Genetic load in cancer cell populations

来源 :第七届全国生物信息学与系统生物学学术大会 | 被引量 : 0次 | 上传用户:protosser
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  Populations accumulate deleterious mutations that have yet to be removed by natural selection.This portion of the population that does not contribute to its fitness is the genetic load,which is proportional to the deleterious mutation rate (Crow and Kimura 1971).Given the genomic instability of cancer cells,the genetic load could be substantial if the instability indeed leads to losses of cell fitness.Since aneuploids and copy number variations (CNVs) are the most common forms of genome instability,their fitness consequences would determine the genetic load in cancers.We first observed large percentage progeny cell with slower growth rate than ancestor were generated within 4-5 times of cell division,then we found recent descendent clones from a single HeLa cell have higher proliferation rate when they have less new born CNVs,vice versa.This indicated CNVs accumulation decreased cell fitness systematically.We speculated due to high deleterious CNVs mutation rate,tumor cell inevitable accumulated deleterious CNVs and a large percentage of tumor ceils were genetically defected.Accordingly,we observed average growth rate of tumor cell population decreased in short term since defected cells were produced and accumulated in the population.By modeling the process of mutation accumulation and growth potential based on extend measurements,we estimated that the proportion of deleterious mutations in HeLa ceils is about 0.2-0.3 per cell division.Interesting,we found a negative correlation of cell proliferation rate and fitness fidelity of HeLa cell,which means the faster cell replication the higher probability of making mistakes.The observation of high proliferation rate and high genetic load & death rate in tumor cell line indicates "high risk,high reward" evolution strategy for tumor cells,and increasing the level of genomic instability may cause the meltdown of tumor cell population by forcing cells to accelerate the cell cycle.
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