Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution
| Autor: | Yong Tao, Wenming Zhao, Lingtong Hao, Richard R. Hudson, Qiang Gong, Pei Lin, Chung-I Wu, Ke Chen, Wen-Hsiung Li, Z.F. Yang, Fang Yang, Zheng Hu, Qingjian Chen, Lihua Cao, Dafei Wu, Chunyi Hao, Daniel V.T. Catenacci, Yawei Li, Xiuyun Tian, Lili Dong, Xuemei Lu, Shaoping Ling, Eric A. Hungate, Wenjie Li |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Mutation rate animal structures Genotype Molecular Sequence Data Population genetics Cell Count Biology Polymorphism Single Nucleotide Corrections Mutation Rate Cell Line Tumor Neoplasms Genetic variation Humans Computer Simulation Selection Genetic Aged Gene Library Genetics Genetic diversity Multidisciplinary Natural selection Evolution of cells Base Sequence Models Genetic Genetic Variation Reproducibility of Results Sequence Analysis DNA Biological Evolution humanities Clone Cells PNAS Plus Mutation (genetic algorithm) Mutation Neutral theory of molecular evolution Microdissection human activities Genes Neoplasm |
| Popis: | The prevailing view that the evolution of cells in a tumor is driven by Darwinian selection has never been rigorously tested. Because selection greatly affects the level of intratumor genetic diversity, it is important to assess whether intratumor evolution follows the Darwinian or the non-Darwinian mode of evolution. To provide the statistical power, many regions in a single tumor need to be sampled and analyzed much more extensively than has been attempted in previous intratumor studies. Here, from a hepatocellular carcinoma (HCC) tumor, we evaluated multiregional samples from the tumor, using either whole-exome sequencing (WES) (n = 23 samples) or genotyping (n = 286) under both the infinite-site and infinite-allele models of population genetics. In addition to the many single-nucleotide variations (SNVs) present in all samples, there were 35 "polymorphic" SNVs among samples. High genetic diversity was evident as the 23 WES samples defined 20 unique cell clones. With all 286 samples genotyped, clonal diversity agreed well with the non-Darwinian model with no evidence of positive Darwinian selection. Under the non-Darwinian model, MALL (the number of coding region mutations in the entire tumor) was estimated to be greater than 100 million in this tumor. DNA sequences reveal local diversities in small patches of cells and validate the estimation. In contrast, the genetic diversity under a Darwinian model would generally be orders of magnitude smaller. Because the level of genetic diversity will have implications on therapeutic resistance, non-Darwinian evolution should be heeded in cancer treatments even for microscopic tumors. |
| Databáze: | OpenAIRE |
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