Defining Functional Human Variants in the HMG Box of SOX Genes of >60,000 Human Individuals for Potential Cardiovascular and Cancer Genetic Risk

Abstract

Our group and others have previously linked SOX (SRY‐related HMG‐box) genes to cardiovascular regulation and cancer. SOX proteins are transcription factors containing a highly conserved HMG (high mobility group) box DNA binding domain that enables sequence specific DNA interaction, bending, and gene regulation. Sequence variation in the HMG box of SOX genes has not been fully explored in humans; therefore, we have evaluated the variants within the 20 human SOX genes from ~60,000 exomes/genomes of gnomAD and also the cancer COSMIC database for somatic variations. Each variant was analyzed using codon selection and molecular modeling. A total of 3,049 variants were identified from gnomAD and 1,566 from COSMIC, with an enrichment of variants that falls within the HMG domain in cancer patients. Uniquely we highlighted an enrichment of HMG box variants in cancers of the large intestine within SOX genes with the highest enrichment in the SOX9 gene. Our most conserved and potentially impactful variant was identified as SOX18 E137K, found within 0.8% of Latino individuals. By comparing stability differences of the E137K variant against wild type SOX18 structures, using molecular dynamics simulations, SNP analysis at amino acid 137 (Glutamic acid to Lysine) was shown to disrupt the structure of the third α‐helix of the HMG box. Since other variants that fall within the HMG box of SOX18 are associated with disorders of the vasculature and lymphatics, we suspect SOX18 E137K to potentially affect vascular function through the alteration of its interaction with DNA. Work is underway to begin to assess the physiologic implications of this novel variant.Support or Funding InformationSupport for this study was from NIH‐K01ES025435 (to JWP) and Walsh UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.