scholarly journals Copy number evolution in simple and complex tandem repeats across the C57BL/6 and C57BL/10 inbred mouse lines

2021 ◽  
Author(s):  
Jullien M Flynn ◽  
Emily J Brown ◽  
Andrew G Clark
Keyword(s):  
Copy Number ◽  
Copy Number Change ◽  
Tandem Repeats ◽  
Inbred Mouse ◽  
Rate Of Change ◽  
Rates Of Change ◽  
Centromeric Repeat ◽  
Genome Wide ◽  
Copy Number Changes ◽  
Simple Repeats

Abstract Simple sequence tandem repeats are among the most rapidly evolving compartments of the genome. Some repeat expansions are associated with mammalian disease or meiotic segregation distortion, yet the rates of copy number change across generations are not well known. Here, we use 14 distinct sub-lineages of the C57BL/6 and C57BL/10 inbred mouse strains, which have been evolving independently over about 300 generations, to estimate the rates of copy number changes in genome-wide tandem repeats. Rates of change varied across repeats and across lines. Notably, CAG, whose expansions in coding regions are associated with many neurological and genetic disorders, was highly stable in copy number, likely indicating stabilizing selection. Rates of change were positively correlated with copy number, but the direction and magnitude of changes varied across lines. Some mouse lines experienced consistent losses or gains across most simple repeats, but this did not correlate with copy number changes in complex repeats. Rates of copy number change were similar between simple repeats and the more abundant complex repeats after normalization by copy number. Finally, the Y-specific centromeric repeat had a 4-fold higher rate of change than the homologous centromeric repeat on other chromosomes. Structural differences in satellite complexity, or restriction to the Y chromosome and elevated mutation rates of the male germline, may explain the higher rate of change. Overall, our work underscores the mutational fluidity of long tandem arrays of repeats, and the correlations and constraints between genome-wide tandem repeats which suggest that turnover is not a completely neutral process.

scholarly journals Copy number evolution in simple and complex tandem repeats across the C57BL/6 and C57BL/10 inbred mouse lines

2021 ◽  
Author(s):  
Jullien M. Flynn ◽  
Emily J. Brown ◽  
Andrew G. Clark
Keyword(s):  
Copy Number ◽  
Copy Number Change ◽  
Tandem Repeats ◽  
Inbred Mouse ◽  
Rate Of Change ◽  
Rates Of Change ◽  
Centromeric Repeat ◽  
Genome Wide ◽  
Copy Number Changes ◽  
Simple Repeats

AbstractSimple sequence tandem repeats are among the most rapidly evolving compartments of the genome. Some repeat expansions are associated with mammalian disease or meiotic segregation distortion, yet the rates of copy number change across generations are not well known. Here, we use 14 distinct sub-lineages of the C57BL/6 and C57BL/10 inbred mouse strains, which have been evolving independently over about 300 generations, to estimate the rates of copy number changes in genome-wide tandem repeats. Rates of change varied across simple repeats and across lines. Notably, CAG, whose expansions in coding regions are associated with many neurological and other genetic disorders, was highly stable in copy number, likely indicating purifying selection. Rates of change were generally positively correlated with copy number, but the direction and magnitude of changes varied across lines. Some mouse lines experienced consistent losses or gains across most genome-wide simple repeats, but this did not correlate with copy number changes in complex repeats. Rates of copy number change were similar between simple repeats and the much more abundant complex repeats once they were normalized by copy number. Finally, the Y-specific centromeric repeat had a 4-fold higher rate of change than the homologous centromeric repeat on other chromosomes. Structural differences in satellite complexity, or restriction to the Y chromosome and the elevated mutation rate of the male germline, may explain the higher rate of change. Overall, our work underscores the mutational fluidity of long tandem arrays of repeats, and the correlations and constraints between genome-wide tandem repeats which suggest that turnover is not a completely neutral process.

scholarly journals Genome-wide patterns of de novo tandem repeat mutations and their contribution to autism spectrum disorders

