scholarly journals Use of signals of positive and negative selection to distinguish cancer genes and passenger genes

2020 ◽  
Author(s):  
László Bányai ◽  
Mária Trexler ◽  
Krisztina Kerekes ◽  
Orsolya Csuka ◽  
László Patthy
Keyword(s):  
Negative Selection ◽  
Cancer Genomics ◽  
Tumor Evolution ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Human Genes ◽  
Strong Negative Selection ◽  
Selection For ◽  
Inactivating Mutations

AbstractA major goal of cancer genomics is to identify all genes that play critical roles in carcinogenesis. Most approaches focused on genes that are positively selected for mutations that drive carcinogenesis and neglected the role of negative selection. Some studies have actually concluded that negative selection has no role in cancer evolution. In the present work we have re-examined the role of negative selection in tumor evolution through the analysis of the patterns of somatic mutations affecting the coding sequences of human genes. Our analyses have confirmed that tumor suppressor genes are positively selected for inactivating mutations. Oncogenes, however, were found to display signals of both negative selection for inactivating mutations and positive selection for activating mutations. Significantly, we have identified numerous human genes that show signs of strong negative selection during tumor evolution, suggesting that their functional integrity is essential for the growth and survival of tumor cells.

scholarly journals Use of signals of positive and negative selection to distinguish cancer genes and passenger genes

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
László Bányai ◽  
Maria Trexler ◽  
Krisztina Kerekes ◽  
Orsolya Csuka ◽  
László Patthy
Keyword(s):  
Negative Selection ◽  
Cancer Genomics ◽  
Tumor Evolution ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Human Genes ◽  
Strong Negative Selection ◽  
Selection For ◽  
Inactivating Mutations

A major goal of cancer genomics is to identify all genes that play critical roles in carcinogenesis. Most approaches focused on genes positively selected for mutations that drive carcinogenesis and neglected the role of negative selection. Some studies have actually concluded that negative selection has no role in cancer evolution. We have re-examined the role of negative selection in tumor evolution through the analysis of the patterns of somatic mutations affecting the coding sequences of human genes. Our analyses have confirmed that tumor suppressor genes are positively selected for inactivating mutations, oncogenes, however, were found to display signals of both negative selection for inactivating mutations and positive selection for activating mutations. Significantly, we have identified numerous human genes that show signs of strong negative selection during tumor evolution, suggesting that their functional integrity is essential for the growth and survival of tumor cells.

scholarly journals Whole Genome Doubling mitigates Muller’s Ratchet in Cancer Evolution

2019 ◽  
Author(s):  
Saioa López ◽  
Emilia Lim ◽  
Ariana Huebner ◽  
Michelle Dietzen ◽  
Thanos Mourikis ◽  
...  
Keyword(s):  
Negative Selection ◽  
Chromosome Complement ◽  
Essential Genes ◽  
Tumour Suppressor Genes ◽  
Whole Genome ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Strong Negative Selection

AbstractWhole genome doubling (WGD) is a prevalent macro-evolutionary event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and clinical prognostic relevance, the evolutionary selection pressures for WGD have not been investigated. Here, we explored whether WGD may act to mitigate the irreversible, inexorable ratchet-like, accumulation of deleterious mutations in essential genes. Utilizing 1050 tumor regions from 816 non-small cell lung cancers (NSCLC), we temporally dissect mutations to determine their temporal acquisition in relation to WGD. We find evidence for strong negative selection against homozygous loss of essential cancer genes prior to WGD. However, mutations in essential genes occurring after duplication were not subject to significant negative selection, consistent with WGD providing a buffering effect, decreasing the likelihood of homozygous loss. Finally, we demonstrate that loss of heterozygosity and temporal dissection of mutations can be exploited to identify signals of positive selection in lung, breast, colorectal cancer and other cancer types, enabling the elucidation of novel tumour suppressor genes and a deeper characterization of known cancer genes.

scholarly journals Interpreting dN/dS under different selective regimes in cancer evolution

2021 ◽  
Author(s):  
Andrés Pérez-Figueroa ◽  
David Posada
Keyword(s):  
Negative Selection ◽  
Mutation Detection ◽  
Cancer Genomics ◽  
Detection Threshold ◽  
Cancer Genes ◽  
Selection Coefficient ◽  
Cancer Evolution ◽  
Synonymous Mutations ◽  
Somatic Evolution ◽  
The Relationship

The standard relationship between the dN/dS statistic and the selection coefficient is contingent upon the computation of the rate of fixation of non-synonymous and synonymous mutations among divergent lineages (substitutions). In cancer genomics, however, dN/dS is typically calculated by including mutations that are still segregating in the cell population. The interpretation of dN/dS within sexual populations has been shown to be problematic. Here we used a simple model of somatic evolution to study the relationship between dN/dS and the selection coefficient in the presence of deleterious, neutral, and beneficial mutations in cancer. We found that dN/dS can be used to distinguish cancer genes under positive or negative selection, but it is not always informative about the magnitude of the selection coefficient. In particular, under the asexual scenario simulated, dN/dS is insensitive to negative selection strength. Furthermore, the relationship between dN/dS and the positive selection coefficient depends on the mutation detection threshold, and, in particular scenarios, it can become non-linear. Our results warn about the necessary caution when interpreting the results drawn from dN/dS estimates in cancer.

scholarly journals Mitochondrial genetic diversity, selection and recombination in a canine transmissible cancer

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Andrea Strakova ◽  
Máire Ní Leathlobhair ◽  
Guo-Dong Wang ◽  
Ting-Ting Yin ◽  
Ilona Airikkala-Otter ◽  
...  
Keyword(s):  
Negative Selection ◽  
Nuclear Genome ◽  
Cancer Evolution ◽  
Global Migration ◽  
Transmissible Cancer ◽  
Clonal Origin ◽  
Canine Transmissible Venereal Tumour ◽  
Global Population ◽  
Transmissible Venereal Tumour

Canine transmissible venereal tumour (CTVT) is a clonally transmissible cancer that originated approximately 11,000 years ago and affects dogs worldwide. Despite the clonal origin of the CTVT nuclear genome, CTVT mitochondrial genomes (mtDNAs) have been acquired by periodic capture from transient hosts. We sequenced 449 complete mtDNAs from a global population of CTVTs, and show that mtDNA horizontal transfer has occurred at least five times, delineating five tumour clades whose distributions track two millennia of dog global migration. Negative selection has operated to prevent accumulation of deleterious mutations in captured mtDNA, and recombination has caused occasional mtDNA re-assortment. These findings implicate functional mtDNA as a driver of CTVT global metastatic spread, further highlighting the important role of mtDNA in cancer evolution.

scholarly journals Paradoxical Signaling Pathways in Developing Thymocytes

2011 ◽  
Vol 14 (3) ◽  
pp. 378 ◽  
Author(s):  
Aws Alshamsan
Keyword(s):  
Cell Death ◽  
Positive Selection ◽  
Cell Fate ◽  
Negative Selection ◽  
Mapk Pathway ◽  
Erk Activation ◽  
Selection For ◽  
Kinetics Of ◽  
Level Order

ABSTRACT- Thymocytes are subjected to processes of selection during their life in the thymus; negative selection for autoreactive thymocytes and positive selection for self-MHC restricted self-tolerant cells. Interestingly, signals for positive or negative selection originate from the same receptor. More importantly, evidence showed that both death and survival signals are mediated by the MAPK pathway. The degree and order of ERK activation, but not other MAPK proteins, has been found to be different in either cases of cell fate. Therefore, it is suspected that the kinetics of ERK after activation may dictate cell death or survival. There are two important GEF proteins that are involved in Ras/ERK activation, RasGRP and SOS. It is thought that the level, order and kinetics of ERK are influenced upstream by the type of GEF. This review discusses the role of both GEF proteins in positive and negative selection and how this reflects on ERK activation. This article is open POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Evolutionary dynamics of neoantigens in growing tumours

