Single-cell DNA sequencing reveals pervasive positive selection throughout preleukemic evolution
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PROVIDER: PRJEB81526 | ENA |
REPOSITORIES: ENA
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Project description:The vertebrate protein SAMHD1 is highly unusual in having roles in cellular metabolic regulation, antiviral restriction, and regulation of innate immunity. Its deoxynucleoside triphosphohydrolase activity regulates cellular dNTP concentration, reducing levels below those required by lentiviruses and other viruses to replicate. To counter this threat, some primate lentiviruses encode accessory proteins that bind SAMHD1 and induce its degradation; in turn, positive diversifying selection has been observed in regions bound by these lentiviral proteins, suggesting that primate SAMHD1 has coevolved to evade these countermeasures. Moreover, deleterious polymorphisms in human SAMHD1 are associated with autoimmune disease linked to uncontrolled DNA synthesis of endogenous retroelements. Little is known about how evolutionary pressures affect these different SAMHD1 functions. Here, we examine the deeper history of these interactions by testing whether evolutionary signatures in SAMHD1 extend to other mammalian groups and exploring the molecular basis of this coevolution. Using codon-based likelihood models, we find positive selection in SAMHD1 within each mammal lineage for which sequence data are available. We observe positive selection at sites clustered around T592, a residue that is phosphorylated to regulate SAMHD1 activity. We verify experimentally that mutations within this cluster affect catalytic rate and lentiviral restriction, suggesting that virus-host coevolution has required adaptations of enzymatic function. Thus, persistent positive selection may have involved the adaptation of SAMHD1 regulation to balance antiviral, metabolic, and innate immunity functions.
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Project description:Cancer is an evolutionary process in which cells acquire new transformative, proliferative and metastatic capabilities. A full understanding of cancer requires learning the dynamics of the cancer evolutionary process. We present here a large-scale analysis of the dynamics of this evolutionary process within tumors, with a focus on breast cancer. We show that the cancer evolutionary process differs greatly from organismal (germline) evolution. Organismal evolution is dominated by purifying selection (that removes mutations that are harmful to fitness). In contrast, in the cancer evolutionary process the dominance of purifying selection is much reduced, allowing for a much easier detection of the signals of positive selection (adaptation). We further show that, as a group, genes that are globally expressed across human tissues show a very strong signal of positive selection within tumors. Indeed, known cancer genes are enriched for global expression patterns. Yet, positive selection is prevalent even on globally expressed genes that have not yet been associated with cancer, suggesting that globally expressed genes are enriched for yet undiscovered cancer related functions. We find that the increased positive selection on globally expressed genes within tumors is not due to their expression in the tissue relevant to the cancer. Rather, such increased adaptation is likely due to globally expressed genes being enriched in important housekeeping and essential functions. Thus, our results suggest that tumor adaptation is most often mediated through somatic changes to those genes that are important for the most basic cellular functions. Together, our analysis reveals the uniqueness of the cancer evolutionary process and the particular importance of globally expressed genes in driving cancer initiation and progression.
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Project description:Complex multicellular organisms have evolved numerous cell types with many different functions. Comparative transcriptomic data yields valuable insights into cell type, tissue, and organ evolution. However, interpreting this data requires understanding how transcriptomes evolve. A particularly difficult problem is that cell type transcriptomes may not evolve independently, a key assumption of most evolutionary analyses. Non-independence of cell types can occur when cell types share regulatory mechanisms. This leads to concerted evolution in gene expression across different cell types, confounding efforts to unravel the history of cell type evolution, and identify cell type-specific patterns of expression. Here we present a statistical model to estimate the level of concerted transcriptome evolution and apply it to published and new data. The results indicate that tissues undergo pervasive concerted evolution in gene expression. Tissues related by morphology or developmental lineage exhibit higher levels of concerted evolution. Concerted evolution also causes tissues from the same species to be more similar in gene expression to each other than to homologous tissues in another species. This result may explain why some tissue transcriptomes cluster by species rather than homology. Our analysis of bird skin appendages data suggests levels of concerted evolution also varies with phylogenetic age of the tissue. Our study illustrates the importance of accounting for concerted evolution when interpreting comparative transcriptome data, and should serve as a foundation for future investigations of cell type evolution.
