scholarly journals A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sanju Sinha ◽  
Karina Barbosa ◽  
Kuoyuan Cheng ◽  
Mark D. M. Leiserson ◽  
Prashant Jain ◽  
...  
Keyword(s):  
Genome Editing ◽  
Cell Types ◽  
Selective Advantage ◽  
Driver Mutations ◽  
Cancer Driver ◽  
Oncogenic Mutation ◽  
Genome Wide ◽  
Selection For ◽  
Mutant Cells ◽  
Selection Of

AbstractRecent studies have reported that genome editing by CRISPR–Cas9 induces a DNA damage response mediated by p53 in primary cells hampering their growth. This could lead to a selection of cells with pre-existing p53 mutations. In this study, employing an integrated computational and experimental framework, we systematically investigated the possibility of selection of additional cancer driver mutations during CRISPR-Cas9 gene editing. We first confirm the previous findings of the selection for pre-existing p53 mutations by CRISPR-Cas9. We next demonstrate that similar to p53, wildtype KRAS may also hamper the growth of Cas9-edited cells, potentially conferring a selective advantage to pre-existing KRAS-mutant cells. These selective effects are widespread, extending across cell-types and methods of CRISPR-Cas9 delivery and the strength of selection depends on the sgRNA sequence and the gene being edited. The selection for pre-existing p53 or KRAS mutations may confound CRISPR-Cas9 screens in cancer cells and more importantly, calls for monitoring patients undergoing CRISPR-Cas9-based editing for clinical therapeutics for pre-existing p53 and KRAS mutations.

scholarly journals A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing

2021 ◽  
Author(s):  
Sanju Sinha ◽  
Karina Guerra ◽  
Kuoyuan Cheng ◽  
Mark Leiserson ◽  
Prashant Jain ◽  
...  
Keyword(s):  
Genome Editing ◽  
Cell Types ◽  
Selective Advantage ◽  
Driver Mutations ◽  
Cancer Driver ◽  
Oncogenic Mutation ◽  
Genome Wide ◽  
Selection For ◽  
Mutant Cells ◽  
Selection Of

Abstract Recent studies have reported that genome editing by CRISPR–Cas9 induces a DNA damage response mediated by p53 in primary cells hampering their growth. This could lead to a selection of cells with pre-existing p53 mutations. In this study, employing an integrated computational and experimental framework, we systematically investigated the possibility of selection of additional cancer driver mutations during CRISPR-Cas9 gene editing. We first confirm the previous findings of the selection for pre-existing p53 mutations by CRISPR-Cas9. We next demonstrate that similar to p53, wildtype KRAS may also hamper the growth of Cas9-edited cells, potentially conferring a selective advantage to pre-existing KRAS-mutant cells. These selective effects are widespread, extending across cell-types and methods of CRISPR-Cas9 delivery and the strength of selection depends on the sgRNA sequence and the gene being edited. The selection for pre-existing p53 or KRAS mutations may confound CRISPR-Cas9 screens in cancer cells and more importantly, calls for monitoring patients undergoing CRISPR-Cas9-based editing for clinical therapeutics for pre-existing p53 and KRAS mutations.

scholarly journals Integrated computational and experimental identification of p53, KRAS and VHL mutant selection associated with CRISPR-Cas9 editing

2018 ◽  
Author(s):  
Sanju Sinha ◽  
Karina Barbosa Guerra ◽  
Kuoyuan Cheng ◽  
Mark DM Leiserson ◽  
David M Wilson ◽  
...  
Keyword(s):  
Gene Editing ◽  
Mutant Cell ◽  
Cell Types ◽  
Driver Mutations ◽  
Mutant Selection ◽  
Cancer Driver ◽  
Genome Wide ◽  
A Genome ◽  
Induced Changes ◽  
Different Cell Types

AbstractRecent studies have reported that CRISPR-Cas9 gene editing induces a p53-dependent DNA damage response in primary cells, which may select for cells with oncogenic p53 mutations11,12. It is unclear whether these CRISPR-induced changes are applicable to different cell types, and whether CRISPR gene editing may select for other oncogenic mutations. Addressing these questions, we analyzed genome-wide CRISPR and RNAi screens to systematically chart the mutation selection potential of CRISPR knockouts across the whole exome. Our analysis suggests that CRISPR gene editing can select for mutants of KRAS and VHL, at a level comparable to that reported for p53. These predictions were further validated in a genome-wide manner by analyzing independent CRISPR screens and patients’ tumor data. Finally, we performed a new set of pooled and arrayed CRISPR screens to evaluate the competition between CRISPR-edited isogenic p53 WT and mutant cell lines, which further validated our predictions. In summary, our study systematically charts and points to the potential selection of specific cancer driver mutations during CRISPR-Cas9 gene editing.

