Navigation Links
Double-teaming a whole-genome hunt
Date:7/12/2010

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.


'/>"/>

Contact: Maryalice Yakutchik
myakutc1@jhmi.edu
443-287-2251
Johns Hopkins Medical Institutions
Source:Eurekalert

Related biology news :

1. Stimulus grant to fund whole-genome sequencing in children with autism
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:1/30/2017)... , Jan. 30, 2017   Invitae Corporation ... fastest growing genetic information companies, today announced that it ... results and provide 2017 guidance on Monday, February 13, ... call that day at 4:45 p.m. Eastern / 1:45 ... management team will briefly review financial results, guidance, and ...
(Date:1/25/2017)... 25, 2017 The Elements of Enterprise Information ... is comprised of a comprehensive set of business ... maintaining digital identities and providing a secured and ... are significant number of programs opted by enterprises ... by optimizing processes and changing policies. However, there ...
(Date:1/23/2017)... latest mobile market research from Acuity Market Intelligence reveals ... average price of a biometric smartphone decreased from $849 ... are now 120 sub-$150 models on the market at ... a year ago at an average price of $127. ... Acuity Market Intelligence Principal, "Biometric Smartphones are a global ...
Breaking Biology News(10 mins):
(Date:2/25/2017)... ... February 25, 2017 , ... ... Trials in an ongoing effort to create meaningful change by increasing communication, ... research with emphasis on consumers and patients’ mental health well-being. , Both organizations ...
(Date:2/24/2017)... 2017 Provectus Biopharmaceuticals, Inc. (OTCQB: PVCT, ... clinical-stage oncology and dermatology biopharmaceutical company, today is ... in its previously announced rights offering of up ... common stock and Series C Convertible Preferred Stock ... As previously announced, the rights ...
(Date:2/24/2017)... HONG KONG, Feb. 24, 2017 China Cord Blood ... "Company"), China,s leading provider of cord blood collection, laboratory ... services, today announced its unaudited financial results for the ... 2017 ended December 31, 2016. Third Quarter ... the third quarter of fiscal 2017 increased by 18.6% ...
(Date:2/24/2017)... , Feb. 24, 2017  OncoSec Medical Incorporated ... immunotherapies, will host a Key Opinion Leader event to ... an oral and poster presentation at the upcoming 2017 ... The KOL event will be held in-person and via ... EST / 9:00 AM PST at the Lotte New ...
Breaking Biology Technology: