Masters Thesis

Origin and Evolution of the Human 70-kda Heat Shock Protein (hspa1a)

Determining the reasons behind how and why evolutionary mechanisms that establish or remove genetic variations within a population is a fundamental question in evolutionary biology. by tying together, the origin, evolutionary patterns, molecular mechanisms, and functional outcomes of genotype to phenotype, we gain insight on how and why genes are conserved or changed. This methodology was followed to investigate the stress-inducible Hsp70 gene in humans (HSPA1A), a critical component of the cellular stress response, and whose modification has been associated with a variety of human diseases. My results indicate that the origin of the HSPA1A gene is in placental mammals. Additionally, a combination of purifying selection and genetic recombination with its closely-related paralog, HSPA1B, have conserved the amino acid sequence of this gene from possibly deleterious mutations in multiple mammalian species. This pattern can also be applied to human microevolution in how single-nucleotide polymorphisms are distributed for both HSPA1A and HSPA1B, in contrast to their closely-linked homolog HSPA1L. This finding is further supported by the fact that natural variants of HSPA1A, that were most likely to change function, only apply small changes to the primary function of HSPA1A and have very low allele frequencies within human populations. Altogether, my experimental observations show HSPA1A is subject to purifying selection and provide functional characterization of two positions, R36 and I480, that appear to have importance in the folding function of HSPA1A. Supplementary Tables 1 and 2 of extended mammalian evolutionary trends are provided.


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