2020 ◽  
Author(s):  
Ileena Mitra ◽  
Bonnie Huang ◽  
Nima Mousavi ◽  
Nichole Ma ◽  
Michael Lamkin ◽  
...  
Keyword(s):  
Copy Number ◽  
Tandem Repeats ◽  
De Novo ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Genome Wide ◽  
A Genome ◽  
Wide Scale ◽  
Copy Number Changes

Autism Spectrum Disorder (ASD) is an early onset developmental disorder characterized by deficits in communication and social interaction and restrictive or repetitive behaviors1,2. Family studies demonstrate that ASD has a significant genetic basis3 with contributions both from inherited and de novo variants. While the majority of variance in liability to ASD is estimated to arise from common genetic variation4, it has been estimated that de novo mutations may contribute to 30% of all simplex cases, in which only a single child is affected per family5. Tandem repeats (TRs), consisting of approximately 1-20bp motifs repeated in tandem, comprise one of the largest sources of de novo mutations in humans6. Yet, largely due to technical challenges they present, de novo TR mutations have not yet been characterized on a genome-wide scale, and their contribution to ASD remains unexplored. Here, we develop novel bioinformatics tools for identifying and prioritizing de novo TR mutations from whole genome sequencing (WGS) data and use these to perform a genome-wide characterization of de novo TR mutations in ASD-affected probands and unaffected siblings. Compared to recent work on TRs in ASD7, we explicitly infer mutation events and their precise changes in repeat copy number, and primarily focus on more prevalent stepwise copy number changes rather than large or complex expansions. Our results demonstrate a significant genome-wide excess of TR mutations in ASD probands. TR mutations in probands tend to be larger, enriched in fetal brain regulatory regions, and predicted to be more evolutionarily deleterious compared to mutations observed in unaffected siblings. Overall, our results highlight the importance of considering repeat variants in future studies of de novo mutations.

scholarly journals Replication Stress Induces Genome-wide Copy Number Changes in Human Cells that Resemble Polymorphic and Pathogenic Variants

2009 ◽  
Vol 84 (3) ◽  
pp. 339-350 ◽  
Author(s):  
Martin F. Arlt ◽  
Jennifer G. Mulle ◽  
Valerie M. Schaibley ◽  
Ryan L. Ragland ◽  
Sandra G. Durkin ◽  
...  
Keyword(s):  
Copy Number ◽  
Replication Stress ◽  
Human Cells ◽  
Pathogenic Variants ◽  
Genome Wide ◽  
Copy Number Changes

Abstract 2018: Genome-wide analysis of DNA methylation and copy number changes in breast cancers.

2013 ◽  
Author(s):  
Olafur A. Stefansson ◽  
Sebastian Moran ◽  
Antonio Gomez ◽  
Sergi Sayols Puig ◽  
Jorunn Eyfjord ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Breast Cancers ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Copy Number Changes

scholarly journals Genetic Profile of Adenoid Cystic Carcinomas (ACC) with High-Grade Transformation versus Solid Type

2010 ◽  
Vol 33 (5-6) ◽  
pp. 217-228 ◽  
Author(s):  
Ana Flávia Costa ◽  
Albina Altemani ◽  
Hedy Vékony ◽  
Elisabeth Bloemena ◽  
Florentino Fresno ◽  
...  
Keyword(s):  
Copy Number ◽  
Genetic Profile ◽  
High Grade ◽  
Ki 67 ◽  
Genetic Changes ◽  
Genome Wide ◽  
Genetic Complexity ◽  
Poorly Differentiated ◽  
High Grade Transformation ◽  
Copy Number Changes

Background: ACC can occasionally undergo dedifferentiation also referred to as high-grade transformation (ACC-HGT). However, ACC-HGT can also undergo transformation to adenocarcinomas which are not poorly differentiated. ACC-HGT is generally considered to be an aggressive variant of ACC, even more than solid ACC. This study was aimed to describe the genetic changes of ACC-HGT in relation to clinico-pathological features and to compare results to solid ACC.Methods: Genome-wide DNA copy number changes were analyzed by microarray CGH in ACC-HGT, 4 with transformation into moderately differentiated adenocarcinoma (MDA) and two into poorly differentiated carcinoma (PDC), 5 solid ACC. In addition, Ki-67 index and p53 immunopositivity was assessed.Results: ACC-HGT carried fewer copy number changes compared to solid ACC. Two ACC-HGT cases harboured a breakpoint at 6q23, near the cMYB oncogene. The complexity of the genomic profile concurred with the clinical course of the patient. Among the ACC-HGT, p53 positivity significantly increased from the conventional to the transformed (both MDA and PDC) component.Conclusion: ACC-HGT may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form in which the poorly differentiated forms (PDC) presents a genetic complexity similar to the solid ACC.

