{"doi":"10.1093/molbev/msz075","title":"Tumorigenesis as the Paradigm of Quasi-neutral Molecular Evolution","abstract":"<jats:title>Abstract</jats:title><jats:p>In the absence of both positive and negative selections, coding sequences evolve at a neutral rate (R = 1). Such a high genomic rate is generally not achievable due to the prevalence of negative selection against codon substitutions. Remarkably, somatic evolution exhibits the seemingly neutral rate R ∼ 1 across normal and cancerous tissues. Nevertheless, R ∼ 1 may also mean that positive and negative selections are both strong, but equal in intensity. We refer to this regime as quasi-neutral. Indeed, individual genes in cancer cells often evolve at a much higher, or lower, rate than R ∼ 1. Here, we show that 1) quasi-neutrality is much more likely when populations are small (N &amp;lt; 50); 2) stem-cell populations in single normal tissue niches, from which tumors likely emerge, have a small N (usually &amp;lt;50) but selection at this stage is measurable and strong; 3) when N dips below 50, selection efficacy decreases precipitously; and 4) notably, N is smaller in the stem-cell niche of the small intestine than in the colon. Hence, the ∼70-fold higher rate of phenotypic evolution (observed as cancer risk) in the latter can be explained by the greater efficacy of selection, which then leads to the fixation of more advantageous and fewer deleterious mutations in colon cancers. In conclusion, quasi-neutral evolution sheds a new light on a general evolutionary principle that helps to explain aspects of cancer evolution.</jats:p>","journal":"Molecular Biology and Evolution","year":2019,"id":46049,"datarank":0.6667317418361088,"base_score":3.5553480614894135,"endowment":3.5553480614894135,"self_citation_contribution":0.5333022092234121,"citation_network_contribution":0.13342953261269674,"self_endowment_contribution":0.5333022092234121,"citer_contribution":0.13342953261269674,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":11,"citers_with_citation_signal":6,"citers_with_endowment":6,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":168109,"name":"Zongkun Shi","orcid":null,"position":1,"is_corresponding":false},{"id":168110,"name":"Qingjian Chen","orcid":null,"position":2,"is_corresponding":false},{"id":214103,"name":"Xu Shen","orcid":null,"position":3,"is_corresponding":false},{"id":168111,"name":"Darryl Shibata","orcid":null,"position":4,"is_corresponding":false},{"id":168112,"name":"Haijun Wen","orcid":null,"position":5,"is_corresponding":false},{"id":72225,"name":"Chung-I Wu","orcid":null,"position":6,"is_corresponding":false},{"id":168108,"name":"Bingjie Chen","orcid":"0000-0001-7689-2146","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":3.5553480614894135,"endowment":3.5553480614894135,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"30912799","pmcid":"PMC7967884","openalex_id":"https://openalex.org/W2925262002","authors":[],"funders":[{"funder_name":"National Science Foundation of China","grant_id":"31730046","title":null},{"funder_name":"National Science Foundation of China","grant_id":"91731301","title":null},{"funder_name":"National Science Foundation of China","grant_id":"91331202","title":null},{"funder_name":"985 Project","grant_id":"33000-18821105","title":null},{"funder_name":"National Basic Research Program","grant_id":"2014CB5420","title":null},{"funder_name":"Science Foundation for Outstanding Young Teachers in Higher Education of Guangdong","grant_id":"Yq2013005","title":null},{"funder_name":"Fundamental Research Funds for the Central Universities","grant_id":"16lgjc75","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA014089","title":null},{"funder_name":"NCI NIH HHS","grant_id":"U54 CA217376","title":null},{"funder_name":"NIH","grant_id":"","title":null}],"total_grants":10,"fwci":1.16,"citation_percentile":0.74158393,"influential_citations":0,"citation_trend":[{"year":2018,"count":1},{"year":2019,"count":4},{"year":2020,"count":5},{"year":2021,"count":3},{"year":2022,"count":3},{"year":2024,"count":14},{"year":2025,"count":3},{"year":2026,"count":1}],"oa_status":"green","license":"https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/7967884","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/7967884","host_type":"repository"},{"url":"http://academic.oup.com/mbe/article-pdf/36/7/1430/36609592/msz075.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/molbev/msz075","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/30912799","host_type":"repository"}],"fields_of_study":["Cancer Genomics and Diagnostics","Evolution and Genetic Dynamics","Genetic factors in colorectal cancer","Medicine","Biology","Carcinogenesis","Evolution, Molecular","Genetic Drift","Humans","Mutation","Neoplasms","Selection, Genetic"],"mesh_terms":["Humans","Mutation","Neoplasms","Selection, Genetic","Evolution, Molecular","Genetic Drift","Carcinogenesis"],"keywords":["Biology","Neutral theory of molecular evolution","Rate of evolution","Negative selection","Carcinogenesis","Positive selection","Selection (genetic algorithm)","Phenotype","Mutation rate","Fixation (population genetics)","Neutral mutation","Genetics","Gene","Cancer","Niche","Natural selection","Evolutionary biology","Genome","Phylogenetics","Ecology","Neutral evolution","Cancer Risk","Cancer Evolution"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-06T00:04:55.573348Z","pmid":null,"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":[]}