scholarly journals Dinucleotide Repeats in the Drosophila and Human Genomes Have Complex, Length-Dependent Mutation Processes

2003 ◽  
Vol 20 (5) ◽  
pp. 715-725 ◽  
Author(s):  
P. Calabrese
Keyword(s):  
Dinucleotide Repeats ◽  
Human Genomes ◽  
Complex Length

scholarly journals A study of transposable element-associated structural variations (TASVs) using a de novo-assembled Korean genome

2021 ◽  
Author(s):  
Seyoung Mun ◽  
Songmi Kim ◽  
Wooseok Lee ◽  
Keunsoo Kang ◽  
Thomas J. Meyer ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Genome Assembly ◽  
De Novo ◽  
Personal Genome ◽  
Human Populations ◽  
Whole Genome ◽  
Structural Variations ◽  
Insert Size ◽  
Human Genomes ◽  
Next Generation Sequencing Ngs

AbstractAdvances in next-generation sequencing (NGS) technology have made personal genome sequencing possible, and indeed, many individual human genomes have now been sequenced. Comparisons of these individual genomes have revealed substantial genomic differences between human populations as well as between individuals from closely related ethnic groups. Transposable elements (TEs) are known to be one of the major sources of these variations and act through various mechanisms, including de novo insertion, insertion-mediated deletion, and TE–TE recombination-mediated deletion. In this study, we carried out de novo whole-genome sequencing of one Korean individual (KPGP9) via multiple insert-size libraries. The de novo whole-genome assembly resulted in 31,305 scaffolds with a scaffold N50 size of 13.23 Mb. Furthermore, through computational data analysis and experimental verification, we revealed that 182 TE-associated structural variation (TASV) insertions and 89 TASV deletions contributed 64,232 bp in sequence gain and 82,772 bp in sequence loss, respectively, in the KPGP9 genome relative to the hg19 reference genome. We also verified structural differences associated with TASVs by comparative analysis with TASVs in recent genomes (AK1 and TCGA genomes) and reported their details. Here, we constructed a new Korean de novo whole-genome assembly and provide the first study, to our knowledge, focused on the identification of TASVs in an individual Korean genome. Our findings again highlight the role of TEs as a major driver of structural variations in human individual genomes.

scholarly journals NGS-based identification and tracing of microsatellite instability from minute amounts DNA using inter-Alu-PCR

2020 ◽  
Author(s):  
Fangyan Yu ◽  
Ka Wai Leong ◽  
Alexander Makrigiorgos ◽  
Viktor A Adalsteinsson ◽  
Ioannis Ladas ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Analysis Tool ◽  
Circulating Dna ◽  
Liquid Biopsies ◽  
Software Analysis ◽  
Multiplexed Pcr ◽  
Human Genomes ◽  
Custom Made ◽  
Alu Element ◽  
Next Generation Sequencing Ngs

Abstract Sensitive detection of microsatellite instability (MSI) in tissue or liquid biopsies using next generation sequencing (NGS) has growing prognostic and predictive applications in cancer. However, the complexities of NGS make it cumbersome as compared to established multiplex-PCR detection of MSI. We present a new approach to detect MSI using inter-Alu-PCR followed by targeted NGS, that combines the practical advantages of multiplexed-PCR with the breadth of information provided by NGS. Inter-Alu-PCR employs poly-adenine repeats of variable length present in every Alu element and provides a massively-parallel, rapid approach to capture poly-A-rich genomic fractions within short 80–150bp amplicons generated from adjacent Alu-sequences. A custom-made software analysis tool, MSI-tracer, enables Alu-associated MSI detection from tissue biopsies or MSI-tracing at low-levels in circulating-DNA. MSI-associated indels at somatic-indel frequencies of 0.05–1.5% can be detected depending on the availability of matching normal tissue and the extent of instability. Due to the high Alu copy-number in human genomes, a single inter-Alu-PCR retrieves enough information for identification of MSI-associated-indels from ∼100 pg circulating-DNA, reducing current limits by ∼2-orders of magnitude and equivalent to circulating-DNA obtained from finger-sticks. The combined practical and informational advantages of inter-Alu-PCR make it a powerful tool for identifying tissue-MSI-status or tracing MSI-associated-indels in liquid biopsies.