scholarly journals Genomic Profiling by Array Comparative Genomic Hybridization Reveals Novel DNA Copy Number Changes in Breast Phyllodes Tumours

2009 ◽  
Vol 31 (1) ◽  
pp. 31-39
Author(s):  
Arno Kuijper ◽  
Antoine M. Snijders ◽  
Els M. J. J. Berns ◽  
Vibeke Kuenen-Boumeester ◽  
Elsken van der Wall ◽  
...  
Keyword(s):  
Comparative Genomic Hybridization ◽  
Copy Number ◽  
Array Comparative Genomic Hybridization ◽  
Copy Number Change ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Genomic Profiling ◽  
Genomic Hybridization ◽  
Dna Copy Number ◽  
Copy Number Changes

Breast phyllodes tumour (PT) is a rare fibroepithelial tumour. The genetic alterations contributing to its tumorigenesis are largely unknown. To identify genomic regions involved in pathogenesis and progression of PTs we obtained genome-wide copy number profiles by array comparative genomic hybridization (CGH).DNA was isolated from fresh-frozen tissue samples. 11 PTs and 3 fibroadenomas, a frequently occurring fibroepithelial breast tumour, were analyzed. Arrays composed of 2464 genomic clones were used, providing a resolution of ~1.4 Mb across the genome. Each clone contains at least one STS for linkage to the human genome sequence.No copy number changes were detected in fibroadenomas. On the other hand, 10 of 11 PT (91%) showed DNA copy number alterations. The mean number of chromosomal events in PT was 5.5 (range 0–16) per case. A mean of 2.0 gains (range 0–10) and 3.0 losses (range 0–9) was seen per case of PT. Three cases showed amplifications. DNA copy number change was not related to PT grade. We observed recurrent loss on chromosome 1q, 4p, 10, 13q, 15q, 16, 17p, 19 and X. Recurrent copy number gain was seen on 1q, 2p, 3q, 7p, 8q, 16q, 20.In this study we used array CGH for genomic profiling of fibroepithelial breast tumours. Whereas most PT showed chromosomal instability, fibroadenomas lacked copy number changes. Some copy number aberrations had not previously been associated with PT. Several well-known cancer related genes, such as TP53 and members of the Cadherin, reside within the recurrent regions of copy number alteration. Since copy number change was found in all benign PT, genomic instability may be an early event in PT genesis.

Comparative Genomic Analyses of Primary Effusion Lymphoma

2000 ◽  
Vol 124 (6) ◽  
pp. 824-826
Author(s):  
B. P. Mullaney ◽  
V. L. Ng ◽  
B. G. Herndier ◽  
M. S. McGrath ◽  
M. G. Pallavicini
Keyword(s):  
Copy Number ◽  
Primary Effusion Lymphoma ◽  
Immune Surveillance ◽  
Comparative Genomic ◽  
Limited Information ◽  
Human Herpes Virus 8 ◽  
Regulatory Pathways ◽  
Genome Wide ◽  
Unique Markers ◽  
Copy Number Changes

