Transcript The Biology of Autism

Refrigerator mothers and beyond
The aetiology of autism
Genetics
Genetics of autism
• Large number of chromosome abnormalities associated with autism, familial
clustering of autism is well above the normal population prevalence, twinbased studies
• Hereditability around 90% (Schizophrenia and major depression around 4050%
• Not simple genetic transmission Autisms rather than autism
• Evidence from twin studies suggest an MZ to DZ concordance rate of 60%
• The rate amongst siblings of an autistic proband is ~3%
• Genome: 6 billion bits of information from father and mother. We have 99%
similarity with only 1% difference
• Only a small section codes for genes, the other ‘dark matter’ relating to how
genes are expressed into proteins
• Suggested that there may be up to 1,000 genes involved in autism. Genes act
in an additive way (synergistic) along with the environment to produce the
final phenotype
Evolution
• Twin studies have suggested that autism has high heritability. This occurs
in the context of environmental risks and gene-environment interplay.
• Autistic traits could have been subject to positive selection pressure,
because the benefits of a solitary single-minded obsessive focus
• Such individuals might have successfully traded products or their building
and fixing skills. Thus acquiring resources and increasing their
reproductive fitness, which could have maintained autism alleles in the
gene pool
Studying the genetics of autism
• ‘Guided missiles’ represent experiments where there is a clear hypothesis
about the role of a particular region of the chromosome or specific
candidate genes
• ‘Carpet bombs’ represent studies whereby the whole genome is looked at
all at once, looking for genes/chromosomal regions that are associated
with ASD. These are ‘genome-wide’ linkage or association studie
Examples
Chromosome
Genes
Function
2
HOX
Early growth and
development
7
AUTS1
MET
Speech and language
Immune function,
cerebellar growth
5
CDH9,10
Proteins
15
17
Genetic errors cause
Angelman and Prader-Willi
syndromes
GABA pathways genes
Serotonin transport
How might genetic variation occur?
Issue
% of people with ASD
Locus heterogeneity
Up to 1,000 genes
implicated
Rare mutations
5%
Chromosomal
abnormalities
5%
Rare copy variations
10%
De novo mutations
Notes
Minor allele frequency
Eg deletion, duplication,
nonsense codes that occur
in germline (especially
paternal) and could be
causal in simplex cases
Families
Cause offamily
Simplex
ASD
Points
Multiplex
family
Only 1be
Might
member
due toof
‘deextended
novo’ changes
family in
has
DNA
a
More than one member of extended
sequence of
diagnosis
(egASD
rare sequence variant or a
family has a diagnosis, or several
copy number variant)
members have very high levels of autistic
traits
Might be due to ‘de novo’ changes in DNA Might never have a formal diagnosis
sequence (eg rare sequence variant or a
copy number variant)
One off-change during formation of
gametes
Can account for nearly 10% of all people
diagnosed with ASD
Specific genetic variations passed down
through generations
Theme: Neural development
Role of genes in neural growth,
patterning and formation of synapses
Altered calcium signalling amongst
mechanisms through which genes
manifest themselves
Neuroimaging shows altered
connectivity and atypical wiring
This class of genes are involved in
developing atypical patterns of neural
connectivity
Theme: Social behaviour
Genes influence social behaviour in
animals eg oxytocin-vasopressin
system and maternal behaviour in
rodents
Oxytocin administration in humans
results in increased trust among
strangers in lab
Atypicalities of social behaviour in
ASD
Oxytocin receptor gene, OXTR, is one
of the few candidate genes associated
with ASD
Theme: Exposure to testosterone
Exposure to prenatal testosterone is
Primary clue has been that ASD is
related to the development of autistic associated with a strong sex
traits in general population
difference, affecting nearly seven
times as many males to females
Recent studies found evidence that
genes related to sex hormone
function are associated with ASD
and/or autistic traits in the general
population