scholarly journals Clonal yeast biofilms can reap competitive advantages through cell differentiation without being obligatorily multicellular

2016 ◽  
Vol 283 (1842) ◽  
pp. 20161303 ◽  
Author(s):  
Birgitte Regenberg ◽  
Kristian Ebbesen Hanghøj ◽  
Kaj Scherz Andersen ◽  
Jacobus J. Boomsma
Keyword(s):  
Cell Differentiation ◽  
Single Gene ◽  
Cell Types ◽  
Selective Advantage ◽  
Division Of Labour ◽  
Competitive Advantages ◽  
Epigenetic Switch ◽  
Organizational Complexity ◽  
Switch Mechanism ◽  
Selection For

How differentiation between cell types evolved is a fundamental question in biology, but few studies have explored single-gene phenotypes that mediate first steps towards division of labour with selective advantage for groups of cells. Here, we show that differential expression of the FLO11 gene produces stable fractions of Flo11 + and Flo11 − cells in clonal Saccharomyces cerevisiae biofilm colonies on medium with intermediate viscosity. Differentiated Flo11 +/− colonies, consisting of adhesive and non-adhesive cells, obtain a fourfold growth advantage over undifferentiated colonies by overgrowing glucose resources before depleting them, rather than depleting them while they grow as undifferentiated Flo11 − colonies do. Flo11 +/− colonies maintain their structure and differentiated state by switching non-adhesive cells to adhesive cells with predictable probability. Mixtures of Flo11 + and Flo11 − cells from mutant strains that are unable to use this epigenetic switch mechanism produced neither integrated colonies nor growth advantages, so the condition-dependent selective advantages of differentiated FLO11 expression can only be reaped by clone-mate cells. Our results show that selection for cell differentiation in clonal eukaryotes can evolve before the establishment of obligate undifferentiated multicellularity, and without necessarily leading to more advanced organizational complexity.

scholarly journals No evidence that HLA genotype influences the driver mutations that occur in cancer patients

2021 ◽  
Author(s):  
Noor Kherreh ◽  
Siobhán Cleary ◽  
Cathal Seoighe
Keyword(s):  
Immune Responses ◽  
Somatic Mutations ◽  
Strong Relationship ◽  
Driver Mutations ◽  
Cell Surfaces ◽  
Cancer Driver ◽  
Mhc Molecules ◽  
Oncogenic Mutation ◽  
Hla Genotype ◽  
Mhc Alleles

AbstractThe major histocompatibility (MHC) molecules are capable of presenting neoantigens resulting from somatic mutations on cell surfaces, potentially directing immune responses against cancer. This led to the hypothesis that cancer driver mutations may occur in gaps in the capacity to present neoantigens that are dependent on MHC genotype. If this is correct, it has important implications for understanding oncogenesis and may help to predict driver mutations based on genotype data. In support of this hypothesis, it has been reported that driver mutations that occur frequently tend to be poorly presented by common MHC alleles and that the capacity of a patient’s MHC alleles to present the resulting neoantigens is predictive of the driver mutations that are observed in their tumour. Here we show that these reports of a strong relationship between driver mutation occurrence and patient MHC alleles are a consequence of unjustified statistical assumptions. Our reanalysis of the data provides no evidence of an effect of MHC genotype on the oncogenic mutation landscape.

scholarly journals Learning the mutational landscape of the cancer genome

2021 ◽  
Author(s):  
Maxwell A Sherman ◽  
Adam Yaari ◽  
Oliver Priebe ◽  
Felix Dietlein ◽  
Po-Ru Loh ◽  
...  
Keyword(s):  
Deep Neural Networks ◽  
Mutation Rates ◽  
Untranslated Regions ◽  
Driver Mutations ◽  
Web Interface ◽  
Cancer Driver ◽  
Genome Wide ◽  
Cancer Types ◽  
Neutral Mutations ◽  
Proliferative Advantage

