Background
At least 10 large and rare recurrent DNA copy number variants (CNVs) have been identified
as risk factors for schizophrenia and other neurodevelopmental disorders. Because
such conditions are associated with reduced fecundity, these pathogenic CNVs should
be filtered out from the population by selection and must be replenished by de novo
events.
Methods
To estimate the mutation rate (μ) for these CNVs and the selection pressure (s) against them, we first conducted a literature review on the rate of each of these
CNVs in the population and the rate of their de novo occurrence. In each generation,
the number of CNVs lost because of reduced fertility must be replenished by the same
number of de novo CNVs. Therefore, the observed ratio of de novo versus all (inherited
+ de novo) CNVs approximates the selection coefficient (s) of that CNV. The mutation rate approximates to μ = s × q, where q is the frequency of the CNV in the population.
Results
High selection pressure operates at all these loci (s = .12 – .88), suggesting that following de novo occurrence, each of these CNVs persists
in the population in only a few generations. The mutation rate for each CNV is high,
affecting between 1:3500 and 1:30,000 individuals. The rarest CNVs have the highest
selection coefficients.
Conclusions
The CNVs that increase risk to develop schizophrenia are caused by recent de novo
mutations and are under strong selection pressure. They persist in the population
because of high mutation rates.
Key Words
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Article info
Publication history
Published online: August 22, 2011
Accepted:
July 14,
2011
Received in revised form:
July 12,
2011
Received:
June 1,
2011
Identification
Copyright
© 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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Access this article on ScienceDirectLinked Article
- Rare Variants and Risk for Schizophrenia: More SupportBiological PsychiatryVol. 70Issue 12
- PreviewCopy number variants (CNVs) have a fundamental role in human disease and population diversity (1-3). Exploration of rare CNVs with genomic microarrays has allowed rapid assessment of structural variation at high resolution and low cost. Studies have implicated various schizophrenia associated CNVs, including deletions on 22q11, 15q13, 1q21.1, 2p16.3, and 15q11.2 and the duplications of 16p11.2. CNVs vary in frequency and with larger sample sizes and greater power. CNVs that are more rare and with less effect are continually being updated.
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