2019 ◽  
Author(s):  
Eszter Lakatos ◽  
Marc J. Williams ◽  
Ryan O. Schenck ◽  
William C. H. Cross ◽  
Jacob Househam ◽  
...  
Keyword(s):  
Negative Selection ◽  
Evolutionary Dynamics ◽  
Immune Escape ◽  
Patient Specific ◽  
Mathematical Framework ◽  
Cancer Evolution ◽  
Sequencing Data ◽  
Clone Size ◽  
Strong Negative Selection ◽  
Immune Escape Mechanisms

ABSTRACTCancer evolution is driven by the acquisition of somatic mutations that provide cells with a beneficial phenotype in a changing microenvironment. However, mutations that give rise to neoantigens, novel cancer–specific peptides that elicit an immune response, are likely to be disadvantageous. Here we show how the clonal structure and immunogenotype of growing tumours is shaped by negative selection in response to neoantigenic mutations. We construct a mathematical model of neoantigen evolution in a growing tumour, and verify the model using genomic sequencing data. The model predicts that, in the absence of active immune escape mechanisms, tumours either evolve clonal neoantigens (antigen– ‘hot’), or have no clonally– expanded neoantigens at all (antigen– ‘cold’), whereas antigen– ‘warm’ tumours (with high frequency subclonal neoantigens) form only following the evolution of immune evasion. Counterintuitively, strong negative selection for neoantigens during tumour formation leads to an increased number of antigen– warm or – hot tumours, as a consequence of selective pressure for immune escape. Further, we show that the clone size distribution under negative selection is effectively– neutral, and moreover, that stronger negative selection paradoxically leads to more neutral– like dynamics. Analysis of antigen clone sizes and immune escape in colorectal cancer exome sequencing data confirms these results. Overall, we provide and verify a mathematical framework to understand the evolutionary dynamics and clonality of neoantigens in human cancers that may inform patient– specific immunotherapy decision– making.

scholarly journals Evidence of positive and negative selection associated with DNA methylation

2021 ◽  
Author(s):  
Charlie Hatcher ◽  
Gibran Hemani ◽  
Santiago Rodriguez ◽  
Tom R Gaunt ◽  
Daniel J Lawson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Complex Traits ◽  
Functional Role ◽  
Joint Distribution ◽  
Negative Selection ◽  
Selection Coefficient ◽  
Parents And Children ◽  
Selection For ◽  
Avon Longitudinal Study

Signatures of negative selection are pervasive amongst complex traits and diseases. However, it is unclear whether such signatures exist for DNA methylation (DNAm) that has been proposed to have a functional role in disease. We estimate polygenicity, SNP-based heritability and model the joint distribution of effect size and minor allele frequency (MAF) to estimate a selection coefficient (S) for 2000 heritable DNAm sites in 1774 individuals from the Avon Longitudinal Study of Parents and Children. Additionally, we estimate S for meta stable epi alleles and DNAm sites associated with aging and mortality, birthweight and body mass index. Quantification of MAF-dependent genetic architectures estimated from genotype and DNAm reveal evidence of positive (S>0) and negative selection (S<0) and confirm previous evidence of negative selection for birthweight. Evidence of both negative and positive selection highlights the role of DNAm as an intermediary in multiple biological pathways with competing function.

scholarly journals Universal patterns of selection in cancer and somatic tissues

2017 ◽  
Author(s):  
Iñigo Martincorena ◽  
Keiran M. Raine ◽  
Moritz Gerstung ◽  
Kevin J. Dawson ◽  
Kerstin Haase ◽  
...  
Keyword(s):  
Positive Selection ◽  
Negative Selection ◽  
Clonal Selection ◽  
Purifying Selection ◽  
Driver Mutations ◽  
Base Substitution ◽  
List Type ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Mutation Burden

ABSTRACTCancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We applied methods from evolutionary genomics to 7,664 human cancers across 29 tumor types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection only detected for truncating mutations in essential genes in haploid regions. This allows exome-wide enumeration of all driver mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We identify novel cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.HIGHLIGHTSUnlike the germline, somatic cells evolve predominantly by positive selectionNearly all (∼99%) coding mutations are tolerated and escape negative selectionFirst exome-wide estimates of the total number of driver coding mutations per tumor1-10 coding driver mutations per tumor; half occurring outside known cancer genes

scholarly journals Clonal status of actionable driver events and the timing of mutational processes in cancer evolution

2015 ◽  
Vol 7 (283) ◽  
pp. 283ra54-283ra54 ◽  
Author(s):  
Nicholas McGranahan ◽  
Francesco Favero ◽  
Elza C. de Bruin ◽  
Nicolai Juul Birkbak ◽  
Zoltan Szallasi ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Tumor Cells ◽  
Mitogen Activated Protein Kinase ◽  
Driver Mutations ◽  
Intratumor Heterogeneity ◽  
Tumor Evolution ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Signaling Axis ◽  
Mutational Processes

Deciphering whether actionable driver mutations are found in all or a subset of tumor cells will likely be required to improve drug development and precision medicine strategies. We analyzed nine cancer types to determine the subclonal frequencies of driver events, to time mutational processes during cancer evolution, and to identify drivers of subclonal expansions. Although mutations in known driver genes typically occurred early in cancer evolution, we also identified later subclonal “actionable” mutations, including BRAF (V600E), IDH1 (R132H), PIK3CA (E545K), EGFR (L858R), and KRAS (G12D), which may compromise the efficacy of targeted therapy approaches. More than 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K (phosphatidylinositol 3-kinase)–AKT–mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal. Mutations in the RAS–MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTOR signaling. Analysis of late mutations revealed a link between APOBEC-mediated mutagenesis and the acquisition of subclonal driver mutations and uncovered putative cancer genes involved in subclonal expansions, including CTNNA2 and ATXN1. Our results provide a pan-cancer census of driver events within the context of intratumor heterogeneity and reveal patterns of tumor evolution across cancers. The frequent presence of subclonal driver mutations suggests the need to stratify targeted therapy response according to the proportion of tumor cells in which the driver is identified.

scholarly journals Pervasive conditional selection of driver mutations and modular epistasis networks in cancer

2022 ◽  
Author(s):  
Jaime Iranzo ◽  
George Gruenhagen ◽  
Jorge Calle-Espinosa ◽  
Eugene V. Koonin
Keyword(s):  
Cancer Genomics ◽  
Mutual Exclusion ◽  
Driver Mutations ◽  
Tumor Evolution ◽  
Cancer Genes ◽  
Cancer Subtypes ◽  
Cancer Driver ◽  
Conditional Selection ◽  
Tcga Dataset ◽  
Complex Scenario

Cancer driver mutations often display mutual exclusion or co-occurrence, underscoring the key role of epistasis in carcinogenesis. However, estimating the magnitude of epistatic interactions and their quantitative effect on tumor evolution remains a challenge. We developed a method to quantify COnditional SELection on the Excess of Nonsynonymous Substitutions (Coselens) in cancer genes. Coselens infers the number of drivers per gene in different partitions of a cancer genomics dataset using covariance-based mutation models and determines whether coding mutations in a gene affect selection for drivers in any other gene. Using Coselens, we identified 296 conditionally selected gene pairs across 16 cancer types in the TCGA dataset. Conditional selection accounts for 25-50% of driver substitutions in tumors with >2 drivers. Conditionally co-selected genes form modular networks, whose structures challenge the traditional interpretation of within-pathway mutual exclusivity and across-pathway synergy, suggesting a more complex scenario, where gene-specific across-pathway interactions shape differentiated cancer subtypes.

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