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The impact of natural selection on the evolution and function of placentally expressed galectins

Zackery A. Ely, Jiyun M. Moon, Gregory R. Sliwoski, Amandeep K. Sangha, Xing-Xing Shen, Abigail L. Labella, View ORCID ProfileJens Meiler, John A. Capra, View ORCID ProfileAntonis Rokas
doi: https://doi.org/10.1101/505339
Zackery A. Ely
Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USA
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Jiyun M. Moon
Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USA
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Gregory R. Sliwoski
Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USA
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Amandeep K. Sangha
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United StatesCenter for Structural Biology, Vanderbilt University, Nashville, Tennessee 37240-7917, United States
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Xing-Xing Shen
Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USA
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Abigail L. Labella
Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USA
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Jens Meiler
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United StatesCenter for Structural Biology, Vanderbilt University, Nashville, Tennessee 37240-7917, United States
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  • ORCID record for Jens Meiler
John A. Capra
Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USADepartment of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
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Antonis Rokas
Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USADepartment of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
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  • ORCID record for Antonis Rokas
  • For correspondence: antonis.rokas@vanderbilt.edu
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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.

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Posted December 23, 2018.
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The impact of natural selection on the evolution and function of placentally expressed galectins
Zackery A. Ely, Jiyun M. Moon, Gregory R. Sliwoski, Amandeep K. Sangha, Xing-Xing Shen, Abigail L. Labella, Jens Meiler, John A. Capra, Antonis Rokas
bioRxiv 505339; doi: https://doi.org/10.1101/505339
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The impact of natural selection on the evolution and function of placentally expressed galectins
Zackery A. Ely, Jiyun M. Moon, Gregory R. Sliwoski, Amandeep K. Sangha, Xing-Xing Shen, Abigail L. Labella, Jens Meiler, John A. Capra, Antonis Rokas
bioRxiv 505339; doi: https://doi.org/10.1101/505339

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