title: A Direct Test of Selection in Cell Populations Using the Diversity in Gene Expression within Tumors.
abstract: Although intratumor diversity driven by selection has been the prevailing view in cancer biology, recent population genetic analyses have been unable to reject the neutral interpretation. As the power to reject neutrality in tumors is often low, it will be desirable to have an alternative means to test selection directly. Here, we utilize gene expression data as a surrogate for functional significance in intra- and intertumor comparisons. The expression divergence between samples known to be driven by selection (e.g., between tumor and normal tissues) is always higher than the divergence between normal samples, which should be close to the neutral level of divergence. In contrast, the expression differentiation between regions of the same tumor, being lower than the neutral divergence, is incompatible with the hypothesis of selectively driven divergence. To further test the hypothesis of neutral evolution, we select a hepatocellular carcinoma tumor that has large intratumor SNV and CNV (single nucleotide variation and copy number variation, respectively) diversity. This tumor enables us to calibrate the level of expression divergence against that of genetic divergence. We observe that intratumor divergence in gene expression profile lags far behind genetic divergence, indicating insufficient phenotypic differences for selection to operate. All these expression analyses corroborate that natural selection does not operate effectively within tumors, supporting recent interpretations of within-tumor diversity. As the expected level of genetic diversity, hence the potential for drug resistance, would be much higher under neutrality than under selection, the issue is of both theoretical and clinical significance.
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences and University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Li
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences and University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences and University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Hospital and Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, China.
authors.forename: Aiqun
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences and University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences and University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Furong
authors.initials: F
authors.lastname: Qi
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences and University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Zuyu
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences and University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences and University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Sixue
authors.initials: S
authors.lastname: Liu
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences and University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Huanwei
authors.initials: H
authors.lastname: Huang
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences and University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Qianfei
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Hospital and Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, China.|Department of Hepatopancreatobiliary Surgery, Beijing Tsinghua Changgung Hospital, Medical Center, Tsinghua University, Beijing, China.
authors.forename: Jiahong
authors.initials: J
authors.lastname: Dong
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences and University of Chinese Academy of Sciences, Beijing, China.|Department of Ecology and Evolution, University of Chicago, Chicago, IL.
authors.forename: Chung-I
authors.initials: CI
authors.lastname: Wu
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences and University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Lu
mesh_terms: D056915:DNA Copy Number Variations / Q000235:genetics; D030561:Databases, Nucleic Acid; D019143:Evolution, Molecular; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D040961:Genetic Drift; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D012641:Selection, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D059467:Transcriptome / Q000235:genetics*
keywords: genetic diversity; intra- and intertumor heterogeneity; selection; variation in gene expression