Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2
Abstract Background The emergence of SARS-CoV-2 underscores the need to better understand the evolutionary processes that drive the emergence and adaptation of zoonotic viruses in humans. In the betacoronavirus genus, which also includes SARS-CoV and MERS-CoV, recombination frequently encompasses th...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-08-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-021-00943-6 |
| _version_ | 1818577311677546496 |
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| author | Juan Ángel Patiño-Galindo Ioan Filip Ratul Chowdhury Costas D. Maranas Peter K. Sorger Mohammed AlQuraishi Raul Rabadan |
| author_facet | Juan Ángel Patiño-Galindo Ioan Filip Ratul Chowdhury Costas D. Maranas Peter K. Sorger Mohammed AlQuraishi Raul Rabadan |
| author_sort | Juan Ángel Patiño-Galindo |
| collection | DOAJ |
| description | Abstract Background The emergence of SARS-CoV-2 underscores the need to better understand the evolutionary processes that drive the emergence and adaptation of zoonotic viruses in humans. In the betacoronavirus genus, which also includes SARS-CoV and MERS-CoV, recombination frequently encompasses the receptor binding domain (RBD) of the Spike protein, which is responsible for viral binding to host cell receptors. In this work, we reconstruct the evolutionary events that have accompanied the emergence of SARS-CoV-2, with a special emphasis on the RBD and its adaptation for binding to its receptor, human ACE2. Methods By means of phylogenetic and recombination analyses, we found evidence of a recombination event in the RBD involving ancestral linages to both SARS-CoV and SARS-CoV-2. We then assessed the effect of this recombination at protein level by reconstructing the RBD of the closest ancestors to SARS-CoV-2, SARS-CoV, and other Sarbecoviruses, including the most recent common ancestor of the recombining clade. The resulting information was used to measure and compare, in silico, their ACE2-binding affinities using the physics-based trRosetta algorithm. Results We show that, through an ancestral recombination event, SARS-CoV and SARS-CoV-2 share an RBD sequence that includes two insertions (positions 432-436 and 460-472), as well as the variants 427N and 436Y. Both 427N and 436Y belong to a helix that interacts directly with the human ACE2 (hACE2) receptor. Reconstruction of ancestral states, combined with protein-binding affinity analyses, suggests that the recombination event involving ancestral strains of SARS-CoV and SARS-CoV-2 led to an increased affinity for hACE2 binding and that alleles 427N and 436Y significantly enhanced affinity as well. Conclusions We report an ancestral recombination event affecting the RBD of both SARS-CoV and SARS-CoV-2 that was associated with an increased binding affinity to hACE2. Structural modeling indicates that ancestors of SARS-CoV-2 may have acquired the ability to infect humans decades ago. The binding affinity with the human receptor would have been subsequently boosted in SARS-CoV and SARS-CoV-2 through further mutations in RBD. |
| first_indexed | 2024-12-16T06:27:54Z |
| format | Article |
| id | doaj.art-f1b913d2838d44289d61f7fca5364a04 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-12-16T06:27:54Z |
| publishDate | 2021-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-f1b913d2838d44289d61f7fca5364a042022-12-21T22:40:58ZengBMCGenome Medicine1756-994X2021-08-0113111410.1186/s13073-021-00943-6Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2Juan Ángel Patiño-Galindo0Ioan Filip1Ratul Chowdhury2Costas D. Maranas3Peter K. Sorger4Mohammed AlQuraishi5Raul Rabadan6Program for Mathematical Genomics, Columbia UniversityProgram for Mathematical Genomics, Columbia UniversityDepartment of Systems Biology, Harvard Medical SchoolDepartment of Chemical Engineering, The Pennsylvania State UniversityDepartment of Systems Biology, Harvard Medical SchoolDepartment of Systems Biology, Harvard Medical SchoolProgram for Mathematical Genomics, Columbia UniversityAbstract Background The emergence of SARS-CoV-2 underscores the need to better understand the evolutionary processes that drive the emergence and adaptation of zoonotic viruses in humans. In the betacoronavirus genus, which also includes SARS-CoV and MERS-CoV, recombination frequently encompasses the receptor binding domain (RBD) of the Spike protein, which is responsible for viral binding to host cell receptors. In this work, we reconstruct the evolutionary events that have accompanied the emergence of SARS-CoV-2, with a special emphasis on the RBD and its adaptation for binding to its receptor, human ACE2. Methods By means of phylogenetic and recombination analyses, we found evidence of a recombination event in the RBD involving ancestral linages to both SARS-CoV and SARS-CoV-2. We then assessed the effect of this recombination at protein level by reconstructing the RBD of the closest ancestors to SARS-CoV-2, SARS-CoV, and other Sarbecoviruses, including the most recent common ancestor of the recombining clade. The resulting information was used to measure and compare, in silico, their ACE2-binding affinities using the physics-based trRosetta algorithm. Results We show that, through an ancestral recombination event, SARS-CoV and SARS-CoV-2 share an RBD sequence that includes two insertions (positions 432-436 and 460-472), as well as the variants 427N and 436Y. Both 427N and 436Y belong to a helix that interacts directly with the human ACE2 (hACE2) receptor. Reconstruction of ancestral states, combined with protein-binding affinity analyses, suggests that the recombination event involving ancestral strains of SARS-CoV and SARS-CoV-2 led to an increased affinity for hACE2 binding and that alleles 427N and 436Y significantly enhanced affinity as well. Conclusions We report an ancestral recombination event affecting the RBD of both SARS-CoV and SARS-CoV-2 that was associated with an increased binding affinity to hACE2. Structural modeling indicates that ancestors of SARS-CoV-2 may have acquired the ability to infect humans decades ago. The binding affinity with the human receptor would have been subsequently boosted in SARS-CoV and SARS-CoV-2 through further mutations in RBD.https://doi.org/10.1186/s13073-021-00943-6SARS-CoV-2RecombinationReceptor binding affinityZoonosis |
| spellingShingle | Juan Ángel Patiño-Galindo Ioan Filip Ratul Chowdhury Costas D. Maranas Peter K. Sorger Mohammed AlQuraishi Raul Rabadan Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2 Genome Medicine SARS-CoV-2 Recombination Receptor binding affinity Zoonosis |
| title | Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2 |
| title_full | Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2 |
| title_fullStr | Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2 |
| title_full_unstemmed | Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2 |
| title_short | Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2 |
| title_sort | recombination and lineage specific mutations linked to the emergence of sars cov 2 |
| topic | SARS-CoV-2 Recombination Receptor binding affinity Zoonosis |
| url | https://doi.org/10.1186/s13073-021-00943-6 |
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