An ongoing challenge to better understand and treat cancer is to distinguish neutral mutations, which do not affect tumor fitness, from those that provide a proliferative advantage. However, the variability of mutation rates has limited our ability to model patterns of neutral mutations and therefore identify cancer driver mutations. Here, we predict cancer-specific mutation rates genome-wide by leveraging deep neural networks to learn mutation rates within kilobase-scale regions and then refining these estimates to test for evidence of selection on combinations of mutations by comparing observed to expected mutation counts. We mapped mutation rates for 37 cancer types and used these maps to identify new putative drivers in understudied regions of the genome including cryptic alternative-splice sites, 5 prime untranslated regions and infrequently mutated genes. These results, available for exploration via web interface, indicate the potential for high-resolution neutral mutation models to empower further driver discovery as cancer sequencing cohorts grow.

scholarly journals Precancer: Mutant clones in normal epithelium outcompete and eliminate esophageal micro-tumors

2021 ◽  
Author(s):  
Bartomeu Colom ◽  
Albert Herms ◽  
Stefan Dentro ◽  
Charlotte King ◽  
Roshan Sood ◽  
...  
Keyword(s):  
Genetic Selection ◽  
Tumor Formation ◽  
Driver Mutations ◽  
Tumor Cell Death ◽  
Cell Competition ◽  
Normal Epithelium ◽  
Cancer Driver ◽  
Tissue Integrity ◽  
Esophageal Carcinogenesis ◽  
Selection Of

Human epithelial tissues accumulate cancer-driver mutations with age1-7, yet tumor formation remains rare. The positive selection of these mutations argues they alter the behavior and fitness of proliferating cells8-10. Hence, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less-competitive neighbors9-12. However, little is known about how such dynamic competition in normal epithelia impacts early tumorigenesis. Here we show that the majority of newly formed esophageal tumors are eliminated through competition with mutant clones in the surrounding normal epithelium. We followed the fate of microscopic tumors in a mouse model of esophageal carcinogenesis. Most neoplasms are rapidly lost despite no indication of tumor cell death, decreased proliferation, or an anti-tumor immune response. Deep-sequencing of 10-day and 1-year-old tumors shows evidence of genetic selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased tumor removal, while pharmacologically inhibiting clonal competition reduced tumor loss. The results are consistent with a model where survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the adjacent normal tissue. We have identified an unexpected anti-tumorigenic role for mutant clones in normal epithelium by purging early neoplasms through cell competition, thereby preserving tissue integrity.

scholarly journals No evidence that HLA genotype influences the driver mutations that occur in cancer patients

2021 ◽  
Author(s):  
Noor Kherreh ◽  
Siobhán Cleary ◽  
Cathal Seoighe
Keyword(s):  
Immune Responses ◽  
Somatic Mutations ◽  
Strong Relationship ◽  
Driver Mutations ◽  
Cell Surfaces ◽  
Cancer Driver ◽  
Mhc Molecules ◽  
Oncogenic Mutation ◽  
Hla Genotype ◽  
Mhc Alleles

AbstractThe major histocompatibility (MHC) molecules are capable of presenting neoantigens resulting from somatic mutations on cell surfaces, potentially directing immune responses against cancer. This led to the hypothesis that cancer driver mutations may occur in gaps in the capacity to present neoantigens that are dependent on MHC genotype. If this is correct, it has important implications for understanding oncogenesis and may help to predict driver mutations based on genotype data. In support of this hypothesis, it has been reported that driver mutations that occur frequently tend to be poorly presented by common MHC alleles and that the capacity of a patient’s MHC alleles to present the resulting neoantigens is predictive of the driver mutations that are observed in their tumor. Here we show that these reports of a strong relationship between driver mutation occurrence and patient MHC alleles are a consequence of unjustified statistical assumptions. Our reanalysis of the data provides no evidence of an effect of MHC genotype on the oncogenic mutation landscape.

scholarly journals The effect of age on the acquisition and selection of cancer driver mutations in sun-exposed normal skin

2020 ◽  
Author(s):  
B. Hernando ◽  
M. Dietzen ◽  
G. Parra ◽  
M. Gil-Barrachina ◽  
G. Pitarch ◽  
...  
Keyword(s):  
Normal Skin ◽  
Driver Mutations ◽  
Cancer Driver ◽  
Effect Of Age ◽  
Selection Of

