Previously discarded, human-specific
'junk' DNA represents untapped resource in the study of diseases like
Alzheimer's and autism
 |
The first printout of the human genome
to be presented as a series of books, displayed in the 'Medicine Now'
room at the Wellcome Collection, London. The 3.4 billion units of DNA
code are transcribed into more than a hundred volumes, each a
thousand pages long, in type so small as to be barely legible.
Photo courtesy of Ross London
|
Short snippets of DNA found in human
brain tissue provide new insight into human cognitive function and
risk for developing certain neurological diseases, according to
researchers from the Departments of Psychiatry and Neuroscience at
Mount Sinai School of Medicine. The findings are published in the
November 20th issue of PLoS Biology.
They found hundreds of regions
throughout the human genome which showed a markedly different
chromatin structure in neurons in the prefrontal cortex, a brain
region that controls complex emotional and cognitive behavior,
compared to non-human primates. The findings of the study provide
important insights for diseases that are unique to humans such as
Alzheimer's disease and autism.
"While mapping the human genome
has taught us a great deal about human biology, the emerging field of
epigenomics may help us identify previously overlooked or discarded
sequences that are key to understanding disease," said Dr.
Akbarian. "We identified hundreds of loci that represent
untapped areas of study that may have therapeutic potential."
Dr. Akbarian and his research team
isolated small snippets of chromatin fibers from the prefrontal
cortex. Next, they analyzed these snippets to determine what genetic
signals they were expressing. Many of the sequences with
human-specific epigenetic characteristics were, until recently,
considered to be "junk DNA" with no particular function.
Now, they present new leads on how the
human brain has evolved, and a starting point for studying
neurological diseases. For example, the sequence of DPP10—a gene
critically important for normal human brain development—not only
showed distinct human-specific chromatin structures different from
other primate brains such as the chimpanzee or the macaque, but the
underlying DNA sequence showed some interesting differences from two
extinct primates—the Neanderthal and Denisovan, most closely
related to our own species and also referred to as 'archaic
hominins'.
"Many neurological disorders are
unique to human and are very hard as a clinical syndrome to study in
animals, such as Alzheimer's disease, autism, and depression,"
said Dr. Akbarian. "By studying epigenetics we can learn more
about those unique pieces of the human genome."
The research team also discovered that
several of these chromatin regions appear to physically interact with
each other inside the cell nucleus, despite being separated by
hundreds of thousands of DNA strands on the genome. This phenomenon
of "chromatin looping" appears to control the expression of
neighboring genes, including several with a critical role for human
brain development.
"There is growing consensus among
genome researchers that much of what was previously considered as
'junk sequences' in our genomes indeed could play some sort of
regulatory role," said Dr. Akbarian.
This study was supported by grants from
the National Institutes of Health. Dr. Akbarian plans to do more
epigenetic studies in other areas of the brain to see if there are
additional chromatin regions that are unique to humans. They also
plan to study the epigenomes of other mammals with highly evolved
social behaviors such as elephants.
Dr. Akbarian joined Mount Sinai in July
2012. He is internationally known for his cutting-edge research on
the epigenetic mechanisms of psychiatric disorders. He is a widely
recognized expert in advanced chromatin tools—many of which were
developed in his laboratory—in conjunction with mouse mutagenesis
and behavioral models of mental illness to bridge molecular,
cellular, and behavioral investigations. He is also a renowned
authority on the epigenetic analysis of human brain tissue examined
postmortem.
Prior to joining Mount Sinai, Dr.
Akbarian was Director of the Brudnick Neuropsychiatric Research
Institute. He received his medical and doctorate degrees from the
Freie Universitaet Berlin. Dr. Akbarian completed his postdoctoral
training in neuroscience at the University of California at Irvine
and the Whitehead Institute, and his residency in psychiatry at
Massachusetts General Hospital.
About The Mount Sinai Medical Center
The Mount Sinai Medical Center
encompasses both The Mount Sinai Hospital and Mount Sinai School of
Medicine. Established in 1968, Mount Sinai School of Medicine is one
of the leading medical schools in the United States. The Medical
School is noted for innovation in education, biomedical research,
clinical care delivery, and local and global community service. It
has more than 3,400 faculty in 32 departments and 14 research
institutes, and ranks among the top 20 medical schools both in
National Institutes of Health (NIH) funding and by US News and World
Report.
The Mount Sinai Hospital, founded in
1852, is a 1,171-bed tertiary- and quaternary-care teaching facility
and one of the nation's oldest, largest and most-respected voluntary
hospitals. In 2011, US News and World Report ranked The Mount Sinai
Hospital 14th on its elite Honor Roll of the nation's top hospitals
based on reputation, safety, and other patient-care factors. Mount
Sinai is one of 12 integrated academic medical centers whose medical
school ranks among the top 20 in NIH funding and US News and World
Report and whose hospital is on the US News and World Report Honor
Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients
last year, and approximately 560,000 outpatient visits took place.
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visit http://www.mountsinai.org/.
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