scholarly journals Low rate of somatic mutations in a long-lived oak tree

2017 ◽  
Author(s):  
Namrata Sarkar ◽  
Emanuel Schmid-Siegert ◽  
Christian Iseli ◽  
Sandra Calderon ◽  
Caroline Gouhier-Darimont ◽  
...  
Keyword(s):  
Stem Cells ◽  
Somatic Mutations ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Cell Divisions ◽  
Gamete Formation ◽  
Oak Tree ◽  
Sequential Appearance ◽  
Low Rate ◽  
Shoot Meristems

Because plants do not possess a proper germline, deleterious somatic mutations can be passed to gametes and a large number of cell divisions separating zygote from gamete formation in long-lived plants may lead to many mutations. We sequenced the genome of two terminal branches of a 234-year-old oak tree and found few fixed somatic single-nucleotide variants (SNVs), whose sequential appearance in the tree could be traced along nested sectors of younger branches. Our data suggest that stem cells of shoot meristems are robustly protected from accumulation of mutations in trees.

scholarly journals Genome aging: somatic mutation in the brain links age-related decline with disease and nominates pathogenic mechanisms

2019 ◽  
Vol 28 (R2) ◽  
pp. R197-R206 ◽  
Author(s):  
Michael A Lodato ◽  
Christopher A Walsh
Keyword(s):  
Human Brain ◽  
Somatic Mutation ◽  
Somatic Mutations ◽  
Late Onset ◽  
Whole Genome ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Age Related ◽  
The Brain ◽  
Over Time

AbstractAging is a mysterious process, not only controlled genetically but also subject to random damage that can accumulate over time. While DNA damage and subsequent mutation in somatic cells were first proposed as drivers of aging more than 60 years ago, whether and to what degree these processes shape the neuronal genome in the human brain could not be tested until recent technological breakthroughs related to single-cell whole-genome sequencing. Indeed, somatic single-nucleotide variants (SNVs) increase with age in the human brain, in a somewhat stochastic process that may nonetheless be controlled by underlying genetic programs. Evidence from the literature suggests that in addition to demonstrated increases in somatic SNVs during aging in normal brains, somatic mutation may also play a role in late-onset, sporadic neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. In this review, we will discuss somatic mutation in the human brain, mechanisms by which somatic mutations occur and can be controlled, and how this process can impact human health.

scholarly journals Aging and neurodegeneration are associated with increased mutations in single human neurons

2017 ◽  
Author(s):  
Michael A. Lodato ◽  
Rachel E. Rodin ◽  
Craig L. Bohrson ◽  
Michael E. Coulter ◽  
Alison R. Barton ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Genetic Disorders ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Age Related ◽  
Genome Wide ◽  
Normal Individuals ◽  
Human Neurons ◽  
Regional Specificity ◽  
Associated Conditions

SummaryIt has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. We used single-cell whole-genome sequencing to perform genome-wide somatic single-nucleotide variant (sSNV) identification on DNA from 161 single neurons from the prefrontal cortex and hippocampus of fifteen normal individuals (aged 4 months to 82 years) as well as nine individuals affected by early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome and Xeroderma pigmentosum). sSNVs increased approximately linearly with age in both areas (with a higher rate in hippocampus) and were more abundant in neurodegenerative disease. The accumulation of somatic mutations with age—which we term genosenium—shows age-related, region-related, and disease-related molecular signatures, and may be important in other human age-associated conditions.One-Sentence SummarySomatic single-nucleotide variants accumulate in human neurons in aging with regional specificity and in progeroid diseases.

scholarly journals Controlling homology-directed repair outcomes in human stem cells with dCas9

2021 ◽  
Author(s):  
William C Skarnes ◽  
Gang Ning ◽  
Sofia Giansiracusa ◽  
Alexander S Cruz ◽  
Cornelis Blauwendraat ◽  
...  
Keyword(s):  
Stem Cells ◽  
High Activity ◽  
Human Disease ◽  
Human Stem Cells ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Homology Directed Repair ◽  
Guide Rnas

Modeling human disease in human stem cells requires precise, scarless editing of single nucleotide variants (SNV) on one or both chromosomes. Here we describe improved conditions for Cas9 RNP editing of SNVs that yield high rates of biallelic homology-directed repair. To recover both heterozygous and homozygous SNV clones, catalytically inactive dCas9 was added to moderate high activity Cas9 RNPs. dCas9 can also block re-cutting and damage to SNV alleles engineered with non-overlapping guide RNAs.

scholarly journals Exome sequencing of glioblastoma-derived cancer stem cells reveals rare clinically relevant frameshift deletion in MLLT1 gene

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Hany E. Marei ◽  
Asmaa Althani ◽  
Nahla Afifi ◽  
Anwarul Hasan ◽  
Thomas Caceci ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Allelic Frequency ◽  
Response To Therapy ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Tissue Samples ◽  
Frameshift Deletion ◽  
Prognostic Outcome ◽  
The Common

