The role of microhomology in genomic structural variation

Ottaviani, Diego; LeCain, Magdalena; Sheer, Denise

doi:10.1016/j.tig.2014.01.001

Cited by 166 publications

(177 citation statements)

References 88 publications

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“…Microhomology at the breakpoint junctions of structural genomic rearrangements is a rather common phenomenon (40). Our analysis based on the 25 WGS cases from the TCGA HGS-OvCa cohort demonstrated that microhomology detected at the breakpoint junctions of TDs in the CDK12 TD-plus phenotype was in general similar to that found in TDs, translocations, and deletions in CDK12-wildtype ovarian tumors ( Fig.…”

Section: Microhomology End Joining Pattern As Compared With Cdk12-wilsupporting

confidence: 55%

“…It is not clear which pathway is employed for TD resolutions, as both nonhomologous end joining frequently operating with 1 to 4 bp microhomology (41) and microhomology-mediated end joining utilizing longer 5 to 25 bp stretches of homologous fragments are consistent with the observed microhomology size distribution (40).…”

Section: Microhomology End Joining Pattern As Compared With Cdk12-wilmentioning

confidence: 99%

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Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display a Distinct Genomic Instability Pattern Characterized by Large Tandem Duplications

et al. 2016

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CDK12 is a recurrently mutated gene in serous ovarian carcinoma, whose downregulation is associated with impaired expression of DNA damage repair genes and subsequent hypersensitivity to DNA-damaging agents and PARP1/2 inhibitors. In this study, we investigated the genomic landscape associated with CDK12 inactivation in patients with serous ovarian carcinoma. We show that CDK12 loss was consistently associated with a particular genomic instability pattern characterized by hundreds of tandem duplications of up to 10 megabases (Mb) in size. Tandem duplications were characterized by a bimodal ($0.3 and $3 Mb) size distribution and overlapping microhomology at the breakpoints.This genomic instability, denoted as the CDK12 TD-plus phenotype, is remarkably distinct from other alteration patterns described in breast and ovarian cancers. The CDK12 TD-plus phenotype was associated with a greater than 10% gain in genomic content and occurred at a 3% to 4% rate in The Cancer Genome Atlas-derived and in-house cohorts of patients with serous ovarian carcinoma. Moreover, CDK12-inactivating mutations together with the TD-plus phenotype were also observed in prostate cancers. Our finding provides new insight toward deciphering the function of CDK12 in genome maintenance and oncogenesis. Cancer Res; 76(7); 1882-91. Ó2016 AACR.

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Section: Microhomology End Joining Pattern As Compared With Cdk12-wilsupporting

confidence: 55%

Section: Microhomology End Joining Pattern As Compared With Cdk12-wilmentioning

confidence: 99%

Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display a Distinct Genomic Instability Pattern Characterized by Large Tandem Duplications

et al. 2016

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“…Patient 1 carried a de novo 81 bp deletion which deleted 7 codons of exon 7 and 60 adjacent base pairs of intron 7 (chr3:g.9477570_9477650del) (Figure 1). The four nucleotides upstream of the 5 0 deletion breakpoint and the last four nucleotides of the deleted segment were identical (AGCA) and thus constituted a junctional microhomology 21 (Figure 1k, blue bar). In addition to the deletion, a de novo nucleotide substitution (chr3:g.9477546A4G, c.523A4G, p.(Ser175Gly)) was detected 25 nucleotides upstream of the 5 0 deletion breakpoint (Figure 1k).…”

Section: Setd5 Sequence Variantsmentioning

confidence: 99%

“…This signature is consistent with mechanisms such as NHEJ, alternative NHEJ (also known as microhomology-mediated end joining), fork stalling and template switching, and microhomology-mediated breakinduced replication. 21 Putative truncating variants (frameshift or nonsense) of SETD5 are in fact rare. None were identified in either the 1000 Genomes Project or in 2500 in-house control exomes.…”

