Genetics of AutismA Bioinformatics Analysis of Suspected Genes and ProductsTeresa LuPoneBIO 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

Prevalence 1992: 1 in 150 affected 2008: 1 in 88 affected Boys 5 times more likely.

Evidence to date: Ruling out of some environmental factors

Vaccines: 2004 findings did not support the rumor that vaccines contributed to incidence of autism (CDC)

Emerging evidence for genetic causation and possible correlation with other diseases. Immunity abnormalities has a significant number of ASD affected individuals with

immune problems. Cytogenetic studies, Oxidative stress.

Suspected genes (short list) FOXP2 UBE3A MECP-2 RELN

The Genetic Component

FOXP2: multivariant gene involved in regulation of other genes. Important roles: speech and language center development in brain. (RefSeq 2010). Located on

Chromosome 7 FOXP2 Map: http://tinyurl.com/cxbxdaf

Sequence: http://www.ncbi.nlm.nih.gov/nuccore/21322221

MECP-2: Located on the X chromosome. Females with Rett syndrome found similar abnormalities to ASD expression. (Persico et. al.)

MECP-2 Map: http://tinyurl.com/btr9nec Sequence: http://www.ncbi.nlm.nih.gov/nuccore/22830571

UBE3A: a gene involved in ubiquitin ligase, essential to ubiquitin activation. Mutations cause severe diseases characterized by: severe motor and intellectual

retardation, ataxia, hypotonia, epilepsy, and absence of speech. UBE3A Map: http://tinyurl.com/d2clzcf

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). RELN Map: http://tinyurl.com/blrc8c2

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

Software/Databases Employed: 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. Largest ORF’s chosen due to the strong likelihood of a functional

protein.

Resulting proposed protein sequences were run through a BLASTp

Analyzed for conserved domains.

Conserved domains or similar protein structures if any were visualized with Cn3d protein visualization tool.

Resu

lts

Resu

ltsFOXP2

BLAST results pictogram for FOXP2

Resu

ltsFOXP2

Above: Sequence alignment of proposed protein with putative p150 protein.

Left: ORF with translated protein.

Resu

ltsMECP-2

BLAST results pictogram for MECP-2

Resu

ltsMECP-2

Above: ORF with translated protein.

Right: Sequence alignment of proposed protein with putative p150 protein.

Top right: methyl CpG binding protein visualization, extremely similar to proposed protein.

Resu

ltsUBE3A

BLAST results pictogram for UBE3A

Resu

ltsUBE3A

Above: Sequence alignment of proposed protein with hCG1777785 protein.

Left: ORF with translated protein.

Resu

ltsRELN

BLAST results pictogram for RELN

Resu

ltsRELN

Above: Sequence alignment of proposed protein with putative p150 protein.

Left: ORF with translated protein.

Resu

ltsConserved Domain of FOXP2, UBE3A and RELN

Above: Phylogram of protein families within this conserved domain.

Left: Virtual proposed protein of the 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 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.

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:10.1186/2040-2392-2-9.

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

NIMH. (2011, October 26). A parent's guide to autism. website: http://www.nimh.nih.gov/health/publications/a-parents-guide-to-autism-spectrum-disorder/what-is-autism-spectrum-disorder-asd.shtml

(n.d.). Autism spectrum disorders. website: http://www.cdc.gov/ncbddd/autism/index.html

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!