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

Unpacking a Complex Genetic Suitcase

Published: Thursday, July 12, 2012
Last Updated: Thursday, July 12, 2012
Bookmark and Share
Long before Homo sapiens lived in Africa, even before Neanderthals roamed part of the world, something interesting was happening on chromosome 17.

Around 2.3 million years ago, a 900-kb chunk of DNA broke off, reversed itself, and reattached on the chromosome in the opposite orientation. These kinds of genomic rearrangements (known as inversions) are not entirely uncommon, but what is unusual is that both versions of the chromosome – each with a substantial chunk of DNA pointing in a different direction – still exist in the human gene pool. For more than 2 million years – throughout the entire course of modern human history – these two, distinct forms have been trundled along in our genetic luggage.

Scientists have known about this ancient inversion for about seven years now, but four researchers at the Broad Institute recently took a closer look at this region of the genome, teasing apart its genetic diversity and complexity. They found that the inversion was just the tip of the iceberg.

“This was a locus that we and a thousand of our closest friends in human genetics knew was interesting,” says Steve McCarroll, senior author of a recent Nature Genetics paper that details their findings. “If you’d asked us or other people in human genetics about it, we would have described this inversion, which is common in Europeans. But the inversion turns out not be the most interesting feature of the locus.”

Steve and his colleagues Linda Boettger, Bob Handsaker, and Michael Zody have found that there aren’t just two structural versions of the locus (a locus is a specific location of a gene, or in this case, a string of many genes). Instead, there are nine. After the initial, 2 million year-old rearrangement, much more recent changes began to emerge, including duplications of different parts of the locus. Steve and his colleagues at the Broad Institute specialize in detecting these extra (or in other cases, missing) copies, known as copy number variation (CNVs for short).

The team used two breakthrough approaches – one molecular and one computational – to detect and characterize these nine structures. The researchers chose this particular region, known as 17q21.31, in part because several markers for female fertility and neurological diseases are associated with it, and in part because it is structurally complicated.

“These regions are often ignored simply because of their complexity and because they seem very difficult to study,” Linda explains. “But that’s also what makes them so interesting.”

Because the region is so diverse, the researchers needed to look across about a thousand samples in order for the nine distinct structures to emerge. Existing methods are difficult to scale and apply to this many samples. Instead, the team used a molecular technique called digital droplet PCR to look at this region of the genome in parents and children to find patterns of copy number inheritance. They also used a complementary, computational method to analyze data from the 1,000 Genomes Project. The results of the two methodologies converged on many of the same findings.

“The key to our success was to combine several different techniques,” explains Bob, a senior principal software engineer. “We leverage the new digital droplet PCR technology, but combined this with sequence data analysis from public sources (the 1,000 Genomes Project), which allowed us to validate each approach against the other.”

Mike, a senior computational biologist, began working on this locus in 2006, publishing a paper with his colleague Evan Eichler at the University of Washington. Mike moved on to other projects, but in 2009 he heard that Steve and Linda had made fresh discoveries in the region. He joined them the following year.

Mike agrees with Bob that the true strength of the project comes from combining different strategies and expertise. “Between the different technologies, including complete, finished sequences for two of the nine versions that we discovered, we were able to describe and classify multiple structural types that we never completely sequenced,” Mike says.

The researchers found many intriguing results, including the fact that two of the structures independently acquired partial duplicate copies of the gene KANSL1. Interestingly, this gene has been shown to affect age-dependent female fertility in fruit flies, offering a potential connection to the relationship between human fertility and this region.

One of the team’s long-term goals is to eventually tie one or more of the nine structures to risk of disease. “We want to get to the point for this locus, and all such loci, where we can see that the phenotype [diseases like Parkinson’s, Celiac, etc.] is traveling with a set of genetic markers for one of these structures,” Steve says.

The methodology that the researchers have used to tease apart structural variation at this locus can now be applied to other complex loci connected to disease.

“Regions of high physical complexity are certainly understudied,” Linda says. “These kinds of projects can be very confusing at the beginning, but when you tease them apart, when you look at copy number and puzzle through it, you will begin to see a beautiful picture of what it all looks like.”