Section: Setd5 Mutations Cause Intellectual Disabilitymentioning

confidence: 99%

Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome

et al. 2014

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Intellectual disability (ID) has an estimated prevalence of 2-3%. Due to its extreme heterogeneity, the genetic basis of ID remains elusive in many cases. Recently, whole exome sequencing (WES) studies revealed that a large proportion of sporadic cases are caused by de novo gene variants. To identify further genes involved in ID, we performed WES in 250 patients with unexplained ID and their unaffected parents and included exomes of 51 previously sequenced child-parents trios in the analysis. Exome analysis revealed de novo intragenic variants in SET domain-containing 5 (SETD5) in two patients. One patient carried a nonsense variant, and the other an 81 bp deletion located across a splice-donor site. Chromosomal microarray diagnostics further identified four de novo non-recurrent microdeletions encompassing SETD5. CRISPR/Cas9 mutation modelling of the two intragenic variants demonstrated nonsense-mediated decay of the resulting transcripts, pointing to a loss-of-function (LoF) and haploinsufficiency as the common disease-causing mechanism of intragenic SETD5 sequence variants and SETD5-containing microdeletions. In silico domain prediction of SETD5, a predicted SET domain-containing histone methyltransferase (HMT), substantiated the presence of a SET domain and identified a novel putative PHD domain, strengthening a functional link to well-known histone-modifying ID genes. All six patients presented with ID and certain facial dysmorphisms, suggesting that SETD5 sequence variants contribute substantially to the microdeletion 3p25.3 phenotype. The present report of two SETD5 LoF variants in 301 patients demonstrates a prevalence of 0.7% and thus SETD5 variants as a relatively frequent cause of ID.

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“…To date, the nature of this RAD51-independent HR is unknown. DSBs in eukaryotes can be repaired by at least three routes: HR, nonhomologous end-joining (NHEJ), and a still poorly understood pathway (or pathways) termed alternative end-joining or microhomology-mediated end-joining (MMEJ) (161). It seems likely that NHEJ can be discounted as a route for VSG gene conversion; not only does this appear mechanistically incompatible, but mutants of the Ku heterodimer that recognize DSBs in this reaction have no effect on VSG switching (162,163).…”

Section: Activation Of Intact Vsgs Involves Homologous Recombinationmentioning

confidence: 99%

DNA Recombination Strategies During Antigenic Variation in the African Trypanosome

2015

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Survival of the African trypanosome in its mammalian hosts has led to the evolution of antigenic variation, a process for evasion of adaptive immunity that has independently evolved in many other viral, bacterial and eukaryotic pathogens. The essential features of trypanosome antigenic variation have been understood for many years and comprise a dense, protective Variant Surface Glycoprotein (VSG) coat, which can be changed by recombination-based and transcription-based processes that focus on telomeric VSG gene transcription sites. However, it is only recently that the scale of this process has been truly appreciated. Genome sequencing of Trypanosoma brucei has revealed a massive archive of >1000 VSG genes, the huge majority of which are functionally impaired but are used to generate far greater numbers of VSG coats through segmental gene conversion. This chapter will discuss the implications of such VSG diversity for immune evasion by antigenic variation, and will consider how this expressed diversity can arise, drawing on a growing body of work that has begun to examine the proteins and sequences through which VSG switching is catalyzed. Most studies of trypanosome antigenic variation have focused on T. brucei , the causative agent of human sleeping sickness. Other work has begun to look at antigenic variation in animal-infective trypanosomes, and we will compare the findings that are emerging, as well as consider how antigenic variation relates to the dynamics of host–trypanosome interaction.

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The role of microhomology in genomic structural variation

Cited by 166 publications

References 88 publications

Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display a Distinct Genomic Instability Pattern Characterized by Large Tandem Duplications

Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display a Distinct Genomic Instability Pattern Characterized by Large Tandem Duplications

Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome

DNA Recombination Strategies During Antigenic Variation in the African Trypanosome

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