Somatic Variation and Multiple Neurofibromatosis

E.M. Nicholls

doi:10.1159/000152255

Genomic Mosaicism Formed by Somatic Variation in the Aging and Diseased Brain

Genes ◽

10.3390/genes12071071 ◽

2021 ◽

Vol 12 (7) ◽

pp. 1071

Author(s):

Isabel Costantino ◽

Juliet Nicodemus ◽

Jerold Chun

Keyword(s):

Dna Sequence ◽

Technology Development ◽

Copy Number Variations ◽

Brain Cell ◽

Brain Diseases ◽

Multiple Forms ◽

Somatic Variation ◽

Dna Content Variation ◽

Effects Of Aging ◽

The Brain

Over the past 20 years, analyses of single brain cell genomes have revealed that the brain is composed of cells with myriad distinct genomes: the brain is a genomic mosaic, generated by a host of DNA sequence-altering processes that occur somatically and do not affect the germline. As such, these sequence changes are not heritable. Some processes appear to occur during neurogenesis, when cells are mitotic, whereas others may also function in post-mitotic cells. Here, we review multiple forms of DNA sequence alterations that have now been documented: aneuploidies and aneusomies, smaller copy number variations (CNVs), somatic repeat expansions, retrotransposons, genomic cDNAs (gencDNAs) associated with somatic gene recombination (SGR), and single nucleotide variations (SNVs). A catch-all term of DNA content variation (DCV) has also been used to describe the overall phenomenon, which can include multiple forms within a single cell’s genome. A requisite step in the analyses of genomic mosaicism is ongoing technology development, which is also discussed. Genomic mosaicism alters one of the most stable biological molecules, DNA, which may have many repercussions, ranging from normal functions including effects of aging, to creating dysfunction that occurs in neurodegenerative and other brain diseases, most of which show sporadic presentation, unlinked to causal, heritable genes.

Download Full-text

Short and long-read genome sequencing methodologies for somatic variant detection; genomic analysis of a patient with diffuse large B-cell lymphoma

Scientific Reports ◽

10.1038/s41598-021-85354-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hannah E. Roberts ◽

Maria Lopopolo ◽

Alistair T. Pagnamenta ◽

Eshita Sharma ◽

Duncan Parkes ◽

...

Keyword(s):

B Cell ◽

Genome Sequencing ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Somatic Variation ◽

Single Nucleotide Variants ◽

Germline Variants ◽

Specificity And Sensitivity ◽

Long Reads ◽

Long Read

AbstractRecent advances in throughput and accuracy mean that the Oxford Nanopore Technologies PromethION platform is a now a viable solution for genome sequencing. Much of the validation of bioinformatic tools for this long-read data has focussed on calling germline variants (including structural variants). Somatic variants are outnumbered many-fold by germline variants and their detection is further complicated by the effects of tumour purity/subclonality. Here, we evaluate the extent to which Nanopore sequencing enables detection and analysis of somatic variation. We do this through sequencing tumour and germline genomes for a patient with diffuse B-cell lymphoma and comparing results with 150 bp short-read sequencing of the same samples. Calling germline single nucleotide variants (SNVs) from specific chromosomes of the long-read data achieved good specificity and sensitivity. However, results of somatic SNV calling highlight the need for the development of specialised joint calling algorithms. We find the comparative genome-wide performance of different tools varies significantly between structural variant types, and suggest long reads are especially advantageous for calling large somatic deletions and duplications. Finally, we highlight the utility of long reads for phasing clinically relevant variants, confirming that a somatic 1.6 Mb deletion and a p.(Arg249Met) mutation involving TP53 are oriented in trans.

Download Full-text

Recovery of Somatic Variation in Resistance of Populus to Septoria Musiva

Plant Aging ◽

10.1007/978-1-4684-5760-5_13 ◽

1990 ◽

pp. 113-116 ◽

Cited By ~ 2

Author(s):

M. E. Ostry ◽

D. D. Skilling ◽

O. Y. Lee-Stadelmann ◽

W. P. Hackett

Keyword(s):

Somatic Variation ◽

Septoria Musiva

Download Full-text

Origins and Consequences of Somatic Variation in Grapevine

Genetics, Genomics, and Breeding of Grapes ◽

10.1201/b10948-8 ◽

2016 ◽

pp. 96-120 ◽

Cited By ~ 21

Keyword(s):

Somatic Variation

Download Full-text

Sensitive detection of DNA contamination in tumor samples via microhaplotypes

10.1101/2020.12.18.423488 ◽

2020 ◽

Author(s):

Brett Whitty ◽

John F. Thompson

Keyword(s):