Abstract Background Glioblastoma multiforme (GBM) is a heterogeneous CNS neoplasm which causes significant morbidity and mortality. One reason for the poor prognostic outcome of GBM is attributed to the presence of cancer stem cells (CSC) which confer resistance against standard chemo- and radiotherapeutics modalities. Two types of GBM-associated CSC were isolated from the same patient: tumor core- (c-CSC) and peritumor tissue-derived cancer stem cells (p-CSC). Our experiments are focused on glioblastoma–IDH-wild type, and no disease-defining alterations were present in histone, BRAF or other genes. Methods In the present study, potential differences in genetic variants between c-CSC versus p-CSC derived from four GBM patients were investigated with the aims of (1) comparing the exome sequences between all the c-CSC or p-CSC to identify the common variants; (2) identifying the variants affecting the function of genes known to be involved in cancer origin and development. Results By comparative analyses, we identified common gene single nucleotide variants (SNV) in all GBM c-CSC and p-CSC, a potentially deleterious variant was a frameshift deletion at Gln461fs in the MLLT1 gene, that was encountered only in p-CSC samples with different allelic frequency. Conclusions We discovered a potentially harmful frameshift deletion at Gln461fs in the MLLT1 gene. Further investigation is required to confirm the presence of the identified mutations in patient tissue samples, as well as the significance of the frameshift mutation in the MLLT1 gene on GBM biology and response to therapy based on genomic functional experiments.

scholarly journals Exome Sequencing of Glioblastoma-Derived Cancer Stem Cells Reveals Rare Clinically Relevant Frameshift Deletion in MLLT1 Gene

2021 ◽  
Author(s):  
Hany Marei ◽  
Asmaa Althani ◽  
Nahla Afifi ◽  
Anwarul Hasan ◽  
Thomas Caceci ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Allelic Frequency ◽  
Common Variants ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Frameshift Deletion ◽  
Prognostic Outcome ◽  
The Common ◽  
Recurrent Nature

Abstract Background: Glioblastoma multiforme (GBM) is a heterogeneous CNS neoplasm which causes significant morbidity and mortality. One reason for the poor prognostic outcome of GBM is attributed to the presence of cancer stem cells (CSC) which confer resistance against standard chemo- and radiotherapeutics modalities. Two types of GBM-associated CSC were isolated from the same patient: tumor core- (c-CSC) and peritumor tissue-derived cancer stem cells (p-CSC).Methods: In the present study, potential differences in genetic variants between c-CSC versus p-CSC derived from four GBM patients were investigated with the aims of 1) comparing the exome sequences between all the c-CSC or p-CSC to identify the common variants; 2) identifying the variants affecting the function of genes known to be involved in cancer origin and development.Results: By comparative analyses, we identified common gene single nucleotide variants (SNV) in all GBM c-CSC and p-CSC, a potentially deleterious variant was a frameshift deletion at Gln461fs in the MLLT1 gene, that was encountered only in p-CSC samples with different allelic frequency.Conclusions: Our study supports the hypothesis that the varied genetic composition of GBM-associated c-CSC and p-CSC may be involved in different therapeutic responses or the recurrent nature of GBM.

Genomic predictors of neoadjuvant chemotherapy (NACT) response in breast cancer (BC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12122-e12122 ◽  
Author(s):  
Andrea Li Ann Wong ◽  
Kar Tong Tan ◽  
Raghav Sundar ◽  
Samuel Ow ◽  
Angela Pang ◽  
...  
Keyword(s):  
Low Dose ◽  
Somatic Mutations ◽  
Target Lesion ◽  
Driver Mutations ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Mutant Variant ◽  
Poor Outcomes ◽  
Clinical Trial Information

e12122 Background: We assessed effects of NACT on BC mutational landscape. Methods: Baseline (BL) and post-NACT tumor / matched normal DNA from 12 newly diagnosed BC patients on NACT (4 x doxorubicin/cyclophosphamide + low dose sunitinib; NCT01176799) were subject to whole exome sequencing. Nonsynonymous somatic single nucleotide variants from 34 genes in known BC signaling pathways were evaluated for changes in mutant variant allele frequency (VAF) according to clinical outcome. Poor outcome was defined as <50% target lesion reduction after NACT or BC relapse / progression (PD) within 2 years; significant change was defined as > 0.2 difference in BL vs post-NACT mutant VAF. Results: Mean tumor size was 6.4 + 2.9cm; 50% were N+; 8% were M1; 7/12 patients had poor outcomes. Tumors harbored mutations in PI3K (58%), NOTCH (42%), Wnt (42%), TP53 (33%) and FOXA (17%) pathways. Change in no. of somatic mutations post-NACT correlated with outcome (mean percent change +14% vs -30% in patients with poor vs good outcome, p=0.04). 11 patients had >1 of 23 putative driver mutations identified ( Table 1). Mutant VAF declined significantly in those with good outcomes, except for a new NOTCH2 mutation in A2 and rise in mutant VAF in A4. In patients with poor outcomes, mutant VAF persisted or rose, and emergent mutations (AKT1, PIK3CA) occurred in 2 patients. Conclusions: Chemoresistance and emergent mutations were revealed by tracking mutant VAF in BC patients on NACT. Clinical trial information: NCT01176799. [Table: see text]