Abstract Background.—A rare subset of human immunodeficiency virus (HIV) lymphomas, known as primary effusion lymphomas (PELs), are high-grade tumors carrying human herpes virus 8. Mechanisms postulated to contribute to lymphomagenesis include impaired immune surveillance, alterations in hemopoietic regulatory pathways due to expressed viral genes, and acquisition of genomic alterations in regions of the genome that contain regulatory genes. In PEL, limited information exists about the nature of genome-wide aberrations in these rare lymphomas. Methods.—We used comparative genomic hybridization to detect regions of sequence gain and loss throughout the genome of 8 PEL cases. Regions of DNA sequence loss or gain were confirmed using forward and reverse hybridization and t-statistic analyses. Results.—Genomic aberrations were identified in 6 of 8 cases, including recurrent gain of sequence in chromosomes 12 [ish enh (12q22;12q23, 12q12;12q23)] in 3 of 8 cases and X [ish enh (X, Xp)] in 2 of 8 cases. Conclusions.—DNA copy number changes occurred in a majority of PEL cases and are consistent with changes observed in other HIV lymphomas. These observations suggest that common genetic events may occur in HIV-associated lymphoid malignancies, but they probably do not contribute to the unique markers and morphology of PEL. Although individual genetic loci have been evaluated previously in a few PEL cases, to our knowledge this study represents the first reported genome-wide scan of copy number changes in these rare HIV-associated tumors.

The Impact of Constitutional Copy Number Variants in Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 496-496
Author(s):  
Matthew W Jenner ◽  
David C Johnson ◽  
Paola E Leone ◽  
Brian A Walker ◽  
David Gonzalez ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Change ◽  
Copy Number Variations ◽  
Genomic Variation ◽  
Chromosome 21 ◽  
Nucleotide Polymorphisms ◽  
Copy Number Changes ◽  
The Impact ◽  
First Time ◽  
Tumor Dna

Abstract Single nucleotide polymorphisms (SNPs) have been long regarded as being important in determining variation and disease predisposition. Recently, chromosomal structural variation in the form of deletions, insertions and duplifications have been identified frequently in the genome of the general population. Such copy number variations (CNVs) have been shown to contribute to a range of human diseases. In recent studies we have utilized Affymetrix 50K and 500K arrays to identify acquired copy number change in myeloma tumor samples. In those studies we had access to paired constitutional DNA and in the present study have been able to report for the first time a CNV map of the constitutional genome of myeloma patients. Affymetrix 500K mapping arrays were used to identify copy number changes in 63 paired samples using DNA from peripheral blood and CD138 selected plasma cells. Tumor samples were analyzed in CNAG using both a paired and unpaired analysis to distinguish between inherited and acquired copy number change. Constitutional DNA was analyzed by both CNAG and GEMCA using 90 Caucasian samples from the Hapmap database as a reference set. For maximum calling accuracy, only those regions identified by both algorithms were called as CNVs. As with similar studies, overlapping CNVs identified using this approach were merged to generate a list of CNV regions (CNVRs) characteristic of the constitutional DNA of these myeloma cases. Using this approach, we identified 292 CNVs across 63 cases, with a median of 4 regions per sample. There were 155 discrete CNVRs, of which 46 were recurrent. The recurrent CNVRs were found most frequently in the pericentric regions of chromosome 14 and 15 in keeping with other studies. We then compared these recurrent CNVRs with a comparable dataset of normal individuals generated using Affymetrix 500K arrays. In this analysis, 25/46 recurrent CNVRs in the myeloma cases were novel. The two most frequent novel CNVRs in the myeloma cases were gains on chromosome 21 and 15. We also compared the characteristics of the constitutional CNVs with the acquired copy number changes in the corresponding tumor samples and identified that the constitutional CNVs were generally considerably smaller. However, using unpaired analysis it was possible to determine the presence of the constitutional CNV in the tumor sample, providing validation of the CNVs. We were also able to demonstrate that acquired copy number change in the tumor cells can either exaggerate or ameliorate the effect of the inherited CNV in the tumor genome, such as cases with acquired trisomy 15 and deletion or gain of regions of 15q in the constitutional DNA. These findings also reinforce the need for paired non-tumor DNA when undertaking copy number analysis of tumor DNA using SNP arrays. In this study we have been able to identify for the first time the presence of CNVs in the constitutional genome of individuals with myeloma. We have been able to systematically catalogue these CNVRs. These results provide the basis for future studies aimed at identifying how this type of genomic variation may influence the development of and outcome of myeloma and a broad range of other hematological conditions.

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