Sequence Data ◽

Accurate Determination ◽

Sensitive Detection ◽

European Ancestry ◽

Somatic Variation ◽

Dna Mixtures ◽

Accurate Identification ◽

Sample Contamination ◽

Dna Contamination ◽

Low Levels

AbstractBackgroundLow levels of sample contamination can have disastrous effects on the accurate identification of somatic variation in tumor samples. Detection of sample contamination in DNA is generally based on observation of low frequency variants that suggest more than a single source of DNA is present. This strategy works with standard DNA samples but is especially problematic in solid tumor FFPE samples because there can be huge variations in allele frequency (AF) due to massive copy number changes arising from large gains and losses across the genome. The tremendously variable allele frequencies make detection of contamination challenging. A method not based on individual AF is needed for accurate determination of whether a sample is contaminated and to what degree.MethodsWe used microhaplotypes to determine whether sample contamination is present. Microhaplotypes are sets of variants on the same sequencing read that can be unambiguously phased. Instead of measuring AF, the number and frequency of microhaplotypes is determined. Contamination detection becomes based on fundamental genomic properties, linkage disequilibrium (LD) and the diploid nature of human DNA, rather than variant frequencies. We optimized microhaplotype content based on 164 single nucleotide variant sets located in genes already sequenced within a cancer panel. Thus, contamination detection uses existing sequence data and does not require sequencing of any extraneous regions. The content is chosen based on LD data from the 1000 Genomes Project to be ancestry agnostic, providing the same sensitivity for contamination detection with samples from individuals of African, East Asian, and European ancestry.ResultsDetection of contamination at 1% and below is possible using this design. The methods described here can also be extended to other DNA mixtures such as forensic and non-invasive prenatal testing samples where DNA mixes of 1% or less can be similarly detected.ConclusionsThe microhaplotype method allows sensitive detection of DNA contamination in FFPE tumor samples. These methods provide a foundation for examining DNA mixtures in a variety of contexts. With the appropriate panels and high sequencing depth, low levels of secondary DNA can be detected and this can be valuable in a variety of applications.

Download Full-text

A unified haplotype-based method for accurate and comprehensive variant calling

10.1101/456103 ◽

2018 ◽

Cited By ~ 3

Author(s):

Daniel P Cooke ◽

David C Wedge ◽

Gerton Lunter

Keyword(s):

De Novo ◽

Variant Calling ◽

Normal Sample ◽

Sequencing Data ◽

Somatic Variation ◽

Data Set ◽

Small Complex ◽

Physical Linkage ◽

Germline Variation ◽

Almost All

Haplotype-based variant callers, which consider physical linkage between variant sites, are currently among the best tools for germline variation discovery and genotyping from short-read sequencing data. However, almost all such tools were designed specifically for detecting common germline variation in diploid populations, and give sub-optimal results in other scenarios. Here we present Octopus, a versatile haplotype-based variant caller that uses a polymorphic Bayesian genotyping model capable of modeling sequencing data from a range of experimental designs within a unified haplotype-aware framework. We show that Octopus accurately calls de novo mutations in parent-offspring trios and germline variants in individuals, including SNVs, indels, and small complex replacements such as microinversions. In addition, using a carefully designed synthetic-tumour data set derived from clean sequencing data from a sample with known germline haplotypes, and observed mutations in large cohort of tumour samples, we show that Octopus accurately characterizes germline and somatic variation in tumours, both with and without a paired normal sample. Sequencing reads and prior information are combined to phase called genotypes of arbitrary ploidy, including those with somatic mutations. Octopus also outputs realigned evidence BAMs to aid validation and interpretation.

Download Full-text

Human brain harbors single nucleotide somatic variations in functionally relevant genes possibly mediated by oxidative stress

F1000Research ◽

10.12688/f1000research.9495.1 ◽

2016 ◽

Vol 5 ◽

pp. 2520 ◽

Cited By ~ 1

Author(s):

Anchal Sharma ◽

Asgar Hussain Ansari ◽

Renu Kumari ◽

Rajesh Pandey ◽

Rakhshinda Rehman ◽

...

Keyword(s):

Oxidative Stress ◽

Corpus Callosum ◽

Human Brain ◽

Frontal Cortex ◽

Oxidative Stress Marker ◽

Somatic Variation ◽

Single Nucleotide ◽

Normal Human Brain ◽

Normal Human ◽

The Brain

Somatic variation in DNA can cause cells to deviate from the preordained genomic path in both disease and healthy conditions. Here, using exome sequencing of paired tissue samples, we show that the normal human brain harbors somatic single base variations measuring up to 0.48% of the total variations. Interestingly, about 64% of these somatic variations in the brain are expected to lead to non-synonymous changes, and as much as 87% of these represent G:C>T:A transversion events. Further, the transversion events in the brain were mostly found in the frontal cortex, whereas the corpus callosum from the same individuals harbors the reference genotype. We found a significantly higher amount of 8-OHdG (oxidative stress marker) in the frontal cortex compared to the corpus callosum of the same subjects (p<0.01), correlating with the higher G:C>T:A transversions in the cortex. We found significant enrichment for axon guidance and related pathways for genes harbouring somatic variations. This could represent either a directed selection of genetic variations in these pathways or increased susceptibility of some loci towards oxidative stress. This study highlights that oxidative stress possibly influence single nucleotide somatic variations in normal human brain.

Download Full-text