Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Double-teaming a whole-genome hunt

13.07.2010
Scientists combine new and classic approaches to discover rare disease gene

By inspecting the sequence of all 3 billion "letters" that make up the genome of a single person affected with a rare, inherited disorder, a Johns Hopkins and Duke University team ferreted out the single genetic mutation that accounts for the disease.

Reporting their results in the June 17 issue of PLoS Genetics, the team says an altered version of the gene PTPN11 is the cause of metachondromatosis, a disorder characterized by bony growths, often on the hands and feet.

The study, the scientists say, demonstrates that new, whole-genome sequencing technology can efficiently and accurately lead investigators to the identification genes that cause Mendelian diseases — those caused by mutations in a single gene and passed on according to classic genetic patterns.

The traditional way of collaring a Mendelian disease-causing gene entails time-consuming and labor-intensive genetic analyses of numerous related individuals across generations. Known as "linkage," this approach depends on collecting families, especially large families with multiple affected members. This can be difficult and time consuming and often does not have sufficient resolution to identify the responsible gene. In fact, the definitive catalog of genes and disorders maintained at Johns Hopkins, Online Mendelian Inheritance in Man (OMIM), lists more than 1,500 disorders for which linkage studies have identified a large genomic region but have failed to pinpoint the responsible gene.

The failures were often due to the absence of enough related and affected individuals to provide linkage evidence of sufficient strength and resolution to identify the genes responsible for rare inherited diseases. Another weakness of linkage studies is that an affected individual may be so mildly affected that they are erroneously classified as unaffected, thereby skewing study results.

Success for metachondromatosis came when researchers combined a linkage study of 11 family members (five affected with metachondromatosis and six unaffected) with the whole-genome sequencing of one affected member. The linkage study identified likely regions of the genome where the suspect mutation could be found, considerably reducing the fraction of the genome that could contain the disease. Focusing on these regions, the team identified a mutation in PTPN11 that was sure to cause loss of function of the gene product.

"This whole-genome study, which took only two months, got us to a place where otherwise we wouldn't have arrived very quickly, if ever," says David Valle, M.D., Henry J. Knott Professor and director of the Institute of Genetic Medicine, Johns Hopkins University School of Medicine. "It's a great example of the power of a broad, agnostic approach."

By comparing the one whole genome of the affected individual with eight non-affected control genomes as well as to a database of single-letter variations known to occur in more than one percent of the population, and to other sequencing data, the researchers came up with a list of 100 possible candidate genes. These were analyzed in light of the linkage evidence which, although modest, allowed the team to narrow its search for variants to just a fraction of the genome and narrowed the list to half a dozen genes. Then they combed the literature to understand what was known of the biological function of these candidates, looking for any that might be involved in bone development.

Nara Sobreira, a graduate student in human genetics at Johns Hopkins and a lead author of the study, found that lots had been published about one of the six genes, PTPN11. Mutations in this gene made it hyperactive, causing Noonan syndrome, a genetic disorder that prevents normal development in various parts of the body, including the skeleton.

This newly discovered mutation or altered version involved a so-called "deletion" in which a piece of the genetic code is missing and likely to cause a loss of function of the gene, disabling its ability to manufacture normal protein, Sobreira explains. She said that gave credibility to the possibility that PTPN11 was responsible for metachondromatosis, which gives rise to different physical characteristics.

To confirm their suspicions, the team first checked to see if all affected members of the family in the linkage studies had the mutation and if all unaffected members didn't. The answer was yes.

The next and final assurance needed to prove that this gene was responsible for metachondromatosis was to find the same mutation of the same gene in an affected person unrelated to the family originally studied. The Hopkins team located a second family already seeking treatment at the Greenburg Center for Skeletal Dysplasias and confirmed that mutations, causing a loss of function of the PTPN11 gene, caused metachondromatosis.

"This discovery has given us clues about the molecular basis of other genetic diseases for which a cause remains unknown and that are not benign like this one," Sobreira says.

Johns Hopkins authors on the paper, in addition to Sobreira and Valle, are Dimitrios Avramopoulos, Elizabeth Wohler, Gretchen L. Oswald, Eric L. Stevens, Jonathan Pevsner, George Thomas and Julie E. Hoover-Fong. Authors from Duke University are Elizabeth T. Cirulli, Dongliang Ge, Kevin V. Shianna, Jason P. Smith, Jessica M. Maia, Curtis E. Gumbs and David B. Goldstein.

On the Web:

Valle lab:
http://www.hopkinsmedicine.org/geneticmedicine/People/Faculty/valle.html
PLoS Genetics:
http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000991

Maryalice Yakutchik | EurekAlert!
Further information:
http://www.jhmi.edu

More articles from Life Sciences:

nachricht Toward a 'smart' patch that automatically delivers insulin when needed
18.01.2017 | American Chemical Society

nachricht 127 at one blow...
18.01.2017 | Stiftung Zoologisches Forschungsmuseum Alexander Koenig, Leibniz-Institut für Biodiversität der Tiere

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

A big nano boost for solar cells

18.01.2017 | Power and Electrical Engineering

Glass's off-kilter harmonies

18.01.2017 | Materials Sciences

Toward a 'smart' patch that automatically delivers insulin when needed

18.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>