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Mol Biol Evol. 2018 Feb 1;35(2):440-450. doi: 10.1093/molbev/msx298.

Human-Specific Mutations and Positively Selected Sites in MARCO Confer Functional Changes.

Author information

1
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
2
Department of Biology, McMaster University, Hamilton, ON, Canada.
3
Department of Microbiology and Immunology and The Centre for Human Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada.
4
Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA.

Abstract

Macrophage Receptor with COllagenous structure (MARCO) is a class A scavenger receptor that binds, phagocytoses, and modifies inflammatory responses to bacterial pathogens. Multiple candidate gene approach studies have shown that polymorphisms in MARCO are associated with susceptibility or resistance to Mycobacterium tuberculosis infection, but how these variants alter function is not known. To complement candidate gene approach studies, we previously used phylogenetic analyses to identify a residue, glutamine 452 (Q452), within the ligand-binding Scavenger Receptor Cysteine Rich domain as undergoing positive selection in humans. Herein, we show that Q452 is found in Denisovans, Neanderthals, and extant humans, but all other nonprimate, terrestrial, and aquatic mammals possess an aspartic acid (D452) residue. Further analysis of hominoid sequences of MARCO identified an additional human-specific mutation, phenylalanine 282 (F282), within the collagenous domain. We show that residue 282 is polymorphic in humans, but only 17% of individuals (rs6761637) possess the ancestral serine residue at position 282. We show that rs6761637 is in linkage disequilibrium with MARCO polymorphisms that have been previously linked to susceptibility to pulmonary tuberculosis. To assess the functional importance of sites Q452 and F282 in humans, we cloned the ancestral residues and loss-of-function mutations and investigated the role of these residues in binding and internalizing polystyrene microspheres and Escherichia coli. Herein, we show that the residues at sites 452 and 282 enhance receptor function.

KEYWORDS:

MARCO; host–pathogen interactions; positive selection; scavenger receptor; single nucleotide polymorphism

PMID:
29165618
PMCID:
PMC5850514
DOI:
10.1093/molbev/msx298
[Indexed for MEDLINE]
Free PMC Article

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