2017-10-13 | GSE89040 | GEO
Project description:How somatic mutations accumulate in normal cells is central to understanding cancer development but is poorly understood. We performed ultradeep sequencing of 74 cancer genes in small (0.8 to 4.7 square millimeters) biopsies of normal skin. Across 234 biopsies of sun-exposed eyelid epidermis from four individuals, the burden of somatic mutations averaged two to six mutations per megabase per cell, similar to that seen in many cancers, and exhibited characteristic signatures of exposure to ultraviolet light. Remarkably, multiple cancer genes are under strong positive selection even in physiologically normal skin, including most of the key drivers of cutaneous squamous cell carcinomas. Positively selected mutations were found in 18 to 32% of normal skin cells at a density of ~140 driver mutations per square centimeter. We observed variability in the driver landscape among individuals and variability in the sizes of clonal expansions across genes. Thus, aged sun-exposed skin is a patchwork of thousands of evolving clones with over a quarter of cells carrying cancer-causing mutations while maintaining the physiological functions of epidermis.
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Project description:We used microarrays to investigate gene expression changes in leukemic bone marrow from Pax5+/-;Myd88+/- mice compared with bone marrow precursor B cells from WT mice and to study the effect of Myd88 downregulation in healthy Pax5+/- proB cells. The initial steps of B-cell acute lymphoblastic leukemia (B-ALL) development usually pass unnoticed in children; germline or somatic alterations affecting transcription factor genes cause the appearance of preleukemic cells still compatible with normal hematopoiesis, and preclinical studies have shown that immune stressors can trigger the malignant transformation of these otherwise silent preleukemic precursors to full-blown B-ALL. Understanding how exposure to immune stressors drives this conversion is a longstanding and unsolved challenge. Here we unveiled a specific “gene/environmental factor” interaction triggering B-ALL development. Our data show that B-ALL development falls into the category of cancers associated with dysregulation of innate immunity, which plays a driving role in the clonal evolution of pre-malignant B-cell precursors toward B-ALL following exposure to an immune stress. Transcriptional profiling of B-ALL allowed the identification of an inflammation-dependent role for Myd88 as a key player in this process. A preleukemic B-cell-autonomous role was evidenced by a significant increase in B-ALL incidence upon Myd88 dowregulation in the leukemia-prone Pax5+/- model. Likewise, early innate immune response induction by Toll-like receptor (TLR) ligation during the preleukemic phase in Pax5+/- mice resulted in a significant delay of B-ALL development. These findings identify a central role for innate immunity dysregulation in B-ALL, with important implications for the understanding and potential therapeutic targeting of the preleukemic state in children.
2023-08-10 | GSE221597 | GEO
Project description:Lyssavirus is a diverse genus of viruses that infect a variety of mammalian hosts, typically causing encephalitis. The evolution of this lineage, particularly the rabies virus, has been a focus of research because of the extensive occurrence of cross-species transmission, and the distinctive geographical patterns present throughout the diversification of these viruses. Although numerous studies have examined pattern-related questions concerning Lyssavirus evolution, analyses of the evolutionary processes acting on Lyssavirus diversification are scarce. To clarify the relevance of positive natural selection in Lyssavirus diversification, we conducted a comprehensive scan for episodic diversifying selection across all lineages and codon sites of the five coding regions in lyssavirus genomes. Although the genomes of these viruses are generally conserved, the glycoprotein (G), RNA-dependent RNA polymerase (L) and polymerase (P) genes were frequently targets of adaptive evolution during the diversification of the genus. Adaptive evolution is particularly manifest in the glycoprotein gene, which was inferred to have experienced the highest density of positively selected codon sites along branches. Substitutions in the L gene were found to be associated with the early diversification of phylogroups. A comparison between the number of positively selected sites inferred along the branches of RABV population branches and Lyssavirus intespecies branches suggested that the occurrence of positive selection was similar on the five coding regions of the genome in both groups.
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Project description:MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism
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2015-07-15 | E-GEOD-59431 | biostudies-arrayexpress
Project description:We used microarrays to investigate gene expression changes in tumor-bearing Sca1-TOMATO-Lmo2 mice and in preleukemic cells from Sca1-TOMATO-Lmo2 mice. Tumor-bearing thymus of eleven Sca1-TOMATO-Lmo2 mice compared with thymus cells from 4 WT mice, with TOMATO-positive thymus preleukemic T cells from 5 Sca1-TOMATO-Lmo2 mice and with TOMATO-negative thymus preleukemic T cells from 5 Sca1-TOMATO-Lmo2 mice GSM2209749 - GSM220975 and GSM2209757 - GSM2209759 were re-analyzed by GSE83571 (GSM2209767 - GSM2209776).
2016-06-22 | E-GEOD-83570 | biostudies-arrayexpress
Project description:Expression profiling of FACS purified Lin-cKit+ cells from preleukemic compound URE-/+::Msh2-/- mice and control animals (two separate pools of 3 mice each)
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