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Download The Biology of Autism
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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