scholarly journals Mechanisms of Dinucleotide Repeat Instability in Escherichia coli

Genetics ◽  
2000 ◽  
Vol 154 (2) ◽  
pp. 533-542
Author(s):  
Marc Bichara ◽  
Isabelle Pinet ◽  
Sylvie Schumacher ◽  
Robert P P Fuchs
Keyword(s):  
Escherichia Coli ◽  
Mismatch Repair ◽  
Genetic Instability ◽  
Positional Cloning ◽  
Dinucleotide Repeats ◽  
Disease Pathogenesis ◽  
Complementary Sequence ◽  
Phylogenetic Studies ◽  
High Level

Abstract The high level of polymorphism of microsatellites has been used for a variety of purposes such as positional cloning of genes associated with diseases, forensic medicine, and phylogenetic studies. The discovery that microsatellites are associated with human diseases, not only as markers of risk but also directly in disease pathogenesis, has triggered a renewed interest in understanding the mechanism of their instability. In this work we have investigated the role of DNA replication, long patch mismatch repair, and transcription on the genetic instability of all possible combinations of dinucleotide repeats in Escherichia coli. We show that the (GpC) and (ApT) self-complementary sequence repeats are the most unstable and that the mode of replication plays an important role in their instability. We also found that long patch mismatch repair is involved in avoiding both short deletion and expansion events and also in instabilities resulting from the processing of bulges of 6 to 8 bp for the (GpT/ApC)- and (ApG/CpT)-containing repeats. For each dinucleotide sequence repeat, we propose models for instability that involve the possible participation of unusual secondary structures.

Determination of the Number of Conserved Chromosomal Segments Between Species

Genetics ◽  
2001 ◽  
Vol 157 (3) ◽  
pp. 1387-1395 ◽  
Author(s):  
Sudhir Kumar ◽  
Sudhindra R Gadagkar ◽  
Alan Filipski ◽  
Xun Gu
Keyword(s):  
Statistical Approach ◽  
Common Ancestor ◽  
Chromosomal Rearrangements ◽  
Structural Similarity ◽  
The Other ◽  
Segment Length ◽  
Human Genomes ◽  
Genomic Divergence ◽  
Human And Mouse

AbstractGenomic divergence between species can be quantified in terms of the number of chromosomal rearrangements that have occurred in the respective genomes following their divergence from a common ancestor. These rearrangements disrupt the structural similarity between genomes, with each rearrangement producing additional, albeit shorter, conserved segments. Here we propose a simple statistical approach on the basis of the distribution of the number of markers in contiguous sets of autosomal markers (CSAMs) to estimate the number of conserved segments. CSAM identification requires information on the relative locations of orthologous markers in one genome and only the chromosome number on which each marker resides in the other genome. We propose a simple mathematical model that can account for the effect of the nonuniformity of the breakpoints and markers on the observed distribution of the number of markers in different conserved segments. Computer simulations show that the number of CSAMs increases linearly with the number of chromosomal rearrangements under a variety of conditions. Using the CSAM approach, the estimate of the number of conserved segments between human and mouse genomes is 529 ± 84, with a mean conserved segment length of 2.8 cM. This length is <40% of that currently accepted for human and mouse genomes. This means that the mouse and human genomes have diverged at a rate of ∼1.15 rearrangements per million years. By contrast, mouse and rat are diverging at a rate of only ∼0.74 rearrangements per million years.

scholarly journals A Mutation of the Yeast Gene Encoding PCNA Destabilizes Both Microsatellite and Minisatellite DNA Sequences

