AN OVERVIEW OF RECENT RESEARCH

Abstract

Discussion

Researchers are focusing their efforts on gaining greater understanding

of how epigenetics functions in the role of Autism Spectrum Disorder
(ASD). Epigenetics looks at gene expression (US National Library of
Medicine, 2014).

This research prompts many additional areas of discussion, including:

Possible development of better identification methods

Epigenetics can helps us understand why gene variations identified

across multiple subjects dont always end in the same result.

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Better understand and identify ASD typology

Develop gene specific treatment regimens and medications

Literature Review

Early identification and continued research may help researchers

discover ways to prevent further genetic expression and damage;
maybe one day even genetic repair

This could reduce confusion in understanding spectrum variability in

ASD

Increase understanding in professionals and lay people that each

person with ASD is an individual, and should be treated as such

Help in determining appropriate level of care

References
Anderson, G., & Maes, M. (2014). Redox regulation and the autistic spectrum: role of tryptophan catabolites,

ASD Risk Factors Related to

Possible Epigenetic Expression

Structures and Functions Impacted by Epigenetic Changes

Autism Spectrum Disorder (ASD)

ASD is a complex neurodevelopmental

disorder resulting in communication, social
interaction, and behavioral impairments.

Paternal Obesity (1)

Low Vitamin D at time of birth (2)
Paternal Age (3)
Maternal weight gain during pregnancy (3)
Viral infection around age two (3)
Fetal distress, breech presentation (3)
Planned Cesarean section (3)
Gestational diabetes (3)
Multiple births (3)
ABO and Rh incompatibility (3)
Pre-eclampsia (3)
Maternal psychotropic medication during
pregnancy and lactation (3)
Environmental toxins (3)
Perinatal mercury (3)
MicroRNAs (3)
DNA Methylation (3)

(1) (Suren, Pal, Gunnes, Nina, Roth, Christine...Mady, 2014) (2)

(Fernell, Bejerot, Westerlund, Miniscalco, Simila, Eyles,...Humble,
2015) (3) (Anderson & Maes, 2014)

Ladd-Acosta, Hansen, Fallin, Kaufman, & Feinberg, 2014

Summary of Genetic Research Efforts Relative to ASD

167.

Regulation of cytoskeleton
dynamics (2)

related to genetic disorders in autism. Molecular A utism 5:11. Retrieved on February 1, 2015 from

Technique

Neuron-specific chromatic
remodeling (4)
Presynaptic vesicle cycling and
exocytosis (2)

Translation regulation and protein degradation (2)

Cell adhesion molecules in trans-synaptic signaling (2)

Immuno-inflammation and mitochondrial dysfunction (5)

Oxytocin receptor gene and mesolimbic reward response (6)

Bruining, H., Eijkemans, J., Kas, M., Curran, S., Vorstman, J., & Bolton, P. (2014). Behavioral signatures

DNA Methylation (1) (3)

Linkage Analysis

Genotype-phenotype correlations in relation to symptomology (8)

Tryptophan catabolites, autoimmunity and the amygdala (5)

(1) (Liyanage, Zachariah, & Rastegar, 2013) (2) (Srivastava & Schwartz, 2014) (3) (Ladd-Acosta, Hansen, Briem, Fallin,
Kaufmann & Feinberg, 2014) (4) (Vogel-Ciernia, & Wood, 2014). (5) (Anderson & Maes, 2014) (6) Damiano, Aloi,
Dunlap, Burrus, Mosner, Kozink, & Dichter. (2014). (7) Velmeshev, Magistri, & Faghihi (2013) (8) (Bruining, Eijkemans, Kas, Curran, Vorstman, & Bolton, 2014)

Implications

ASD Related Findings

Reveals consistency in
Linkage has been found on
regions of variance in
nearly every chromosome
genomes and presence of
disease in genetic relatives

Genome-wide
Association Study

Typically compares
genomes between disease
affected and non-affected
persons in order to find
genetic variation

Many replicated genomewide significant loci

identified, including 3p25,
7p35, 5p14-15

Structural Variation
Analysis

Identifies structural
variation in genomes,
including copy number
variants, translocations and
inversions

Potentially hundreds of
CNV mutations implicated
in ASD, contributing to
between 5-8% of cases

Analyzes how
environmental
mechanisms regulate gene
expression throughout life
cycle

Highly active area of study;

hypermethylation
identified on OXTR, RELN,
MECP2, and BDNF genes.
Serotonin related genes
currently under study.

