Featured publications
Variation in the life history strategy underlies functional diversity of tumors
Tao Li#, Jialin Liu#, Jing Feng#, Zhenzhen Liu, Sixue Liu, Minjie Zhang, Yuezheng Zhang, Yali Hou, Dafei Wu, Chunyan Li5, Young-Bin Chen6, Hua Chen & Xuemei Lu*
Key words
density-dependent selection, trade-offs, cancer cell,phenotypic
diversity, competition
Our simulations, fitted to empirical data, establish a competitive relationship between phenotypically diverse cancer cells. It indicates that a tumor is not a “Darwinian demon” per se, but is a mix of diverged cell populations. The populations with trade-off phenotypes are competing for space and different resources in the micro-ecosystem during the cancer progression. In the short term, the competition may decrease whole-population fitness, whereas, it triggers niche differentiation leading cell types to occupy different niches, thus maximizing the use of available resources in the ecosystem and leading to the emergence of resistance to environmental stress, such as drug treatment as well. Therefore, the competitive interaction between tumor cells further improves the total fitness of a tumor in the long term. Our analyses of life-history trade-offs are pertinent to evolutionary ecology as well as cancer biology.
We provide an improved reference-quality de novo genome for allotetraploid goldfish whose origin dates to ~15 million years ago. Comprehensive analyses identify changes in subgenomic evolution from asymmetrical oscillation in goldfish and common carp to diverse stabilization and balanced gene expression during continuous rediploidization. The homoeologs are coexpressed in most pathways, and their expression dominance shifts temporally during embryogenesis. Homoeolog expression correlates negatively with alternation of DNA methylation. The results show that allotetraploid cyprinids have a unique strategy for balancing subgenomic stabilization and diversification. Rediploidization process in these fishes provides intriguing insights into genome evolution and function in allopolyploid vertebrates.
EVOLUTIONARY BIOLOGY
From asymmetrical to balanced genomic diversification During rediploidization:Subgenomic evolution in allotetraploid fish
Jing Luo#, Jing Chai#, Yanling Wen#, Min Tao#, Guoliang Lin#, Xiaochuan Liu, Li Ren, Zeyu Chen, Shigang Wu, Shengnan Li, Yude Wang, Qinbo Qin, Shi Wang, Yun Gao, Feng Huang, Lu Wang, Cheng Ai, Xiaobo Wang, Lianwei Li, Chengxi Ye, Huimin Yang, Mi Luo, Jie Chen, Hong Hu, Liujiao Yuan, Li Zhong, Jing Wang, Jian Xu, Zhenglin Du, Zhanshan (Sam) Ma, Robert W. Murphy, Axel Meyer, Jianfang Gui, Peng Xu†, Jue Ruan†, Z. Jeffrey Chen†, Shaojun Liu†, Xuemei Lu†, Ya-ping Zhang†
Genomic evolution,Allotetraploid goldfish,Rediploidization polyploidy
Key words
Genetic Load and Potential Mutational
Meltdown in Cancer Cell Populations
Yuezheng Zhang†, Yawei Li†, Tao Li†, Xu Shen†, Tianqi Zhu, Yong Tao, Xueying Li, Di Wang, Qin Ma, Zheng Hu, Jialin Liu, Jue Ruan, Jun Cai, Hurng-Yi Wang*, and Xuemei Lu*
Key words
genetic load, Muller’s ratchet, HeLa cell line, copy number variation
Large genomes with elevated mutation rates are prone to accumulating deleterious mutations more rapidly than natural selection can purge (Muller’s ratchet). As a consequence, it may lead to the extinction of small populations. However, the most common type of mutation in organismal evolution, namely, deleterious mutation, has received relatively little attention in the cancer biology literature. We observed single-cell clones from HeLa cell lines bear a high level of genetic load . Tumor cells appear to evolve neutrally within a selected evolution process. Suppressing clones with less passenger mutations but high level of fitness may improve clinical therapeutic performance.
To 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.
A Direct Test of Selection in Cell Populations Using the Diversity in Gene Expression within Tumors
Chunyan Li†, Yali Hou†, Jin Xu†, Aiqun Zhang, Zhenzhen Liu, Furong Qi, Zuyu Yang, Ke Chen, Sixue Liu, Huanwei Huang, Qianfei Wang, Jiahong Dong, Chung-I Wu, and Xuemei Lu*
genetic diversity, intra- and intertumor heterogeneity, selection
Key words
Functional Conservation of Both CDS- and
3’-UTR -Located MicroRNA Binding Sites between Species
Guojing Liu#, Rui Zhang#, Jin Xu, Chung-I Wu*, and Xuemei Lu*
Key words
microRNA, CDS targets, 3’-UTR targets, conservation
To address the functional conservation of both CDS- and 3'-UTR -located microRNA binding sites, we use public data to dig out how miRNA interact to targeted genes. we performed RNA-sequencing to quantify the regulatory effect of miR-15a/miR-16 and miR-92a on their CDS and 3’-UTR targets in human and macaque cells. We observed that both groups
of targets are functionally conserved.
