washington search and more info website

not rated yet  

Rank not rated yet
Relevant PhysicsForums posts

More news stories

Researchers identify new circadian clock component

Northwestern University scientists have shown a gene involved in neurodegenerative disease also plays a critical role in the proper function of the circadian clock.

Genetics created May 16, 2013 | popularity not rated yet | comments 0 | with audio podcast

Returning genetic incidental findings without patient consent violates basic rights, experts say

Informed consent is the backbone of patient care. Genetic testing has long required patient consent and patients have had a "right not to know" the results. However, as 21st century medicine now begins to use the tools of ...

Genetics created May 16, 2013 | popularity 5 / 5 (1) | comments 3 | with audio podcast

Ethicists provide framework supporting new recommendations on reporting incidental findings in gene sequencing

In a paper published in Science Express, a group of experts led by bioethicists in the Center for Medical Ethics and Health Policy at Baylor College of Medicine provide a framework for the new American College of Medical Geneti ...

Genetics created May 16, 2013 | popularity not rated yet | comments 0

Experts urge caution over use of new genetic sequencing techniques

The use of genome-wide analysis (GWA), where the entirety of an individual's DNA is examined to look for the genomic mutations or variants which can cause health problems is a massively useful technology for diagnosing disease. ...

Genetics created May 16, 2013 | popularity not rated yet | comments 0

Collecting DNA for human rights: How to help while safeguarding privacy

DNA databases might help identify victims of crime and human trafficking, but how do we safeguard the personal privacy of innocent victims and family members? A new report online May 15 in the Cell Press journal Trends in ...

Genetics created May 15, 2013 | popularity not rated yet | comments 0


New research identifies risks, interventions for children's GI health

An increasing number of U.S. children are experiencing gastrointestinal issues that require interventions to resolve, according to research presented at Digestive Disease Week (DDW).

US psychiatry gets makeover in new manual

The latest makeover to a massive psychiatric tome honored by some, reviled by others and even called the "Bible" of mental disorders is being released Saturday with a host of new changes.

New case of SARS-like virus in Saudi: ministry

A new case of the deadly coronavirus has been detected in Saudi Arabia where 15 people have already died after contracting it, the health ministry announced on Saturday on its Internet website.

AIDS science at 30: 'Cure' now part of lexicon

Big names in medicine are set to give an upbeat assessment of the war on AIDS on Tuesday, 30 years after French researchers identified the virus that causes the disease.

For combat veterans suffering from post-traumatic stress disorder, 'fear circuitry' in the brain never rests

Chronic trauma can inflict lasting damage to brain regions associated with fear and anxiety. Previous imaging studies of people with post-traumatic stress disorder, or PTSD, have shown that these brain regions can over-or ...

New colonoscope provides ground-breaking view of colon

A ground-breaking advance in colonoscopy technology signals the future of colorectal care, according to research presented today at Digestive Disease Week(DDW). Additional research focuses on optimizing the minimal withdrawal ...