Alternative Splicing of the Human AS3MT Gene Based on Number of Variable Nucleotide Tandem Repeats

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  • June 17, 2020
Creator
  • Dontu, Pragnya
    • Affiliation: College of Arts and Sciences, Department of Chemistry
Abstract
  • Arsenic is an environmental toxin that is metabolized in humans by reduction and methylation of inorganic arsenic. Arsenite methyltransferase, encoded by AS3MT, methylates trivalent arsenic so that it can be excreted in urine. Genetic studies indicate that variants at the AS3MT locus confer risk for the development of schizophrenia. Alternate splicing of this gene leads to the production of an alternate isoform, AS3MTd2d3, predominately in the brain, and this alternative isoform is present at higher levels in tissue from individuals with schizophrenia. AS3MTd2d3, lacks arsenite methyltransferase activity, and its formation is linked to variable nucleotide tandem repeats (VNTRs) in exon 1 of AS3MT. It is hypothesized that VNTR copy number determines the relative production of the two transcripts by altering DNA methylation at the locus, and this in turn alters risk for schizophrenia. This hypothesis is tested using embryonic stem (ES) cell lines humanized with either the common AS3MT allele, an allele with three VNTRs in exon 1, or humanized with an allele we generated that carries four VNTRs. Expression of the two AS3MT isoforms is compared in ES cell lines that carry either the triple or quadruple VNTR human DNA. While no correlation between VNTR number and ratio of the AS3MTd2d3 isoform exists in ES cells, the ES cells will be differentiated into neuronal cells for further analysis to confirm or deny the original hypothesis.
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Rights statement
  • In Copyright
Advisor
  • Koller, Beverly
Degree
  • Bachelor of Science
Academic concentration
  • Chemistry
Honors level
  • Honors
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2019
Language
  • English

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