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 2,500+ scientific posters on ePosters
  • More than 3,700+ 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 TechnologyNetworks.com 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.

Related Content

Single-cell Analysis Hits its Stride
Advances in technology and computational analysis enable scale and affordability, paving the way for translational studies.
Saturday, May 23, 2015
In vivo CRISPR-Cas9 Screen Sheds Light On Cancer Metastasis And Tumor Evolution
Genome-scale study points to drivers of tumor evolution and metastasis, provides roadmap for future in vivo Cas9 screens.
Friday, March 06, 2015
Two Studies Identify A Detectable, Pre-Cancerous State In The Blood
Findings pave way for new lines of cancer research focused on detection and prevention.
Thursday, November 27, 2014
Dramatic Response And Resistance To Cancer Drug Traced
Sequencing reveals why thyroid tumor responded to, and eventually resisted, treatment.
Friday, October 10, 2014
Predicting Cancer’s Next Move
Research offers a new approach to studying drug resistance in cancer.
Monday, November 11, 2013
Global Alliance to Enable Secure Sharing of Genomic and Clinical Data
Over 70 leading organizations have taken the first steps to form an international alliance dedicated to enabling secure sharing of genomic and clinical data.
Monday, June 10, 2013
Surveying Cells, One At a Time
When studying any kind of population — people or cells — averaging is a useful, if flawed, form of measurement.
Wednesday, May 22, 2013
Breast Cancer’s Many Drivers
Extensive sequencing effort looks at the genetic changes associated with various breast cancers.
Thursday, June 21, 2012
Mapping the Healthy Human Microbiome
Broad scientists create molecular tools and applying standardized protocols, generating vast amounts of data to identify the microbiome's most elusive organisms for whole genome sequencing.
Friday, June 15, 2012
Zooming in on Early Embryonic Development
Broad Institute researchers show a high-resolution view of mouse embryogenesis, down to individual bases, showing genetic changes.
Monday, May 21, 2012
Scientific News
Liquid Biopsies: Utilization of Circulating Biomarkers for Minimally Invasive Diagnostics Development
Market Trends in Biofluid-based Liquid Biopsies: Deploying Circulating Biomarkers in the Clinic. Enal Razvi, Ph.D., Managing Director, Select Biosciences, Inc.
DNA Damage Seen in Patients Undergoing CT Scanning
Along with the burgeoning use of advanced medical imaging tests over the past decade have come rising public health concerns about possible links between low-dose radiation and cancer.
Web App Helps Researchers Explore Cancer Genetics
Brown University computer scientists have developed a new interactive tool to help researchers and clinicians explore the genetic underpinnings of cancer.
New Research Advances Genetic Studies in Wildlife Conservation
‘Next-gen’ DNA sequencing of non-invasively collected hair expands field of conservation genetics.
Gene Testing Now Allows Precision Medicine for Thoracic Aneurysms
Researchers at the Aortic Institute at Yale have tested the genomes of more than 100 patients with thoracic aortic aneurysms, a potentially lethal condition, and provided genetically personalized care.
OGT’s Popular ESHG Workshop Free to View Online
Learn about the next generation of microarrays in one of the best attended workshops of the conference.
Discordant NIPT Test Results May Reflect Presence of Maternal Cancer
Results published in Journal of the American Medical Association.
Sperm RNA Test May Improve Evaluation of Male Infertility
To help resolve uncertainty—and guide prospective parents to the right fertility treatments—scientists propose the use of a new kind of fertility test. It involves examining sperm RNA by means of next-generation sequencing.
How the Mammoth Got its Wool
Evolutionary change in a gene reconstructed in the lab from the woolly mammoth was part of a suite of adaptations that allowed the mammoth to survive in harsh arctic environments, according to new research.
NuGEN Scientists Screen 400+ Genes for Fusion Events in Single Assay
Breakthrough proves efficacy of new sample preparation method that could accelerate cancer research and development of treatments and diagnostic tests.
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
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!