Transcript File - BIO 283: Bioinformatics Project

Genetics of Autism
A Bioinformatics Analysis of Suspected Genes and Products
Teresa LuPone
BIO 283
What is Autism?
 Defined by a spectrum of disorders containing varying
degrees of the following three basic symptomologies
 Social Impairment
 Inattention, delayed or non-responsiveness, inability to
respond to social cues.
 Communication Difficulties
 Delayed speech development, difficulties with self
expression, conversational difficulties.
 Repetitive and Stereotyped behaviors
 Repetitive words, phrases or motor movements, obsessive
focus on interests.
(National Institute of Mental Health)
More on Autism
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Prevalence
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1992: 1 in 150 affected
2008: 1 in 88 affected
Boys 5 times more likely.
Evidence to date:
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Ruling out of some environmental factors
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Emerging evidence for genetic causation and possible correlation with other diseases.
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Vaccines: 2004 findings did not support the rumor that vaccines contributed to incidence of
autism (CDC)
Immunity abnormalities has a significant number of ASD affected individuals with immune
problems.
Cytogenetic studies, Oxidative stress.
Suspected genes (short list)
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FOXP2
UBE3A
MECP-2
RELN
The Genetic Component
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FOXP2: multivariant gene involved in regulation of other genes.
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Important roles: speech and language center development in brain. (RefSeq 2010). Located on Chromosome 7
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FOXP2 Map: http://tinyurl.com/cxbxdaf
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MECP-2: Located on the X chromosome.
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Females with Rett syndrome found similar abnormalities to ASD expression. (Persico et. al.)
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MECP-2 Map: http://tinyurl.com/btr9nec
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Sequence: http://www.ncbi.nlm.nih.gov/nuccore/22830571
UBE3A: a gene involved in ubiquitin ligase, essential to ubiquitin activation.
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Mutations cause severe diseases characterized by: severe motor and intellectual retardation, ataxia, hypotonia,
epilepsy, and absence of speech.
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UBE3A Map: http://tinyurl.com/d2clzcf
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Sequence: http://www.ncbi.nlm.nih.gov/nuccore/21322221
Sequence: http://www.ncbi.nlm.nih.gov/nuccore/21306876
RELN: large ECM protein that is believed to control cell-cell interactions and neuronal migration that is essential in
brain development. Mutations of this gene are associated with autosomal recessive lissencephaly with cerebellar
hypoplasia (RefSeq, 2008).
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RELN Map: http://tinyurl.com/blrc8c2
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Sequence: http://www.ncbi.nlm.nih.gov/nuccore/1809222
Purpose
 The goal of this project is to analyze the emerging
evidence for the genetic basis of autism, using
bioinformatics computational tools for similarities
to support the following claim. Genes that may have
a role within autism must have some similarity in
their gene products, which may have some
influence over the spectrum disorders of autism..
Materials & Methods
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Software/Databases Employed:
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NCBI: ORF Finder, Gene, Nucleotide, RefSeq, Conserved Domain, MeSH,
PubMed and BLASTp
EMBL-EBI protein tools not employed but used as reference.
Cn3D used for protein visualization.
Suspected Genes are run through the ORF finder in NCBI.
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Largest ORF’s chosen due to the strong likelihood of a functional protein.
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Resulting proposed protein sequences were run through a BLASTp
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Analyzed for conserved domains.
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Conserved domains or similar protein structures if any were visualized
with Cn3d protein visualization tool.
Results
FOXP2
Results
BLAST results
pictogram for
FOXP2
FOXP2
Results
Above: Sequence alignment of proposed
protein with putative p150 protein.
Left: ORF with translated protein.
MECP-2
Results
BLAST results
pictogram for
MECP-2
MECP-2
Right: Sequence
alignment of
proposed protein
with putative p150
protein.
Top right: methyl
CpG binding
protein
visualization,
extremely similar
to proposed
protein.
Results
Above: ORF with
translated protein.
UBE3A
Results
BLAST results
pictogram for
UBE3A
UBE3A
Results
Above: Sequence alignment of proposed
protein with hCG1777785 protein.
Left: ORF with translated protein.
RELN
Results
BLAST results
pictogram for
RELN
RELN
Results
Above: Sequence alignment of proposed
protein with putative p150 protein.
Left: ORF with translated protein.
Conserved Domain of FOXP2, UBE3A and RELN
Left: Virtual proposed
protein of the conserved
domain.
Results
Above: Phylogram of protein
families within this
conserved domain.
Evaluations
 Some structural similarity. Three shared a
conserved domain in their longest ORF gene
product.
 No evidence has been found yet in their causal roles
in autism, future wet lab work is suggested.
 Partial support for the claim:
 Genes that may have a role within autism must have some
similarity in their gene products, which may have some
influence over the spectrum disorders of autism.
References
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Ameis, S. H., & Szatmari, P. (2012). Imaging-genetics in autism spectrum disorder: Advances,
translational impact, and future directions. Frontiers in Psychiatry, 3(46), 16. Retrieved from
www.frontiersin.org.
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Klei, L., Sanders, S. J., Murtha, M. T., & ET AL (2012). Common genetics variants, acting
additively, are a major source of risk for autism. Molecular Autism, 3(9), 28. doi:10.1186/20402392-2-9.
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Muhle, R., Trentacoste, S. V., & Rapin, I. (2004, May). The Genetics of Autism.Pediatrics.
Retrieved October 10, 2012, from http://www.pediatrics.org/cgi/content/full/113/e472
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NIMH. (2011, October 26). A parent's guide to autism. website:
http://www.nimh.nih.gov/health/publications/a-parents-guide-to-autism-spectrumdisorder/what-is-autism-spectrum-disorder-asd.shtml
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(n.d.). Autism spectrum disorders. website: http://www.cdc.gov/ncbddd/autism/index.html
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Perisco, A. M., Van de Water, J., & Pardo, C. A. (2012). Autism: Where Genetics Meets the
Immune System. Autism Research and Treatment, 2012. doi:10.1155/2012/486359.
Questions?
A special thank you to Erin Ramirez for her help in experimental
design and our professor Dr. Dash!