Spontaneous Mutations Rife in Non-Familial
Non-Hereditary Genetic Variations May Help Explain Illnessís
Evolutionary Staying Power
People with schizophrenia (http://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml)
from families with no history of the illness were found to harbor
eight times more spontaneous mutations — most in pathways
affecting brain development — than healthy controls, in
a study supported in part the National Institutes of Healthís (NIH)
National Institute of Mental Health (NIMH). By contrast, no spontaneous
mutations were found in people with schizophrenia who had family
histories of the illness.
"Our findings strongly suggest that rare, spontaneous mutations
likely contribute to vulnerability in cases of schizophrenia from
previously unaffected families," said Maria Karayiorgou, M.D.,
of Columbia University, who led the research team. "This may
also shed light on why the illness has frustrated efforts to implicate
gene variants with major effects, and seems to defy natural selection
by persisting in the population even though relatively few of those
affected have children."
Karayiorgou and her colleagues report on their whole genome study
online in Nature Genetics, May 30, 2008.
"Such abnormal deletions or duplications of genetic material
are increasingly being implicated in schizophrenia and autism (http://www.nimh.nih.gov/science-news/2008/autism-gene-scans-converge-on-two-suspect-sites-two-types-of-genetic-risk.shtml)," explained
NIMH Director Thomas R. Insel, M.D. "Now we have a dramatic
demonstration that genetic vulnerabilities for these illnesses
may not be inherited from parents, at least in the sense that these
vulnerabilities were not present in the parental genome. This line
of research holds promise for improved treatments — and perhaps
someday even prevention — of developmental brain disorders."
Although it's known that genetics plays a major role in the transmission
of both autism and schizophrenia, most cases are sporadic rather
Echoing findings of another recent study (http://www.nimh.nih.gov/science-news/2008/rates-of-rare-mutations-soar-three-to-four-times-higher-in-schizophrenia.shtml),
Karayiorgou and her colleagues determined that most of the suspect
mutations were not random, but found in genes and pathways involved
in brain development. However, whether a mutation was spontaneous
or inherited was not determined for most of the subjects included
in the earlier study.
To pinpoint the sources of the glitches, the researchers in the
new study compared genetic data from 369 subjects with data from
their biological parents — in a total sample of 1,077 individuals
drawn from the European ancestry Afrikaner population in South
Africa. Including parental genes makes it possible to definitively
determine whatís inherited.
Scans of each person's genome detected the spontaneous mutations
in 15 of 152 individuals (10 percent) with non-familial schizophrenia,
and only in two of 159 people (1 percent) without the illness — the
eight-fold difference. Such sporadic cases were only 1.5 times
more likely than controls to harbor inherited mutations.
The researchers also found three deletions of genetic material
at a site on chromosome 22 previously implicated in schizophrenia,
confirming it as the only known recurrent such mutation linked
to schizophrenia. In addition to NIMH, the current study also cites
support from the NIHís National Cancer Institute, National Institute
of Diabetes and Digestive and Kidney Diseases, National Eye Institute,
and the Lieber Center for Schizophrenia Research at Columbia University.
The National Institute of Mental Health (NIMH) mission is to reduce
the burden of mental and behavioral disorders through research
on mind, brain, and behavior. More information is available at
the NIMH website, http://www.nimh.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M.
Strong association of de novo copy number mutations with sporadic
schizophrenia. Nat Genet. 2008 May 30. [Epub ahead of print]