genetic findings in autism: toward a biological understanding... · 2016-10-19 · genetic findings...
TRANSCRIPT
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Genetic Findings in Autism:
Toward a Biological Understanding
Daniel B. Campbell, Ph.D. Assistant Professor
Department of Psychiatry and the Behavioral Sciences
Zilkha Neurogenetic Institute
Center for Genomic Psychiatry
Keck School of Medicine
University of Southern California
Los Angeles, CA USA
Email: [email protected]
The Help Group Summit
October 26, 2013
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Outline
• Introduction to Non-Coding RNAs
• Overview of Autism Genetics
• Genome-Wide Association Study results
– Point to non-coding RNAs
• Exome Sequencing results
– Point to a transcription factor that regulates … non-coding RNAs
• A New Type of Pharmacology Targets Non-Coding RNAs
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The Central Dogma
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In the Human Brain,
62% of All Long RNAs are Non-Coding
Human Brain
Fruit Fly
Protein-coding RNA
Non-coding RNA (intragenic)
Non-coding RNA (intergenic)
Kapranov et al. 2010.
BMC Biol.
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Non-Coding RNAs and Complexity
Liu, Mattick, & Taft. 2013. Cell Cycle.
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Nature. 2013.
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Outline
• Introduction to Non-Coding RNAs
• Overview of Autism Genetics
• Genome-Wide Association Study results
– Point to non-coding RNAs
• Exome Sequencing results
– Point to a transcription factor that regulates … non-coding RNAs
• A New Type of Pharmacology Targets Non-Coding RNAs
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The Contributions to Autism?
• Rare Genetic Variants
– Whole Exome Sequencing
– Copy Number Variations
• Common Genetic Variants
– Genome-Wide Association
– Candidate Gene Association
• Environmental Factors
• The debate continues …
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Stein et al. 2013. Neuron.
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Devlin & Scherer. 2012.
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3 Autism Exome Sequencing Papers:
April 2012
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April Exome: Major Findings
• Each paper finds a few genes with mutations in 2 affected individuals and 0 controls
• In a total of 584 families, the same gene was found to have a de novo mutation in no more than 2 (<0.4%) families – 4 genes: SCN2A, CHD8, NTNG1, KATNAL2
• Each paper concludes that there is no gene that is causal for autism, and that several hundred genes will contribute to risk
Sanders et al. 2012. Nature.
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The 4th Autism Exome Sequencing Paper
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Autism Exome Sequencing: June 2012
• 967 families (quads) exome sequenced
• Still no gene with de novo LGD mutations
in more than 2 (0.2%) families
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“Mutations” that Cause Loss of Protein
Function are Shockingly Common
Science. 2012.
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Bamshad et al. 2011. Nature Reviews Genetics.
All “Mutations” are Shockingly Common
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O’Roak et al. 2012 (Nov 15). Science.
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CHD8: 11 de novo LoF mutations
… and association with autism P<10-8
… note: next best genes have 3 de novo LGD
O’Roak et al. 2012. Science.
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Devlin & Scherer. 2012.
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Outline
• Introduction to Non-Coding RNAs
• Overview of Autism Genetics
• Genome-Wide Association Study results
– Point to non-coding RNAs
• Exome Sequencing results
– Point to a transcription factor that regulates … non-coding RNAs
• A New Type of Pharmacology Targets Non-Coding RNAs
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Genome Wide Association Study (GWAS)
Revealed Association of Common
Genetic Variants on Chromosome 5
Wang et al. 2009. Nature.
Possible Interpretations:
1. The GWAS peak implicates the neighboring CDH10 and CDH9 genes in ASD.
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rs4307059 Genotype Did Not Correlate with
Expression of CDH9 or CDH10
Wang et al. Nature. 2009.
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Genome Wide Association Study (GWAS)
Revealed Association of Common
Genetic Variants on Chromosome 5
Wang et al. 2009. Nature.
