Building a Rare Resource: Brain Tissue DNA
The Autism Tissue Program (ATP), a science program of Autism Speaks, has made precious brain tissue available for research since 1998. Now the ATP offers genetic data derived from brain tissue as well as providing the tissue itself for further study. A newly published paper1 describes this joint project of Autism Speaks and The Centre for Applied Genomics in Toronto.
DNA extracts from 52 brain samples of donors (26 subjects with confirmed or suspected autism, five subjects known to have duplications of a portion of chromosome 15q, one donor with Angleman Syndrome, two with epilepsy, and 18 age-matched normal controls) were analyzed for genetic “markers”– unique alterations in the DNA. Using common gene microarray ‘chips’ to capture small variations within the genome, the investigators found many instances of repeating blocks of genetic code termed genomic copy number variation (CNV).
A CNV is a submicroscopic duplication or deletion of a stretch of DNA in the genome. The preliminary observations show over 150 CNVs found in the autism cases that are not observed in individuals with no known neurodevelopmental disorders. Some of these CNV overlap with known autism susceptibility genes: For example, the NRXN1 gene encodes a protein that helps synapses between neurons connect and has repeatedly been associated with autism.
The genotype data and DNA samples are available to the autism research community through a peer-reviewed approval process by the Autism Tissue Program’s Tissue Advisory Board. One of the board members, Stephen D. Ginsberg, Ph.D., a Professor at Nathan Kline Institute in New York, participated in the dissection and analysis of the brain samples and is an author on the paper. Dr. Ginsberg kindly agreed to a Q&A on the implications of this research and this new biological resource.
What is your research background and role on the Tissue Advisory Board (TAB)?
I have been a member of the TAB since 2007. I am formally trained in neuroanatomy (studying the structure of the human brain), neuropathology (assessing dysfunction of the brain in specific disease states), and molecular biology. My interest lies in understanding why specific neurons are vulnerable to neurodegeneration. I use precise methods to identify differential changes in gene and protein expression in specific neuronal populations in several neurodegenerative and neuropsychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, and recently in autism spectrum disorders through collaborations fostered through the TAB community. My original impetus for joining the TAB was to give back to the research community, as I have particular expertise in assessing brain tissue quality in postmortem samples for high throughput genomic-based studies. I am grateful for the health of my own children and feel obligated to help those families who are struggling with loved ones affected by autism spectrum disorders.
Why is this research important to understanding autism?
The collaborative group has proven that a library of DNA information (obtained using microarray technology) can be created from postmortem brains of individuals with autism as well as samples from age-matched typically-developed individuals. This ‘proof of concept’ demonstration is critical for the success of this type of exploratory research. Importantly, the microarray assays were run on brain regions that are abundant, saving rarer and critical areas for future autism research. The DNA assays are available to researchers via a web-based system, meaning that many investigators around the world will benefit from the new repository.
How is this new library different from information from DNA from blood or cell lines?
The answer to this question has not been determined to my satisfaction at this point. Future work comparing DNA fingerprints extracted from blood, cell lines, and postmortem brain tissue are required. The fact that highly useful information was obtained from the most difficult tissue to work with (postmortem human brain) likely means that some overlap will be identified with more readily available blood and cell lines. Of course, this will demand more research to lay the groundwork for important discovery science.
How important is brain donation for autism research?
Simply stated, this work cannot be done without the selfless (and often uncredited) support from the donors and their families. There is no perfect animal or cellular model for autism to date, and we are dependent upon studying human tissues to give clues as to the underlying causes and potential treatments for autism spectrum disorders. As someone who also works in the Alzheimer’s disease field, I am tremendously aware of the difficulty of obtaining brain tissues from individuals with autism (as well as cognitively-matched typical controls). Many of the brains are collected from children who were lost to accidents. In comparison, the acquisition of brains of older individuals afflicted with neurodegenerative disorders is more common, as awareness of the importance of studying the aged brain is widely accepted, and there are both federal granting agencies and private foundations that support the high cost of maintaining brain banks and distributing tissues. The families involved in the donation in the latter case may often have more time to consider the option of donation prior to the precious few hours in which a brain may be donated after death. By contrast, the field of autism research is relatively new and greater awareness and community outreach will be required for the brain repository aspect of research to reach its full potential. We have begun to make real progress, and I am honored to be part of this exciting endeavor.
This genetic information and the rare DNA resource is made possible by the support of the ATP donor families. To register you or your family to make a lasting gift to science, please visit www.autismtissueprogram.org for information and online registration, or call 877-333-0999 for information or to initiate a brain donation. Please direct questions about the genotype data and application process for DNA samples to Dr. Jane Pickett (firstname.lastname@example.org).
1. Wintle RF, Lionel AC, Hu P, Ginsberg SD, Pinto D, Thiruvahindrapduram B, Wei J, Marshall CR, Pickett J, Cook EH, Scherer SW. A genotype resource for postmortem brain samples from the autism tissue program. Autism Res. 2011 Jan 19. doi: 10.1002/aur.173. [Epub ahead of print]