Epigenetics and ASD Flashcards
ASD is characterized by
problems in social interactions, communication, or repetitive behaviors
Rett syndrome
mutation in MECP2, gene regulates epigenetic information (X-linked)
Most common mutation linked to ASD
15q11-13 deletion/duplication
Why are epigenetic marks linked to neurodevelopment abnormalities?
plasticity; integrate genetic and environmental factors
Early signs of ASD
no emotional display, no/regression of babbling and communication, no gesturing
DSM-V criteria for ASD
social deficits and repetitive behavior or interests present in early childhood development, can’t be explained by intellectual disability (no genetic component)
Deficits in social communication and social interactions
deficits in social-emotional reciprocity, deficits in communicative behaviors, deficits in developing, maintaining, and understanding relationships
Restricted, repetitive patterns of behavior, interests, or activities
stereotyped repetitive motor movements, insistence on sameness or inflexibility to change in routine, ritualized patterns, restricted, fixated interests, hyper- and hyporeactivity to sensory input
Incidence of ASD
1 in 88, Males > Females by 4X
Neurological abnormalities
alterations in size and time course of development that affects the proper brain connectivity
What areas are affected by ASD
cerebral cortex, amygdala, hippocampus, and corpus callosum
ASD brain structure
abnormal cortical development, abnormal size of amygdala (mature size by age 8)
Long-term consequences of ASD
not progressive, but life-long
Co-morbitites with ASD
seizures, allergies, asthma, digestive disorders
ASD etiology is considered to be a combination of
genetic and environmental factors
ASD genetic component
not a single allele, rather a combination of predisposing alleles
Copy number variation
10% ASD patients have de novo acquired ASD
Angelman Syndrome
imbalanced imprinting, Chr15 (q11-13)
Beckwith-Wiedemann Syndrome
imbalanced imprinting, Chr11 (p15)
Fragile X Syndrome
loss of FMR1 expression
Turner Syndrome
45, X in females
Enivornmental Factors
viral infection, vaccination, chemical agent exposure, parental age, pharmaceutical exposure
Epigenetics
integrates environmental influences and genetics by altering expression of genes without changing the primary sequence of DNA
2 types of Epigenetic marks
post-translational modification of histones and DNA methylation
What enzyme causes DNA methylation
DNA methyltransferases
Site of DNA methylation
cytosines of CpG dinucleotides
DNA Methylation INHIBITS
gene expression
DNA Methylation works by
DIRECTLY preventing binding of TFs
DIRECTLY recruiting factors that repress transcription
INDIRECTLY recruiting methyl-CpG binding proteins/enzymes to alter chromatin structure
Epigenome
differs in cell types/tissues to allow cells to express a particular set of genes
Epimutations
may occur due to genetic mutations or environmental exposures (or randomly)
Genomic Imprinting
epigenomic markers silence parent-of-origin-specific gene expression
Imprinting is established in
germ lines and maintained throughout
Imprinted domains
cluster of imprinted genes allows for shared common regulatory features
Imprinted gene functions
most involved with embryonic development and growth (placental development), postnatal functions (suckling and metabolism)
Parental conflict hypothesis
Paternal Expressed genes: growth and fitness and ind survival
Maternal Expressed genes: growth limiting for mother’s survival
Imprinting disorders
Prader-willi, Angelman, Beckwith-Wiedemann, Silver-Russel
Prader-Willi
paternal inheritance defect in 15q11-13 (paternal SNRPN and NDN, and maternal UBE3A)
Angelman’s
maternal inheritance defect in 15q11-13 (paternal SNRPN and NDN, and maternal UBE3A)
Epigenetic etiology of ASD
clear association to epigenetics
Epigenetic syndroms result from deregulation of
- genes regulated by epigenetic markers
2. genes involved in epigenetic mechanisms
Uniparental disomy
both copies of chromosomal pair form 1 parent, chromosome carries imprinted genes will result in overexpression or silenced
Chromosomal region 7q
linked to ASD, contians imprinted gene clusters
Genes involved in brain function/dev
epigenetic markers can cause aberrant brain development when on genes involved
ASD’s causes are
multifactorial and epigenetic markers integrate the environmental influences
State with highest incidence of ASD
Utah and NJ
State with lowest incidence
WI, AL, and FL
