THE CONTRIBUTION OF MOSAIC MUTATION TO AUTISM SPECTRUM DISORDER

Autism;Genetics;Bioinformatics;Neuroscience

Freed, DonaldNathans, Jeremy ;

Johns Hopkins University

关键词: Autism;    Genetics;    Bioinformatics;    Neuroscience;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/40826/FREED-DISSERTATION-2017.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

BackgroundGenetic variation arises as the result of both spontaneous and artificial processes. While genetic variation and natural selection are the only tools of evolution, genetic variation is also known to also cause disease, including inherited disease and cancer. Here we explore the consequences of human genetic variation first as a tool for testing identity from a mixture of DNA and second as a contributor to autism spectrum disorder.MethodsOne of the most comprehensive datasets of human genetic variation across all human populations is the 1000 Genomes Project. We use genetic variants from the 1000 Genomes Project to identify polymorphic loci in extant human populations using custom computational tools. For our studies of mosaic mutation in individuals with autism, we use publicly available data and a combination of publically available and custom software. ResultsThrough our analysis of publically available data, we find genomic loci that may be used for identity testing across many human populations. In addition we show that mosaic genetic variation detectable in blood contribute significantly to autism spectrum disorder while mosaic genetic variants that are unique to affected tissues are not frequently detectable from bulk sequence data.ConclusionsOur results have implications for the fields of identity testing and disease genetics. Using the genomic loci we identify, it is possible to develop assays to identify DNA from an individual within a mixture even if that individual’s DNA makes up less than one-millionth of the total DNA in the mixture.Our identification of a contribution of mosaic mutations to disease has implications for our understanding of heritability. In classic measurements of heritability, identical twins are used as individuals of constant genetic background and any phenotypic differences between identical twins are assumed to come from the ;;environment”. While genetic variation unique to a single individual within a twin pair has been identified, our results are the first to indicate that these mutations play a role in the phenotypic differences between identical twins. Our results also have implications for the field of genetic counseling. The parents of probands with high-confidence mosaic mutations may be less likely to have additional children with an autism diagnosis compared to parents with children with ASD overall.Advisor: Jonathan PevsnerReader: Robert Scharpf