{"doi":"10.1038/s41467-024-46262-3","title":"Reply to: Population genetic considerations regarding the interpretation of within-patient SARS-CoV-2 polymorphism data","abstract":"In comments on our paper “Within-host genetic diversity of SARS-CoV-2 lineages in unvaccinated and vaccinated individuals,” Soni et al. argue that the methods we employed for detecting natural selection are unreliable. Our study examined nucleotide diversity ( π ) 1 , the mean number of pairwise differences per nucleotide site, which is a common metric for quantifying within-host viral polymorphism 2 . Comparison of π at nonsynonymous ( π N ) and synonymous ( π S ) sites is thought to provide evidence for positive ( π N > π S or π N / π S > 1) or purifying ( π N < π S or π N / π S < 1) selection acting on amino acid changes 3 , 4 . This method has been used to study the intrahost evolution of viruses like influenza, often with evidence of positive selection in regions encoding immune epitopes 5 . Intrahost π N and π S have also been examined in SARS-CoV-2 6 , 7 , 8 , 9 , 10 , and our study 11 compared π N – π S across distinct COVID-19 patient subsets. We found that breakthrough infections in 2- or 3-dose Comirnaty and CoronaVac vaccinated individuals do not show elevated viral π N and may not change the direction of selection. These negative conclusions inherently control for viral demographic factors like bottlenecks that operate similarly in each patient, allowing straightforward interpretation of π N – π S differences.","journal":"Nature Communications","year":2024,"id":496695,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9423,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":77539,"name":"Leo L. M. Poon","orcid":"0000-0002-9101-7953","position":1,"is_corresponding":false},{"id":326917,"name":"Haogao Gu","orcid":"0000-0002-7541-4262","position":2,"is_corresponding":false},{"id":37908,"name":"Chase W. Nelson","orcid":"0000-0001-6287-1598","position":0,"is_corresponding":true}],"reference_count":26,"raw_metadata":null,"created_at":"2026-07-19T02:09:27.134858Z","pmid":"38627383","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}