Expression of non-protein-coding antisense RNAs (7)

Definition

http://www.molecularautism.com/content/5/1/11
Damiano, C., Aloi, J., Dunlap, K., Burrus, C., Mosner, M., Kozink, R., Dichter, G. (2014). Association

Epigenetic Analysis

Therapeutic Implications and Challenges

Numerous studies attempting to identify specific autism-predisposing

genes have ended in frustration for many reasons, including:

immune-inflammation, autoimmunity, and the amygdala. Current Neuropharmocology 2014(12): 148-

(Meek, Lemery-Chalfant, Jahromi, & Valiente, 2013)

Introduction

Once researchers can match symptomology to genetic typology, they

may be able to create specific medications and treatment protocols for
specific types of ASD

To Be or Not to Be?
What is epigenetics anyway?
It might be easiest to think of epigenetics like a
light switch. We are born with basic DNA coding
and that doesnt change, but whether or not a
certain gene may be expressed (or turned on)
by environmental influences is called epigenetics.

Many opportunities for early intervention are lost due to late

diagnosis

Development of gene specific treatment protocols and medications

Increased understanding of the role that epigenetics plays in the

development of ASD can help researchers:

Better understanding of and ability to identify typology in ASD

The answer lies in epigeneticsthe expression of the mutated gene.

Scientists now believe that external influences contribute to whether or
not a gene will be expressed, and they are turning this thinking towards a
better understanding of the genetic influences in ASD.

Develop better early identification methods

Early intervention continues to be best chance for optimal functioning

Tamara McKlveen

For Example: Not everyone who demonstrates mutations in the BRCA1

gene will develop breast cancer, although mutations in this gene have
been identified as a leading cause of breast cancer (National Cancer
Institute, 2014). Why?

Candidate Gene
Analysis

Identifies specific genetic

alleles and disease; risky
alleles are typically over
represented in affected
individuals

between the oxytocin receptor (OXTR) gene and mesolimbic responses to rewards. Molecular A utism
5:7. Retrieved on February 1, 2015 from http:www.molecularautism.com/content/5/1/7
Duncan, L., Rollastri, A., & Smoller, J. (2014). Why many geneticists and psychological scientists have
discrepant views about gene-environment interaction (GxE) research. American Psychologist 69(3):
249-268. doi: 10.1037/a0036320
Ladd-Acosta, C., Hansen, KD., Briem, E., Fallin, MD., Kaufman, WE., & Feinberg, AP. (2014). Common
DNA methylation alterations in multiple brain regions in autism. Molecular Psychiatry 2014(19), 862871. doi: 10.1038/mp.2013.114
Liyanage, V., Zachariah, R., & Rastegar, M. (2013). Decitabine alters the expression of Mecp2 isoforms via
dynamic DNA methylation at the Mecp2 regulatory elements in neural stem cells. Molecular A utism 4

Replicated identified
candidate genes include
SLC6A4, ADAM10, OXTR,
RELN, RORA, and CNTNAP2
among others

(46). Retrieved on February 1, 2015 from http://www.molecularautism.com/content/4/1/46

Meek, S., Lemery-Chalfant, L., Jahromi, L., & Valiente, C. (2013). A review of gene-environment correlations and their implications for autism: A conceptual model. Psychological Review 120(3): 497-521.
doi: 10.1037/a0033139
National Cancer Institute. (2014). BRCA 1 and BRCA 2: Cancer risk and genetic testing. Retrieved January
25, 2015 from http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA

Discrepancies in defining Autism Spectrum Disorder

Small and ill defined sample sizes

-Early research on some diseases related to epigenetics suggests the possibility of

rescuing or reversing neurological deficits (Fragile X, Rett syndrome) (Shrivastava &
Schwartz, 2014)

Lack of interdisciplinary communication

-Differential sensitivity of Mecp2 is important for future drug therapy research

Inability to replicate findings in follow up studies

Challenges

mechanisms underlying synaptic plasticity, memory, and intellectual disability disorders.