Genetics ◽  
1999 ◽  
Vol 151 (2) ◽  
pp. 511-519 ◽  
Author(s):  
Robert J Kokoska ◽  
Lela Stefanovic ◽  
Andrew B Buermeyer ◽  
R Michael Liskay ◽  
Thomas D Petes
Keyword(s):  
Dna Polymerase ◽  
Repetitive Dna ◽  
Dna Sequences ◽  
Repeat Unit ◽  
Nuclear Antigen ◽  
Temperature Sensitive ◽  
Dinucleotide Repeats ◽  
Yeast Saccharomyces Cerevisiae ◽  
Dna Polymerase Δ ◽  
Repeat Units

AbstractThe POL30 gene of the yeast Saccharomyces cerevisiae encodes the proliferating cell nuclear antigen (PCNA), a protein required for processive DNA synthesis by DNA polymerase δ and ϵ. We examined the effects of the pol30-52 mutation on the stability of microsatellite (1- to 8-bp repeat units) and minisatellite (20-bp repeat units) DNA sequences. It had previously been shown that this mutation destabilizes dinucleotide repeats 150-fold and that this effect is primarily due to defects in DNA mismatch repair. From our analysis of the effects of pol30-52 on classes of repetitive DNA with longer repeat unit lengths, we conclude that this mutation may also elevate the rate of DNA polymerase slippage. The effect of pol30-52 on tracts of repetitive DNA with large repeat unit lengths was similar, but not identical, to that observed previously for pol3-t, a temperature-sensitive mutation affecting DNA polymerase δ. Strains with both pol30-52 and pol3-t mutations grew extremely slowly and had minisatellite mutation rates considerably greater than those observed in either single mutant strain.

scholarly journals MODL-21. INTEGRATIVE APPROACHES IN FUNCTIONAL GENOMICS TO IDENTIFY GENETIC DEPENDENCIES IN PEDIATRIC BRAIN CANCER

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii415-iii415
Author(s):  
Claire Sun ◽  
Caroline Drinkwater ◽  
Dhanya Sooraj ◽  
Gabrielle Bradshaw ◽  
Claire Shi ◽  
...  
Keyword(s):  
Functional Genomics ◽  
Precision Medicine ◽  
Brain Cancer ◽  
Human Genomes ◽  
Pediatric Cancer Patients ◽  
Crispr Screen ◽  
The Central Nervous System ◽  
Molecular Aberrations ◽  
Genetic Profiles ◽  
Pediatric Brain

Abstract The precise decoding of human genomes facilitated by the advancements in next-generation sequencing has led to a better understanding of genetic underpinnings of pediatric brain cancers. Indeed, it is now evident that tumours of the same type harbour distinct driving mutations and molecular aberrations that can result in different prognosis and treatment outcomes. The profounder insight into the the identity, amount and types of molecular aberrations has paved the way for the advent of targeted therapies in precision medicine. Nevertheless, less than 10% of pediatric cancer patients harbour actionable mutations. Strictly limited therapeutic options that are firstly available for brain cancers and secondly acceptable for children’s development further impede the breakthrough in the survival rate in pediatric brain cancers. This underscores a desperate need to delve beyond genomic sequencing to identify biomarker coupled therapies that not only featured with treatment efficacy in the central nervous system but also acceptable side effects for children. The Hudson-Monash Paediatric Precision Medicine (HMPPM) Program focuses on utilising genetic profiles of patients’ tumour models to identify new therapeutic targets and repurpose existing ones using high-throughput functional genomics screens (2220 drugs and CRISPR screen of 300 oncogenic genes). Using a large compendium of over sixty patient derived paediatric brain cancer models, we provide proof-of-concept data that shows an integrative pipeline for functional genomics with multi-omics datasets to perform genotype-phenotype correlations and, therefore, identify genetic dependencies. Herein, using several examples in ATRT, DIPG and HGG, we show how functional interrogations can better define molecular subclassification of tumours and identify unique vulnerabilities.

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