The Impact of Natural Selection on the Evolution and Function of Placentally Expressed Galectins

Author:

Ely Zackery A1,Moon Jiyun M1,Sliwoski Gregory R1,Sangha Amandeep K23,Shen Xing-Xing1,Labella Abigail L1,Meiler Jens23,Capra John A14,Rokas Antonis14ORCID

Affiliation:

1. Department of Biological Sciences, Vanderbilt University

2. Department of Chemistry, Vanderbilt University

3. Center for Structural Biology, Vanderbilt University

4. Department of Biomedical Informatics, Vanderbilt University School of Medicine

Abstract

Abstract Immunity genes have repeatedly experienced natural selection during mammalian evolution. Galectins are carbohydrate-binding proteins that regulate diverse immune responses, including maternal–fetal immune tolerance in placental pregnancy. Seven human galectins, four conserved across vertebrates and three specific to primates, are involved in placental development. To comprehensively study the molecular evolution of these galectins, both across mammals and within humans, we conducted a series of between- and within-species evolutionary analyses. By examining patterns of sequence evolution between species, we found that primate-specific galectins showed uniformly high substitution rates, whereas two of the four other galectins experienced accelerated evolution in primates. By examining human population genomic variation, we found that galectin genes and variants, including variants previously linked to immune diseases, showed signatures of recent positive selection in specific human populations. By examining one nonsynonymous variant in Galectin-8 previously associated with autoimmune diseases, we further discovered that it is tightly linked to three other nonsynonymous variants; surprisingly, the global frequency of this four-variant haplotype is ∼50%. To begin understanding the impact of this major haplotype on Galectin-8 protein structure, we modeled its 3D protein structure and found that it differed substantially from the reference protein structure. These results suggest that placentally expressed galectins experienced both ancient and more recent selection in a lineage- and population-specific manner. Furthermore, our discovery that the major Galectin-8 haplotype is structurally distinct from and more commonly found than the reference haplotype illustrates the significance of understanding the evolutionary processes that sculpted variants associated with human genetic disease.

Funder

Beckman Scholar Award

National Institutes of Health

Burroughs Wellcome Fund Preterm Birth Initiative

March of Dimes Prematurity Research Center Ohio Collaborative

Publisher

Oxford University Press (OUP)

Subject

Genetics,Ecology, Evolution, Behavior and Systematics

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