When chromosomes replicate, sometimes there is an exchange of genetic material within a chromosome or between two or more chromosomes without a significant loss of genetic material. This exchange, known as a balanced chromosomal abnormality (BCA), can cause rearrangements in the genetic code.
Researchers from 15 institutions in three countries including Brigham and Women's Hospital (BWH), Massachusetts General Hospital, Harvard Medical School, and the Broad Institute found that due to these rearrangements, BCAs harbor a reservoir of disruptions in the code that could lead to autism and other neurodevelopmental disorders. The researchers also uncovered 22 new genes that may contribute to or increase the risk of autism or abnormal neurodevelopment.
The study will be published in the print issue of Cell on April 27, 2012.
The researchers used a strategy that involved directly sequencing BCAs to reveal genes at the breakpoints and show that these genes are related to autism and other neurodevelopmental disorders.
This study is part of a larger, ongoing collaborative endeavor, the Developmental Genome Anatomy Project (DGAP), to identify genes critical in human development.
The researchers discovered that the genetic code can be disrupted at various distinct sites and still result in autism. The disruptions occur in several different groups of genes, including those already individually suspected to be associated with abnormal neurodevelopment; those which illuminate a single gene as important in large regions previously defined as genomic disorders; as well as those associated with psychiatric disorders that can have much later onset than neurodevelopmental disorders.
"BCAs provide a unique opportunity to pinpoint a gene and validate it in a disorder," said Cynthia Morton, PhD, BWH director of cytogenetics, and principal investigator of DGAP. "These discoveries can illuminate biological pathways that may be a window to a new therapy. We are all grateful to the individuals and their families who make these fundamental findings possible through their participation as subjects in these studies."
This research was supported by the Simons Foundation Autism Research Initiative; Autism Speaks; Massachusetts General Hospital ECOR Fund for Medical Discovery Award; and the National Institutes of Health (NIH) and Human Services including the National Institute of General Medical Sciences, the National Institute of Mental Health and the National Human Genome Research Institute. NIH and NIMH grants included P01-GM061354, R21-HD065286 and F32-MH087123.
Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries. Michael E. Talkowski, Jill A. Rosenfeld, Ian Blumenthal, Vamsee Pillalamarri, Colby Chiang, Adrian Heilbut, Carl Ernst, Carrie Hanscom, Elizabeth Rossin, Amelia M. Lindgren, Shahrin Pereira, Douglas Ruderfer, Andrew Kirby, Stephan Ripke, David J. Harris, Ji-Hyun Lee, Kyungsoo Ha, Hyung-Goo Kim, Benjamin D. Solomon, Andrea L. Gropman, Diane Lucente, Katherine Sims, Toshiro K. Ohsumi, Mark L. Borowsky, Stephanie Loranger, Bradley Quade, Kasper Lage, Judith Miles, Bai-Lin Wu, Yiping Shen, Benjamin Neale, Lisa G. Shaffer, Mark J. Daly, Cynthia C. Morton, James F. Gusella. Cell, 19 April 2012. doi:10.1016/j.cell.2012.03.028
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