Negative selection in tumor genome evolution acts on essential cellular functions and the immunopeptidome

Zapata, Luís; Pich, Oriol; Serrano, Luís; Kondrashov, Fyodor A.; Ossowski, Stephan; Schaefer, Martin H.

doi:10.1186/s13059-018-1434-0

Cited by 104 publications

(150 citation statements)

References 103 publications

(140 reference statements)

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“…paralog genes are less likely to cause cell death when mutated. This suggests that buffering between paralogs may act as a source of genetic robustness in tumors, consistent with recent work analyzing mutational patterns in tumor genomes that demonstrated that paralog genes appear to be under weaker negative selection than singleton genes [53].…”

Section: Paralogs Are a Source Of Genetic Robustness In Tumor Cellssupporting

confidence: 86%

Paralog buffering contributes to the variable essentiality of genes in cancer cell lines

Kegel

Ryan

2019

Preprint

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What makes a gene essential for cellular survival? In model organisms, such as budding yeast, systematic gene deletion studies have revealed that paralog genes are less likely to be essential than singleton genes and that this can partially be attributed to the ability of paralogs to buffer each other's loss. However, the essentiality of a gene is not a fixed property and can vary significantly across different genetic backgrounds. It is unclear to what extent paralogs contribute to this variation, as most studies have analyzed genes identified as essential in a single genetic background. Here, using gene essentiality profiles of 558 genetically heterogeneous tumor cell lines, we analyze the contribution of paralogy to variable essentiality. We find that, compared to singleton genes, paralogs are less frequently essential and that this is more evident when considering genes with multiple paralogs or with highly sequence similar paralogs. We determine that paralogs derived from whole genome duplication exhibit more variable essentiality than those derived from small-scale duplications. We estimate that in 13-17% of cases the variable essentiality of paralogs can be attributed to buffering relationships between paralog pairs, as evidenced by synthetic lethality. Paralog pairs derived from whole genome duplication and pairs that function in protein complexes are significantly more likely to display such synthetic lethal relationships. Overall we find that many of the observations made using a single strain of budding yeast can be extended to understand patterns of essentiality in genetically heterogeneous cancer cell lines.

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Section: Paralogs Are a Source Of Genetic Robustness In Tumor Cellssupporting

confidence: 86%

Paralog buffering contributes to the variable essentiality of genes in cancer cell lines

Kegel

Ryan

2019

Preprint

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“…To estimate the extent of selection acting on somatic mutations in healthy tissues we used the SSB-dN/dS method (Zapata et al, 2018), which calculates the trinucleotide-corrected ratio of nonsynonymous to synonymous mutations from NGS data (Zapata et al, 2018). Somatic mutations identified by RF-RNAmut were annotated using Variant Effect Predictor (VEP).…”

Section: Identifying Signatures Of Positive Selection In Cancer Genesmentioning

confidence: 99%

“…However, we only computed dN/dS values for those tissues having at least 3 non-silent or silent somatic mutations in the analyzed genes. In addition to the exome-wide dN/dS provided in the output of the SSB-dN/dS method, we calculated the global dN/dS for 198 cancer genes (Martincorena et al, 2015) and 995 essential genes (Zapata et al, 2018). Finally, we focused on NOTCH1 and TP53 genes in order to replicate the findings of strong positive selection described recently (Martincorena et al, 2015(Martincorena et al, , 2018Yizhak et al, 2019;Yokoyama et al, 2019).…”