To assess whether intratumor evolution follows the Darwinian or the non-Darwinian mode of evolution, we choose a hepatocellular carcinoma (HCC) tumor and used either whole-exome sequencing (WES) (n = 23 samples) or genotyping (n = 286) under both the infinite-site and infinite-allele models of population genetics. With all 286 samples genotyped, clonal diversity agreed well with the non-Darwinian model with no evidence of positive Darwinian selection. Because the level of genetic diversity will have implications on therapeutic resistance, nonDarwinian evolution should be heeded in cancer treatments even for microscopic tumors.
Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution
Shaoping Ling#, Zheng Hu#, Zuyu Yang#, Yang Fang#, Yawei Li, Pei Lin, Ke Chen, Lili Dong, Lihua Cao, Yong Tao, LingtongHao, Qingjian Chen, Qiang Gong, Dafei Wu, Wenjie Li, Wenming Zhao, Xiuyun Tian, ChunyiHao*, Eric A. Hungate, Daniel V. T. Catenacci, Richard R. Hudson, Wen-Hsiung Li*, Xuemei Lu* , Chung-I Wu*
intratumor heterogeneity, genetic diversity, neutral- evolution, cancer
evolution, natural selection
Key words
The dynamics of DNA methylation
fidelity during
mouse embryonic stem cell self-renewal and differentiation
Lei Zhao#, Ming-an Sun#, Zejuan Li#, Xue Bai, Miao Yu, Min Wang, Liji Liang, Xiaojian Shao, Stephen Arnovitz, Qianfei Wang, Chuan He, Xuemei Lu*, Jianjun Chen*, HehuangXie*
Key words
Methylation，methylation fidelity，mouse embryonic stem cells
To achieve a comprehensive assessment of methylation fidelity, we implemented a genome-scale hairpin bisulfite sequencing approach to generate methylation data for DNA double strands simultaneously. We show here that methylation fidelity increases globally during differentiation of mouse embryonic stem cells (mESCs), and is particularly high in the promoter regions. Our findings may shed new light on our understanding of the origins of methylation variations and the mechanisms underlying DNA methylation transmission.
Although tumorigenesis has been accepted as an evolutionary process, many forces may operate differently in cancers than in organisms, as they evolve at vastly different time scales. Among such forces, natural selection, here defined as differential cellular proliferation among distinct somatic cell genotypes. We analyzed selection in two stages of cancer evolution: Stage I is the evolution between tumors and normal tissues, and Stage II is the evolution within tumors. The Cancer Genome Atlas (TCGA) data show both positive and negative selection are evident but they neatly cancel each other out, rendering total selection ineffective in the absence of recombination. The efficacy of selection is even lower in Stage II, where neutral (non-Darwinian) evolution is increasingly supported by high-density sampling studies. Because natural selection is not a strong deterministic force, cancers usually evolve divergently even in similar tissue environments.
The Ecology and
Evolutionof
Cancer: The Ultra-Microevolutionary Process
Chung-I Wu*, Hurng-Yi Wang, Shaoping Ling, and Xuemei Lu*
cancer evolution, natural selection, convergent evolution,
cell population， genetics, intratumor heterogeneity
Key words
Histone Demethylase KDM4B Promotes
DNA Damage by Activating Long Interspersed Nuclear Element-1
Ying Xiang, Kai Yan, Qian Zheng, Haiqiang Ke, Jie Cheng, Wenjun Xiong, Xin Shi, Lei Wei, Min Zhao, Fei Yang, Ping Wang, Xing Lu, Li Fu, Xuemei Lu* and Feng Li*
Key words
H3K9me3 ,LINE-1, KDM4B, tumorigenesis, DNAdamage
In this study, we assess whole-genome H3K9me3 distribution in cancer cells and find that H3K9me3 is largely enriched in long interspersed nuclear element-1 (LINE-1). A significant proportion of KDM4B-dependent H3K9me3 was located in evolutionarily young LINE-1 elements, which likely retain retrotransposition activity. Pharmacologic inhibition of KDM4B significantly reduced LINE-1 expression and DNA damage in breast cancer cells with excessive KDM4B. Our study not only identifies KDM4B as a novel regulator of LINE-1, but it also suggests an unexpected oncogenic role for KDM4B overexpression in tumorigenesis, providing clues for the development of new cancer prevention strategies and therapies.
Cells of multi-cellular organisms evolve toward uni-cellularity in the form of cancer and, if humans intervene, continue to evolve in cell culture. During this process, gene dosage relationships may evolve in novel ways to cope with the new environment and may regress back to the ancestral uni-cellular state. In this context, the evolution of sex chromosomes vis-a-vis autosomes is of particular interest. Here, we report the chromosomal evolution in ~ 600 cancer cell lines. Many of them jettisoned either Y or the inactive X; thus, free-living male and female cells converge by becoming ‘de-sexualized’. Surprisingly, the active X often doubled, accompanied by the addition of one haploid complement of autosomes, leading to an X:A ratio of 2:3 from the extant ratio of 1:2. Theoretical modeling of the frequency distribution of X:A karyotypes suggests that the 2:3 ratio confers a higher fitness and may reflect aspects of sex chromosome evolution.
Free-living human cells reconfigure their chromosomes in the evolution back to uni-cellularity
Jin Xu#, Xinxin Peng#, Yuxin Chen#, Yuezheng Zhang, Qin Ma, Liang Liang, Ava C. Carter, Xuemei Lu* and Chung-I Wu*
cancer cell line，sex chromosome evolution, uni-cellularity
Key words