Project

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Our previous research has identified novel genetic variants in Native populations. Although these variants are predicted to be function altering in silico, recruitment efforts and the existence of archaic variants make it difficult to assess variant function in vivo. We are deploying VAMP-Seq, a Multiplexed Assay for Variant Effects (MAVE), in order to functionally characterize variants of cytochrome P450 genes at massive scale. 

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Additional Information

 

While population genetics tools are adept at identifying signatures of positive selection from genomic data, most studies do not follow up with cellular assays to identify how archaic and low-abundance variants function differently than modern, high-abundance variants.  A powerful alternative approach to determining the effect of novel genetic variants within underrepresented and extinct populations is a Multiplexed Assay for Variant Effects (MAVEs). VAMP-Seq (Variant Abundance by Massively Parallel Sequencing) is a MAVE that assesses the functionality of thousands of variants at once using high-throughput sequencing. VAMP-Seq has previously been used to  characterize missense variants in the PTEN and TPMT proteins, which revealed that thousands of mutations result in low protein abundance. Because these assays are generalizable and scalable, they potentiate characterization of many additional genes, including those in the CYP450 family. This approach offers an innovative method to understand and assess genetic variation found in now-extinct human relatives.  

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Future Directions

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We are assessing CYP2A6 variation with VAMP-seq initially and hope to expand to other enzymes in the future. We are interested in assessing variants that are novel in Indigenous populations and that potentially function altering in archaic individuals.