Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Bryan Heit

Abstract

The TAM (TYRO3, AXL, and MERTK) family of receptor tyrosine kinases allow phagocytes to engage in the phagocytic removal of apoptotic cells. Although all three members of the TAM family are structurally homologous and function in a similar fashion, both human genome-wide association studies and knockout mice models have demonstrated that MERTK is the critical member of the TAM family for maintaining homeostasis. In this thesis, an evolutionary analysis was used to provide insight into the function of MERTK. Selection analysis in primates unexpectedly revealed a high degree of recent positive selection in MERTK’s signal peptide and transmembrane domain, absent from TYRO3 and AXL. Reconstruction of hominid and primate ancestral signal peptides revealed three nonsynonymous mutations in humans, with a G14C mutation producing a potential non-B DNA cruciform motif, which may regulate MERTK expression. Reconstruction of MERTK’s transmembrane domain determined that humans acquired three amino acid substitutions and two insertion/deletion mutations (INDELs) which added four amino acids. These new amino acids were largely leucines and isoleucines, and create a new interaction motif that increased self-clustering of MERTK. Although we found no significant difference among human MERTK and primate- or hominid-ancestral reconstructed signal peptides in expression levels or protein trafficking, recent evolutionary changes in MERTK’s transmembrane revealed significantly higher self-clustering with human MERTK, and hominid ancestral, compared to the reconstructed primate-ancestral transmembrane. This project highlights the importance of recent MERTK evolution, which has increased self-clustering.

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