A seemingly never-ending variations in findings

-Some individuals have deficits in opposing neural pathways, suggesting that attempts
at reversal or repair in one area may further damage another

Neuropharmocology 2014(80): 18-27. doi: 10.1016/j.neuropharm.2013.10.002

These studies identified hundreds of genetic loci suspects (Yuen,

Thiruvahindrapuram, Merico, Walker, Tammimies, Hoang, Fernandez,
2015). It was difficult to understand how there could be so many
possible genetic markers for ASD, and why these markers showed a
predisposition for ASD, but not everyone with the markers actually had
the disorder.

-Epigenetic mechanisms may prove to be at least as complex as gene sequence studies

and researchers are likely to encounter some of the similar pitfalls (Duncan, Pollastri, &
Smoller, 2014)

Conclusions

In a study released in January 2015, researchers found that most siblings

with autism (about 70% off the sample population) actually have
different genetic risk variants! (Yuen, et al., 2015).
What does that mean? In most cases, ASD is not caused by one
damaged gene that is passed from parents to children, but rather a host
of genomic weaknessess that may or may not be activated thats
epigenetics! This helps explain why two siblings with ASD can have such
great variation in symptoms, why some children with ASD experience
great recovery while others do not, and why interventions dont work the
same for every child.

US National Library of Medicine. (2014). Genetics home reference: Your guide to understanding genetic
conditions. Retrieved March 1-March 27, 2014 from http://ghr.nlm.nih.gov/
Vogel-Ciernia, A., & Wood, M. (2014). Neuron-specific chromatin remodeling: A missing link in epigenetic

Velmeshev, D., Magistri, M., & Faghihi, MA. (2013). Expression of non-protein-coding antisense RNAs in
genomic regions related to autism spectrum disorders. Molecular A utism 4:32. Retrieved on February
1, 2015 from http:www.molecularautism.com/content/4/1/32
Yuen, R., Thiruvahindrapuram, B., Merico, D., Walker, S., Tammimies, K., Hoang, N., Fernandez, B.
(2015). Whole-genome sequencing of quartet families with autism spectrum disorder. Nature
Medicine. doi: 10.1038/nm.3792

Recent research in family genotypes proves that even within family groups, ASD is highly heterogenous (Yuen, et al., 2015). While researchers will most likely continue with linkage, structure, and
genome analysis, there are a multitude of new research avenues to be explored in the area of epigenetics.

Acknowledgements

There are many factors that may influence damaging gene expression, including damage to parental sex cells, high-risk pregnancy, introduction of toxins, and disease. It should be noted that many of
these factors are correlational, but not necessarily causational in all cases.

A grateful thanks to my professors at South University, who have never wavered in their
encouragement and support of my efforts:

Epigenetic changes are suspected to play a role in many levels of molecular functioning, including DNA methylation, protein degradation, and mitochondrial dysfunction, leading to damage in the
construction of neural pathways and structure function in the brain.
Further research in the area of epigenetics can help researchers better understand ASD typology, which in turn could help us to identify earlier warning signs for ASD in children, improving treatment
outcomes and possibly contributing to new treatments designs.

Dr. Denny Cecil-Van den Heuvel

Dr. Antoinette Hollis

Dr. Scott Laurence

Dr. Davele Bursor

Dr. Darlene Silvernail

Thanks also to my family for all of their love and support.

For more information, please feel free to visit my website
at tlmcklveen.weebly.com or use the QR Reader. Thanks!