Refining language for chromosomes

Now a study by researchers at Brigham and Women's Hospital (BWH) proposes a new classification system that may standardize how structural chromosomal rearrangements are described. Known as Next-Gen Cytogenetic Nomenclature, it is a major contribution to the classification system to potentially revolutionize how cytogeneticists worldwide translate and communicate chromosomal abnormalities. The study will be published online April 17, 2014 in The American Journal of Human Genetics.

"As scientists we are moving the field of cytogenetics forward in the clinical space," said Cynthia Morton, PhD, BWH director of Cytogenetics, senior study author. "We will be able to define chromosomal abnormalities and report them in a way that is integral to molecular methods entering clinical practice."

According to the researchers, advances in next-generation sequencing methods and results from BWH's Developmental Genome Anatomy Project (DGAP) revealed an assortment of genes disrupted and dysregulated in human development in over 100 cases. Given the wide variety of chromosomal abnormalities, the researchers recognized that more accurate and full descriptions of structural chromosomal rearrangements were needed.

The nomenclature proposed by Morton and her team goes beyond uncovering chromosomal abnormalities under a microscope to focusing on the unique molecules that are the building blocks of DNA -- nucleotides.

"Cytogeneticists compare karyograms, or pictures of chromosomes, to identify chromosomal abnormalities," said Morton. "In the current system available, we are able to describe certain characteristics of chromosomes, such as chromosome band levels. What we have developed is a new system for describing chromosomal abnormalities at a much more precise level."

"Currently, most DNA sequencing reports only provide nucleotide numbers of the breakpoints in various formats based on the reference genome sequence alignment," said Zehra Ordulu, MD, BWH Department of Obstetrics, Gynecology and Reproductive Medicine, lead study author. "But there are other important characteristics of the rearrangement -- including reference genome identification, chromosome band level, direction of the sequence, homology, repeats, and nontemplated sequence -- that are not described."

The proposed system addresses these characteristics and builds upon the International System for Human Cytogenetic Nomenclature, which is the current official classification system used to describe structural chromosome rearrangements.

To enable use and implementation of the proposed system, the researchers are developing an online tool called "BLA(S)T Output Sequence Tool of Nomenclature," or BOSToN. The tool works by aligning nucleotide sequences to reference human genome sequence. After processing the genetic information, the end result is the Next-Gen Cytogenetic Nomenclature that researchers and clinicians can then incorporate into their reports.

"BOSToN will reduce errors in sequence assessment and save time in generating nomenclature," according to Morton, "both of critical importance in the clinical setting."