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. 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
Affiliations

Pleiotropy of positive selection in ancient ACE2 suggests an alternative hypothesis for bat-specific adaptations to host coronaviruses

Yuan-Ting Guo et al. Proc Natl Acad Sci U S A. .

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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Conflict of interest statement

Competing interests statement:The authors declare no competing interest.

Figures

Fig. 1.
Fig. 1.
Functional pleiotropy of positive selection in AncBat-ACE2. (A) Detection of enzymatic activities of AncBat-ACE2 and AncBat-ACE2-mut. The curves of the relative fluorescence intensity of the catalytic product over time for AncBat-ACE2 and AncBat-ACE2-mut are presented. The slope of the curve represents the enzymatic activity of ACE2. (B) The enzymatic activity of AncBat-ACE2 is significantly higher than that mediated by AncBat-ACE2-mut. (C) An illustration of behavioral experiments of mice carrying AncBat-ACE2 and AncBat-ACE2-mut. (D) The heart rates for mice carrying AncBat-ACE2 and AncBat-ACE2-mut are compared before and after injecting dobutamine hydrochloride. BPM represents beats per minute. (E) The exhaustion time of mice carrying AncBat-ACE2 and AncBat-ACE2-mut is compared. (F) The exhaustion distance of mice carrying AncBat-ACE2 is significantly greater than that of mice carrying AncBat-ACE2-mut. (G) Comparison of the relative amount of SARS-CoV-2 RNA in the supernatant mediated by AncBat-ACE2 and by AncBat-ACE2-mut. The dots indicate the number of biological replicates. The P values are from the two-tailed Student’s t test.
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