Characterization of variation in transmembrane domain coding regions
Little is known about local patterns of genetic variation in transmembrane protein coding regions. These proteins are common targets of medical drugs and therefore, understanding patterns of coding variation may help explain differences in drug response. Using existing whole exome sequence data from the Starr County Health Studies' Genetics of Diabetes Study, patterns of variation in transmembrane protein coding regions were characterized. Transmembrane domain coding regions of a set of alpha-helical transmembrane proteins were compared to extracellular and cytoplasmic regions as well as to the rest of the exome. First, variants were sorted by region of interest, and broadly grouped into categories by their effect: synonymous, missense, and stop-gain. Chi-square tests for independence of each protein region versus the whole exome identified a significant (p=0.018) difference in the distribution of variants across these groups in the extracellular region relative to the whole exome and a very significant (p=1.55×10–5 ) difference in the distribution of variants across these groups in the transmembrane region relative to the whole exome. Variants were also categorized by filtering annotation results for their reference and variant amino acids. In this step, each variant was grouped by several chemical properties of both its reference and variant amino acids that are important to transmembrane domains, including hydrophobicity, side chain pKa, and polarity. Variants were classified by whether they were synonymous, resulted in a change of amino acids within the same group (e.g. from one hydrophobic amino acid to another), or resulted in a change of amino acid group (e.g. from a hydrophobic amino acid to a hydrophilic amino acid). For each region of interest and each chemical property, the distribution of variants across these categories was compared to the whole exome. Chi-square tests identified strongly significant differences for side chain pKa (p<2.2×10 –16) and polarity (p=1.52×10–9 ) in the transmembrane region, and slightly weaker differences for hydrophobicity (p=0.0001) in the transmembrane region and pKa (p=0.023) and polarity (p=0.057) in the cytoplasmic region. The results of this study highlight a decreased number of variants with protein-altering effects in transmembrane domain coding regions and give insight into a preference for chemically similar amino acids in non-synonymous variation in the region.
Petty, Lauren, "Characterization of variation in transmembrane domain coding regions" (2014). Texas Medical Center Dissertations (via ProQuest). AAI1586831.