Possible Interpretations:
1. The GWAS peak implicates the neighboring CDH10 and CDH9 genes in ASD.
2. The GWAS data indicate that no common variants contribute to ASD.
3. The GWAS peak indicates significant contribution of a functional, non-protein-
coding genetic element to ASD risk.
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A Long Non-Coding RNA is Expressed
Directly Under the ASD GWAS Peak
UCSC Genome Browser
Moesin Pseudogene 1 (MSNP1)
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Northern Hybridization: The Long Non-
Coding RNA is Complementary to MSNP1
Kerin et al. 2012. Science Translational Medicine.
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MSNP1AS is the Long Non-Coding RNA
Directly Under the ASD GWAS Peak
Kerin et al. 2012. Science Translational Medicine.
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Postmortem Temporal Cortex: MSNP1AS
Expression is Increased 12.7-Fold in ASD
Kerin et al. 2012. Science Translational Medicine.
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MSNP1AS Expression is Correlated with
ASD Risk Allele Genotypes
Kerin et al. 2012. Science Translational Medicine.
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Neither CDH9 nor CDH10 Expression is
Correlated with ASD Risk Allele Genotype
Kerin et al. 2012. Science Translational Medicine.
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Despite 2.4-fold Increase in MSN RNA,
Moesin Protein Levels are Unchanged
Kerin et al. 2012. Science Translational Medicine.
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Over-Expression of MSNP1AS Causes a
Decrease in Moesin Protein
Kerin et al. 2012. Science Translational Medicine.
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Correlations Among MSN, MSNP1AS, and
Moesin Protein in Postmortem Cortex
Kerin et al. 2012. Science Translational Medicine.
MSN is the major determinant
of moesin protein levels
MSN and MSNP1AS appear
to be co-regulated
MSNP1AS contributes to the
regulation of moesin protein
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Over-Expression of MSNP1AS Causes a
Decrease in the Average Neurite Length
Preliminary Data
Neurite Length
0
20
40
60
80
100
120
Control MSN MSNP1AS +
MSN
MSNP1 MSNP1AS
Construct Transfected
Avera
ge N
eu
rite
Len
gth
HEK 24 hr
HEK 72 hr
SK-N-SH 24 hr
SK-N-SH 72 hr
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MSNP1AS Summary
• MSNP1AS is the second anti-sense of a
pseudogene demonstrated to regulate
expression of a gene on a different chromosome
– First was Oct4-pg5 regulation of Oct4 (Hawkins &
Morris, 2010)
• Moesin is an X chromosome-encoded protein
that acts:
– (1) presynaptically to maintain axonal growth cones;
– (2) postsynaptically to induce dendritic spine
formation; and
– (3) at the immune synapse (APCs-lymphocytes)
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Devlin & Scherer. 2012.
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An Uncharacterized Long Non-Coding RNA
is Highly Expressed Near rs4141463
RPS10P2AS
Ribosomal Protein S10 Pseudogene 2, Anti-sense
UCSC Genome Browser
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Expression: The Uncharacterized RPS10P2AS is
Highly Expressed in Multiple Tissues
0.0001
0.001
0.01
0.1
1
10
FC TC OC Cb SC PB He Lu Ki Sk FC TC He Lu Ki
Rela
tive E
xp
ressio
n
MACROD2
MACROD2AS1
RPS10
RPS10P2AS
Adult Fetal
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The Non-Coding RNA RPS10P2AS is
Increased in Expression in Postmortem
Autism Brain
RPS10P2AS
5-fold increase
P=0.002
MACROD2
No Sign Diff
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Expression of the Non-Coding RNA
RPS10P2AS is Correlated with the Autism-
Associated rs4141463 C/C Genotype
*
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RPS10P2AS Summary
• Under an autism GWAS peak
• Expression is increased in postmortem
brains of individuals with autism
• Increased expression is correlated with the
autism GWAS allele
• Function? …
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Outline
• Introduction to Non-Coding RNAs
• Overview of Autism Genetics
• Genome-Wide Association Study results
– Point to non-coding RNAs
• Exome Sequencing results
– Point to a transcription factor that regulates … non-coding RNAs
• A New Type of Pharmacology Targets Non-Coding RNAs
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O’Roak et al. 2012 (Nov 15). Science.
