Question

After reading Chapter 2 in Kandel's book, please choose and discuss one possible cause for autism (copy number variations, de novo mutations or neural circuits as targets for mutations).

please choose and discuss one possible cause for autism

discuss one possible cause for autism

please Ignore the book, and just choose and discuss ONE possible cause for autism.

Answer 1

Genetic factors may be the most significant cause for autism spectrum disorders. Early studies of twins had estimated heritability to be over 90%, meaning that genetics explains over 90% of whether a child will develop autism. However, this may be an overestimation, as new twin studies estimate the heritability at between 60–90%.Many of the non-autistic co-twins had learning or social disabilities. For adult siblings the risk for having one or more features of the broader autism phenotype might be as high as 30%.

However, in spite of the strong heritability, most cases of ASD occur sporadically with no recent evidence of family history. It has been hypothesized that spontaneous de novo mutations in the father's sperm or mother's egg contribute to the likelihood of developing autism.[20] There are two lines of evidence that support this hypothesis. First, individuals with autism have significantly reduced fecundity, they are 20 times less likely to have children than average, thus curtailing the persistence of mutations in ASD genes over multiple generations in a family.Second, the likelihood of having a child develop autism increases with advancing paternal age,and mutations in sperm gradually accumulate throughout a man's life.

The first genes to be definitively shown to contribute to risk for autism were found in the early 1990s by researchers looking at gender-specific forms of autism caused by mutations on the X chromosome. An expansion of the CGG trinucleotide repeat in the promoter of the gene FMR1 in boys causes fragile X syndrome, and at least 20% of boys with this mutation have behaviors consistent with autism spectrum disorder.Mutations that inactivate the gene MECP2 cause Rett syndrome, which is associated with autistic behaviors in girls, and in boys the mutation is embryonic lethal.

Besides these early examples, the role of de novo mutations in ASD first became evident when DNA microarray technologies reached sufficient resolution to allow the detection of copy number variation (CNV) in the human genome.CNVs are the most common type of structural variation in the genome, consisting of deletions and duplications of DNA that range in size from a kilobase to a few megabases. Microarray analysis has shown that de novo CNVs occur at a significantly higher rate in sporadic cases of autism as compared to the rate in their typically developing siblings and unrelated controls. A series of studies have shown that gene disrupting de novo CNVs occur approximately four times more frequently in ASD than in controls and contribute to approximately 5–10% of cases Based on these studies, there are predicted to be 130–234 ASD-related CNV loci.The first whole genome sequencing study to comprehensively catalog de novo structural variation at a much higher resolution than DNA microarray studies has shown that the mutation rate is approximately 20% and not elevated in autism compared to sibling controls.However, structural variants in individuals with autism are much larger and four times more likely to disrupt genes, mirroring findings from CNV studies.

CNV studies were closely followed by exome sequencing studies, which sequence the 1–2% of the genome that codes for proteins (the "exome"). These studies found that de novo gene inactivating mutations were observed in approximately 20% of individuals with autism, compared to 10% of unaffected siblings, suggesting the etiology of ASD is driven by these mutations in around 10% of cases.There are predicted to be 350-450 genes that significantly increase susceptibility to ASDs when impacted by inactivating de novo mutations. A further 12% of cases are predicted to be caused by protein altering missense mutations that change an amino acid but do not inactivate a gene.Therefore approximately 30% of individuals with autism have a spontaneous de novo large CNV that deletes or duplicates genes, or mutation that changes the amino acid code of an individual gene. A further 5–10% of cases have inherited structural variation at loci known to be associated with autism, and these known structural variants may arise de novo in the parents of affected children.

Tens of genes and CNVs have been definitively identified based on the observation of recurrent mutations in different individuals, and suggestive evidence has been found for over 100 others.The Simons Foundation Autism Research Initiative (SFARI) details the evidence for each genetic locus associated with autism.

These early gene and CNV findings have shown that the cognitive and behavioral features associated with each of the underlying mutations is variable. Each mutation is itself associated with a variety of clinical diagnoses, and can also be found in a small percentage of individuals with no clinical diagnosis. Thus the genetic disorders that comprise autism are not autism-specific. The mutations themselves are characterized by considerable variability in clinical outcome and typically only a subset of mutation carriers meet criteria for autism. This variable expressivity results in different individuals with the same mutation varying considerably in the severity of their observed particular trait.

The conclusion of these recent studies of de novo mutation is that the spectrum of autism is breaking up into quanta of individual disorders defined by genetics.

One gene that has been linked to autism is SHANK2.Mutations in this gene act in a dominant fashion. Mutations in this gene appear to cause hyperconnectivity between the neurons.