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RSRT scientific advisor, Rusty Gage has made yet another remarkable discovery.  He has found that brain cells are fraught with spontaneous mutations. In fact as many as 40% of neurons in the frontal cortex have mutations. Tom Insel, director of the National Institute of Mental Health comments on these findings in his latest blog post.

One Person Many Genomes

Dr. InselBy Thomas Insel on November 6, 2013

Of late, the word “government” has been frequently followed by dispiriting nouns like “shutdown,” “gridlock,” and “dysfunction.” By contrast, government-funded science has recently produced some high profile discoveries, although most news coverage of the work did not link the discoveries to government funding. One game changing finding worth highlighting from last week changes the way we think about genetics, the brain, and individual differences. First, a little background.

The world of genetics was shaken in 2007 by the discovery of “de novo” mutations associated with autism.1 These mutations were spontaneous changes in DNA sequence that were present in affected children but not in DNA from either parent’s blood cells. Apparently these mutations accumulated in the father’s sperm cells as these cells divided through multiple generations during his lifespan. Presumably older fathers had more of these spontaneous mutations. Indeed, epidemiological studies had reported that fathers over 40 were at higher risk for having children diagnosed with autism or schizophrenia.

Over the past 3 years, spontaneous mutations have been found to be much more common than we thought. And these mutations are not only transmitted from sperm but develop later in the fetus or even in rapidly dividing cells in adults. In fact, it appears that mutations are occurring all the time because DNA replication is surprisingly prone to errors. Many of these replication errors are of no consequence, but mutations in tumor suppressor genes appear to be the mechanism by which cancers arise in rapidly dividing cells of the gut or skin. These errors are called “somatic mutations” because they occur in select mature cells of the body. They are distinguished from “germline” mutations found in the stem cells of the embryo and retained in all cells of the body. Because of somatic mutations our bodies have multiple genomes: different mutations may be found in cells from gut, skin, or blood.

Somatic mutations have been a hot topic for cancer and stem cell biologists, but neuroscientists or psychiatric geneticists did not really worry about this problem because adult neurons do not divide. The genetics of mental illness has been based on DNA extracted from blood cells. Because we were not worried about the possibility of multiple genomes in a single person, we assumed that the genome of blood cells should tell us what we needed to know about DNA. Until recently, no one even worried enough about somatic mutations in brain to look for them.

Last year, Chris Walsh and his team at Harvard’s Children’s Hospital showed that rare neurodevelopmental disorders could result from somatic mutations found in a single area of the brain.2 Increased growth of one hemisphere of the brain was caused by a mutation in a growth gene called AKT3 only in cells from the enlarged hemisphere, not in the normally developing hemisphere and, importantly, not in blood cells.

Last week, groups led by Fred Gage of the Salk Institute and Ira Hall of the University of Virginia took the first careful look at DNA sequences in single neurons of a normal human frontal cortex.3 In a Science paper published online on Halloween, they reported the rather spooky finding that 41 percent of neurons had a major mutation, often unique to that cell. These mutations were not subtle: many involved deletions of more than a million bases of DNA and some involved duplications of chromosomes. Just as our bodies contain multiple genomes, it appears that our brains exhibit intense variation, perhaps greater than other tissues. How could this happen if neurons don’t divide? Actually, neurons during fetal development divide more rapidly than almost any other tissue known, with replication rates estimated at 100,000 divisions per minute from week 10 to week 24 of gestation when the brain surpasses 10 billion cells. It should therefore come as no surprise that somatic mutations are abundant in brain. Indeed, wouldn’t it be even more amazing if they did not occur?

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It seems that cholesterol and the brain is becoming a hot field.  Following up on the RSRT-funded results of the Justice lab comes an intriguing (and unpublished) study highlighted by the Simons Foundation.

New autism gene plays key role in cholesterol synthesis

ImageMutations in a gene that plays a role in producing cholesterol in the body increase the risk for autism, pointing the way toward therapies for some people with the disorder. The research was presented in a poster Tuesday at the Autism Consortium’s 2013 Research Symposium.

Mutations in the gene, DHCR24, are known to result in a severe metabolic disease linked to cholesterol. The gene’s newly discovered role in autism suggests that statins, drugs that lower cholesterol levels, may treat symptoms of autism.

The potential is exciting,” says Timothy Yu, a neurologist at Massachusetts General Hospital and a researcher at the Broad Institute of the Massachusetts Institute of Technology and Harvard University in Cambridge, Massachusetts.

“If you can find these kids who are swimming around in an otherwise generic autism pool and figure out a way to treat them appropriately, then you actually have the possibility of therapy.”

The researchers screened 2,000 families that have at least one child with autism to identify rare recessive gene variants for the disorder. In one family, they found that a girl diagnosed with pervasive developmental disorder-not otherwise specified and two boys diagnosed with intellectual disability and autism had all inherited two copies of the mutation, one from each parent.

“The gene is involved with the cholesterol synthesis pathway, so it started us thinking about the pathway’s role in autism and intellectual disability,” says Elaine Lim, a graduate student in Mark Daly’s lab at Harvard who presented the research.

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