Identifying Measurement Invariant Item Sets in Cross-Cultural Settings Using an Automated Item Selection Procedure

Methodology ◽  
2018 ◽  
Vol 14 (4) ◽  
pp. 177-188 ◽  
Author(s):  
Martin Schultze ◽  
Michael Eid
Keyword(s):  
Measurement Invariance ◽  
Optimal Solution ◽  
Selection Procedure ◽  
Cross Cultural ◽  
Item Selection ◽  
Ant System ◽  
Item Quality ◽  
Ant System Algorithm ◽  
Selection For ◽  
Selection Of

Abstract. In the construction of scales intended for the use in cross-cultural studies, the selection of items needs to be guided not only by traditional criteria of item quality, but has to take information about the measurement invariance of the scale into account. We present an approach to automated item selection which depicts the process as a combinatorial optimization problem and aims at finding a scale which fulfils predefined target criteria – such as measurement invariance across cultures. The search for an optimal solution is performed using an adaptation of the [Formula: see text] Ant System algorithm. The approach is illustrated using an application to item selection for a personality scale assuming measurement invariance across multiple countries.

ESTIMASI NILAI HERITABILITAS BOBOT IKAN MAS VARIETAS PUNTEN DALAM PROGRAM SELEKSI INDIVIDU

2016 ◽  
Vol 11 (3) ◽  
pp. 217
Author(s):  
Estu Nugroho ◽  
Budi Setyono ◽  
Mochammad Su’eb ◽  
Tri Heru Prihadi
Keyword(s):  
Body Weight ◽  
Selection Response ◽  
Base Population ◽  
Breeding Programs ◽  
Male And Female ◽  
Body Weight Trait ◽  
Population Selection ◽  
Selection For ◽  
Weight Trait ◽  
Selection Of

Program pemuliaan ikan mas varietas Punten dilakukan dengan seleksi individu terhadap karakter bobot ikan. Pembentukan populasi dasar untuk kegiatan seleksi dilakukan dengan memijahkan secara massal induk ikan mas yang terdiri atas 20 induk betina dan 21 induk jantan yang dikoleksi dari daerah Punten, Kepanjen (delapan betina dan enam jantan), Kediri (tujuh betina dan 12 jantan), Sragen (27 betina dan 10 jantan), dan Blitar (15 betina dan 11 jantan). Larva umur 10 hari dipelihara selama empat bulan. Selanjutnya dilakukan penjarangan sebesar 50% dan benih dipelihara selama 14 bulan untuk dilakukan seleksi dengan panduan hasil sampling 250 ekor individu setiap populasi. Seleksi terhadap calon induk dilakukan saat umur 18 bulan pada populasi jantan dan betina secara terpisah dengan memilih berdasarkan 10% bobot ikan yang terbaik. Calon induk yang terseleksi kemudian dipelihara hingga matang gonad, kemudian dipilih sebanyak 150 pasang dan dipijahkan secara massal. Didapatkan respons positif dari hasil seleksi berdasarkan bobot ikan, yaitu 49,89 g atau 3,66% (populasi ikan jantan) dan 168,47 g atau 11,43% (populasi ikan betina). Nilai heritabilitas untuk bobot ikan adalah 0,238 (jantan) dan 0,505 (betina).Punten carp breeding programs were carried out by individual selection for body weight trait. The base population for selection activities were conducted by mass breeding of parent consisted of 20 female and 21 male collected from area Punten, eight female and six male (Kepanjen), seven female and 12 male (Kediri), 27 female and 10 male (Sragen), 15 female and 11 male (Blitar). Larvae 10 days old reared for four moths. Then after spacing out 50% of total harvest, the offspring reared for 14 months for selection activity based on the sampling of 250 individual each population. Selection of broodstock candidates performed since 18 months age on male and female populations separately by selecting based on 10% of fish with best body weight. Candidates selected broodstocks were then maintained until mature. In oder to produce the next generation 150 pairs were sets and held for mass spawning. The results revealed that selection response were positive, 49.89 g (3.66%) for male and 168.47 (11.43%) for female. Heritability for body weight is 0.238 (male) and 0.505 (female).

Sign in / Sign up

Export Citation Format

Share Document