Section: Identifying Signatures Of Positive Selection In Cancer Genesmentioning

confidence: 99%

The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues

Muyas

Zapata

Guigó

et al. 2019

Preprint

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Background: Mosaic mutations acquired during early embryogenesis can lead to severe earlyonset genetic disorders and cancer predisposition, but are often undetectable in blood samples. The rate and mutational spectrum of embryonic mosaic mutations (EMMs) have only been studied in few tissues and their contribution to genetic disorders is unknown. Therefore, we investigated how frequent mosaic mutations occur during embryogenesis across all germ layers and tissues.Results: Using RNA sequencing data from the Genotype-Tissue Expression (GTEx) cohort comprising 49 normal tissues and 570 individuals, we found that new-borns on average harbour 0.5 -1 EMMs in the exome affecting multiple organs (1.3230 x 10 -8 per nucleotide per individual), a similar frequency as reported for germline de novo mutations. Our multi-tissue, multiindividual study design allowed us to distinguish mosaic mutations acquired during different stages of embryogenesis and adult life, as well as to provide insights into the rate and spectrum of mosaic mutations. We observed that EMMs are dominated by a mutational signature associated with spontaneous deamination of methylated cytosines and the number of cell divisions. After birth, cells continue to accumulate somatic mutations, which can lead to the development of cancer. Investigation of the mutational spectrum of the gastrointestinal tract revealed a mutational pattern associated with the food-borne carcinogen aflatoxin, a signature that has so far only been reported in liver cancer. Conclusion:In summary, our multi-tissue, multi-individual study reveals a surprisingly high number of embryonic mosaic mutations in coding regions, implying novel hypotheses and diagnostic procedures for investigating genetic causes of disease and cancer predisposition.

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“…In humans, somatic mutations play a key role in senescence and tumorigenesis 1 . Pioneering work on somatic evolution in cancer has led to the characterization of cancer driver genes 2 and mutation signatures 3 ; the interplay between chromatin, nuclear architecture, carcinogens and the mutational landscape [4][5][6][7] ; the evolutionary forces acting on somatic mutations [8][9][10][11] ; and clinical implications of somatic mutations 12 .…”

Section: Introductionmentioning

confidence: 99%

The somatic mutation landscape of the human body

García-Nieto

Morrison

Fraser

2019

Preprint

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Somatic mutations in healthy tissues contribute to aging, neurodegeneration, and cancer initiation, yet remain largely uncharacterized. To gain a better understanding of their distribution and functional impacts, we leveraged the genomic information contained in the transcriptome to uniformly call somatic mutations from over 7,500 tissue samples, representing 36 distinct tissues. This catalog, containing over 280,000 mutations, revealed a wide diversity of tissuespecific mutation profiles associated with gene expression levels and chromatin states. We found pervasive negative selection acting on missense and nonsense mutations, except for mutations previously observed in cancer samples, which were under positive selection and were highly enriched in many healthy tissues. These findings reveal fundamental patterns of tissue-specific somatic evolution and shed light on aging and the earliest stages of tumorigenesis. RESULTS Somatic mutation calling across 36 non-disease tissues from 547 peopleOur method considers genomic positions where we observed two alleles in the RNA-seq reads and assesses whether they are likely to be bona fide DNA somatic mutations (Fig 1a). We optimized the minimum levels of RNA-seq read depth, sequence quality, and number of reads supporting the variant allele to limit the impact of sequencing errors (Supp. Fig. 1a; see Methods). We then applied extensive filters to eliminate false-positives from biological and technical sources, including RNA editing, sequencing errors, and mapping errors (see Methods ; Fig 1b- Fig. 2a; Supp. Table 1).To validate the method, we compared somatic mutation calls from 105 blood RNA-seq samples to exome DNA sequencing performed on the same samples 23 (Fig. 1d). We observed a false-discovery rate (FDR) of 29% which represents the percentage of somatic mutations called from RNA-seq not having evidence in the corresponding DNA exome-seq sample (Fig. 1d, Supp. Fig. 1c; see methods). This is comparable to the 40% FDR in a previous study that inferred mutations from scRNA-seq in pancreas 22 .After applying the pipeline and filters to RNA-seq data from the GTEx project, we retained a total of 7,584 samples from 36 different tissues and 547 different individuals with no detectable cancer (Supp. Table 2). This resulted in a total of 280,843 unique mutations (Supp. Table 3), most of which were rare across the entire data set (median frequency = 0.026% of samples; Supp. Fig. 2b).We first investigated the factors influencing mutation counts per sample and tissue (see Methods). The main contributor was sequencing depth and to a lesser extent other biological and technical factors (Supp. Fig. 2c, Supp. Table 4). Tissues that have more mutations than expected from sequencing depth include those most often exposed to environmental mutagens or with a high cellular turnover like skin, lung, blood, esophagus mucosa, spleen, liver and small intestine ( Fig. 2a). On the other end of the spectrum are those with low environmental exposure or low cellular turnover such as brain, adre...

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Negative selection in tumor genome evolution acts on essential cellular functions and the immunopeptidome

Cited by 104 publications

References 103 publications

Paralog buffering contributes to the variable essentiality of genes in cancer cell lines

Paralog buffering contributes to the variable essentiality of genes in cancer cell lines

The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues

The somatic mutation landscape of the human body

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