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Proc Natl Acad Sci U S A . Pleiotropy of positive selection in ancient ACE2 suggests an alternative hypothesis for bat-specific adaptations to host coronaviruses

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  • Proc Natl Acad Sci U S A . Pleiotropy of positive selection in ancient ACE2 suggests an alternative hypothesis for bat-specific adaptations to host coronaviruses

    Proc Natl Acad Sci U S A


    . 2024 Jun 11;121(24):e2321619121.
    doi: 10.1073/pnas.2321619121. Epub 2024 Jun 4. Pleiotropy of positive selection in ancient ACE2 suggests an alternative hypothesis for bat-specific adaptations to host coronaviruses

    Yuan-Ting Guo # 1 2 , Ji-Bin Jiang # 2 3 , Guan-Rong Qiao # 4 , Rong-Hua Luo 5 , Xin Zhou 2 3 , Rong Hua 2 3 , Chang-Bo Zheng 4 , Zhen Liu 2 6 7



    AffiliationsFree article Abstract

    Angiotensin-convertingenzyme 2 (ACE2) has dual functions, regulating cardiovascular physiology and serving as the receptor for coronaviruses. Bats, the only true flying mammals and natural viral reservoirs, have evolved positive alterations in traits related to both functions of ACE2. This suggests significant evolutionary changes in ACE2 during bat evolution. To test this hypothesis, we examine the selection pressure in ACE2 along the ancestral branch of all bats (AncBat-ACE2), where powered flight and bat-coronavirus coevolution occurred, and detect a positive selection signature. To assess the functional effects of positive selection, we resurrect AncBat-ACE2 and its mutant (AncBat-ACE2-mut) created by replacing the positively selected sites. Compared to AncBat-ACE2-mut, AncBat-ACE2 exhibits stronger enzymatic activity, enhances mice's performance in exercise fatigue, and shows lower affinity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our findings indicate the functional pleiotropy of positive selection in the ancient ACE2 of bats, providing an alternative hypothesis for the evolutionary origin of bats' defense against coronaviruses.

    Keywords: adaptive evolution; bat; pleiotropy.

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