scholarly journals ProTECT – Prediction of T-cell Epitopes for Cancer Therapy

2019 ◽  
Author(s):  
Arjun A. Rao ◽  
Ada A. Madejska ◽  
Jacob Pfeil ◽  
Benedict Paten ◽  
Sofie R. Salama ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Cytotoxic T Cells ◽  
T Cell Epitopes ◽  
Sequencing Data ◽  
Single Nucleotide Variants ◽  
Binding Prediction ◽  
Local Cluster ◽  
Single Nucleotide ◽  
Protein Coding ◽  
Cell Therapies

AbstractSomatic mutations in cancers affecting protein coding genes can give rise to potentially therapeutic neoepitopes. These neoepitopes can guide Adoptive Cell Therapies (ACTs) and Peptide Vaccines (PVs) to selectively target tumor cells using autologous patient cytotoxic T-cells. Currently, researchers have to independently align their data, call somatic mutations and haplotype the patient’s HLA to use existing neoepitope prediction tools. We present ProTECT, a fully automated, reproducible, scalable, and efficient end-to-end analysis pipeline to identify and rank therapeutically relevant tumor neoepitopes in terms of immunogenicity starting directly from raw patient sequencing data, or from pre-processed data. The ProTECT pipeline encompasses alignment, HLA haplotyping, mutation calling (single nucleotide variants, short insertions and deletions, and gene fusions), peptide:MHC (pMHC) binding prediction, and ranking of final candidates. We demonstrate ProTECT on 326 samples from the TCGA Prostate Adenocarcinoma cohort, and compare it with published tools. ProTECT can be run on a standalone computer, a local cluster, or on a compute cloud using a Mesos backend. ProTECT is highly scalable and can process TCGA data in under 30 minutes per sample when run in large batches. ProTECT is freely available at https://www.github.com/BD2KGenomics/protect.

scholarly journals Somatic mutation in single human neurons tracks developmental and transcriptional history

Science ◽  
2015 ◽  
Vol 350 (6256) ◽  
pp. 94-98 ◽  
Author(s):  
Michael A. Lodato ◽  
Mollie B. Woodworth ◽  
Semin Lee ◽  
Gilad D. Evrony ◽  
Bhaven K. Mehta ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Somatic Mutations ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Single Cell Sequencing ◽  
Normal Individuals ◽  
Human Neurons ◽  
Active Transcription ◽  
Lineage Trees ◽  
The Brain

Neurons live for decades in a postmitotic state, their genomes susceptible to DNA damage. Here we survey the landscape of somatic single-nucleotide variants (SNVs) in the human brain. We identified thousands of somatic SNVs by single-cell sequencing of 36 neurons from the cerebral cortex of three normal individuals. Unlike germline and cancer SNVs, which are often caused by errors in DNA replication, neuronal mutations appear to reflect damage during active transcription. Somatic mutations create nested lineage trees, allowing them to be dated relative to developmental landmarks and revealing a polyclonal architecture of the human cerebral cortex. Thus, somatic mutations in the brain represent a durable and ongoing record of neuronal life history, from development through postmitotic function.

scholarly journals Investigation of somatic mutations in human brains targeting genes associated with Parkinson's disease

2020 ◽  
Author(s):  
Melissa Leija-Salazar ◽  
Alan Pittman ◽  
Katya Mokretar ◽  
Huw Morris ◽  
Anthony HV Schapira ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Monozygotic Twin ◽  
Brain Regions ◽  
Somatic Variation ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Somatic Variant ◽  
Lrrk2 G2019s ◽  
Variant Detection ◽  
Human Brains

Background: Somatic mutations occur in neurons but their role in synucleinopathies is unknown. Aim: We aimed to identify disease-relevant low-level somatic single nucleotide variants (SNVs) in brains from sporadic patients with synucleinopathies and a monozygotic twin carrying LRRK2 G2019S, whose penetrance could be explained by somatic variation. Methods and Results: We included different brain regions from 26 Parkinsons disease (PD), 1 Incidental Lewy body, 3 multiple system atrophy cases and 12 controls. The whole SNCA locus and exons of other genes associated with PD and neurodegeneration were deeply sequenced using molecular barcodes to improve accuracy. We selected 21 variants at 0.33-5% allele frequencies for validation using accurate methods for somatic variant detection. Conclusions: We could not detect disease-relevant somatic SNVs, however we cannot exclude their presence at earlier stages of degeneration. Our results support that coding somatic SNVs in neurodegeneration are rare, but other types of somatic variants may hold pathological consequences in synucleinopathies.

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