New process could be key to understanding complex rearrangements in genome

December 5, 2017, Tufts University
Complex gemonic rearrangement (CGR) between yeast chromosomes II and III, involving deletions, duplications and triplications. Credit: The Mirkin Lab at Tufts University

Understanding complex genomic rearrangements (CGRs), the culprit in the development of many types of cancer and genetic disorders, has always been a challenge because of the limitations of established DNA sequencing techniques. However, a team led by Tufts University biologists has successfully harnessed new technology to develop an approach that could allow for rapid and precise identification of the CGRs involved in disease, cancer and disorder development, which is critical for diagnosis and treatment. The results appeared this week in the December issue of Genome Research.

CGRs are created by DNA double-strand breaks that are not repaired properly. Many types of cancer are characterized by the presence of CGRs. They can also occur at the beginning of life, leading to severe congenital disorders such as Pelizaeus-Merzbacher disease. Repetitive DNA sequences, are also subject to double-strand breaks, which can lead to CGRs. Expansions of repetitive DNA sequences are implicated in hereditary diseases, such as Huntington's disease, fragile X syndrome and Friedreich's ataxia.

Mapping the outcomes of CGRs is crucial for understanding their causes and the potential impact they have on DNA and abnormal cellular formation. Ideally, this mapping would occur through high-resolution imaging. However, high-resolution bio-imaging of CGRs has traditionally been a laborious, time-intensive process that required a good deal of skill.

Led by Ryan J. McGinty, a Ph.D. candidate in the Department of Biology at Tufts University's Graduate School of Arts and Sciences, the research group sought to develop a more efficient process to analyze CGRs.

Use of a new hand-held DNA sequencing device was instrumental to the team's approach. Previous DNA sequencing technologies read DNA in segments of a few hundred nucleotides. The new device, developed by Oxford Nanopore Technologies, allowed researchers to analyze DNA fragments that were tens of thousands of nucleotides in length, showing a fuller picture of the CGRs.

Using a yeast model system, the researchers analyzed the longer fragments to study various CGRs resulting from unstable DNA repeats. Doing so enabled them to read complex events in their entirety and allowed them to uncover the underlying mechanisms that led to each of the complex events.

"This is a groundbreaking approach to analyzing CGRs and determining their origins and outcomes," said Sergei Mirkin, Ph.D., professor and chair of the Department of Biology at Tufts and the study's corresponding author. "This research could significantly advance the way the scientific community deciphers, diagnoses and treats certain genetic disorders and other diseases caused by disruptions of the genome."

The Mirkin Lab at Tufts studies DNA structure and functioning, with a primary focus on various DNA repeats, their role in the maintenance of the genome and their effects on major genetic transactions. A significant part of the lab's research is devoted to unusual DNA structures and their biological roles.

Explore further: A link between DNA transcription and disease-causing expansions

More information: Ryan J. McGinty et al, Nanopore sequencing of complex genomic rearrangements in yeast reveals mechanisms of repeat-mediated double-strand break repair, Genome Research (2017). DOI: 10.1101/gr.228148.117

Related Stories

A link between DNA transcription and disease-causing expansions

November 25, 2014
Researchers in human genetics have known that long nucleotide repeats in DNA lead to instability of the genome and ultimately to human hereditary diseases such Freidreich's ataxia and Huntington's disease.

Recommended for you

Overcoming a major barrier to developing liquid biopsies

July 16, 2018
The idea of testing blood or urine to find markers that help diagnose or treat disease holds great promise. But as technology has improved to allow researchers to examine tiny fragments of RNA, one major problem has led to ...

Genetic marker for drug risk in multiple sclerosis offers path toward precision medicine

July 16, 2018
A team of researchers has uncovered a specific gene variant associated with an adverse drug reaction resulting in liver injury in a people with multiple sclerosis (MS). It is the first time researchers have been able to establish ...

Researchers suggest new treatment for rare inherited cancers

July 16, 2018
Studying two rare inherited cancer syndromes, Yale Cancer Center (YCC) scientists have found the cancers are driven by a breakdown in how cells repair their DNA. The discovery, published today in Nature Genetics, suggests ...

AI accurately predicts effects of genetic mutations in biological dark matter

July 16, 2018
A new machine learning framework, dubbed ExPecto, can predict the effects of genetic mutations in the so-called "dark matter" regions of the human genome. ExPecto pinpoints how specific mutations can disrupt the way genes ...

Researchers discover gene that controls bone-to-fat ratio in bone marrow

July 12, 2018
In an unexpected discovery, UCLA researchers have found that a gene previously known to control human metabolism also controls the equilibrium of bone and fat in bone marrow as well as how an adult stem cell expresses its ...

Massive genome havoc in breast cancer is revealed

July 12, 2018
In cancer cells, genetic errors wreak havoc. Misspelled genes, as well as structural variations—larger-scale rearrangements of DNA that can encompass large chunks of chromosomes—disturb carefully balanced mechanisms that ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.