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CHD8: 11 de novo LoF mutations
… and association with autism P<10-8
… note: next best genes have 3 de novo LGD
O’Roak et al. 2012. Science.
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CHD8 = Chromodomain Helicase
DNA-Binding Protein 8 • Known to … ?
– Chd8 knockout mouse is embryonic lethal before a brain appears (Nishiyama et al. 2004. Mol Cell Biol.)
– CHD8 protein is known to interact with a handful of other proteins in cancer cells
• Histone H1 and b-catenin (Nishiyama et al. 2012. Mol Cell Biol.)
• Androgen Receptor (Menon et al. 2010. Mol Endocrinology.)
• RNA Polymerase III (Yuan et al. 2009. Mol Cell Biol.)
• Bottom line: CHD8 interacts with multiple proteins, but its function has not been studied in the brain or neurons
• We found: CHD8 over-expression in human neuronal cell lines increased expression of the non-coding RNA MSNP1AS
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Outline
• Introduction to Non-Coding RNAs
• Overview of Autism Genetics
• Genome-Wide Association Study results
– Point to non-coding RNAs
• Exome Sequencing results
– Point to a transcription factor that regulates … non-coding RNAs
• A New Type of Pharmacology Targets Non-Coding RNAs
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Weinberg & Morris.
2013. Nucleic Acid
Therapies.
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Proposed Mechanism of MSNP1AS
Long Non-Coding RNA
Chromosome X DNA Chromosome 5 DNA
Chromosome X Moesin RNA
Transcription
Chromosome 5 Non-Coding RNA
Transcription
Translation
Moesin Protein Chromosome 5 Non-Coding RNA
Binds Chromosome X Moesin RNA
Alters Translation
of Moesin Protein
Antisense
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“Antisense to the Antisense”
Chromosome X DNA Chromosome 5 DNA
Chromosome X Moesin RNA
Transcription
Chromosome 5 Non-Coding RNA
Transcription
Translation
Moesin Protein Chromosome 5 Non-Coding RNA
Binds Chromosome X Moesin RNA
Alters Translation
of Moesin Protein
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Conclusions
Non-coding RNAs are abundant in
human brain
Non-coding RNAs are the functional
elements revealed by autism GWAS
Non-coding RNAs are treatment
targets in HIV, cancer, diabetes
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The Team Campbell Lab (ZNI):
Nicole Grepo
Brent Wilkinson
Jessica DeWitt
Grace Kim
Christina Zdawczyk
Ani Misirian
Emily Holmes
Sarah Danehower
Kasey Rivas
Tara Kerin
Anita Ramanathan
Elisabeth Rutledge
Ranjita Raghavan
Young Kim
Giovanni Dandekar
Elizabeth Cortez-Toledo
Rachel Marshall
USC Collaborators:
Pat Levitt
Heather Volk
Gerry Coetzee
Jim Knowles
Carlos Pato
Kai Wang
Oleg Evgrafov
Marcelo Coba
Barbara Thompson
Wange Lu
Rob McConnell
Carrie Breton
Outside Collaborators:
Kevin Morris (Scripps)
Judy Van de Water (UC-Davis)
Paul Ashwood (UC-Davis)
Isaac Pessah (UC-Davis)
Irva Hertz-Picciotto (UC-Davis)
Susan Swedo (NIMH)
Audrey Thurm (NIMH)
Lisa Croen (Kaiser Permanente)
Funding:
NIMH
Autism Speaks
Resources:
Autism Tissue Program