Genome-wide identification of pseudogenes capable of disease-causing gene conversion

Bischof, Jared M.; Chiang, An‐Jen; Scheetz, Todd E.; Stone, Edwin M.; Casavant, Thomas L.; Sheffield, Val C.; Braun, Terry A.

doi:10.1002/humu.20335

Cited by 83 publications

(54 citation statements)

References 38 publications

(47 reference statements)

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“…The maternal transmission pattern could point to such a mechanism. A number of pseudogenes have been described where gene conversion between a functional copy of a gene and a neighboring pseudogene causes disease (36). However, in the present case the mechanism is likely to be more complex.…”

Section: Discussionmentioning

confidence: 92%

Three Novel Collagen VI Chains with High Homology to the α3 Chain

Gara

Grumati

Urciuolo

et al. 2008

Journal of Biological Chemistry

154

182

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Here we describe three novel collagen VI chains, ␣4, ␣5, and ␣6. The corresponding genes are arranged in tandem on mouse chromosome 9. The new chains structurally resemble the collagen VI ␣3 chain. Each chain consists of seven von Willebrand factor A domains followed by a collagenous domain, two C-terminal von Willebrand factor A domains, and a unique domain. In addition, the collagen VI ␣4 chain carries a Kunitz domain at the C terminus, whereas the collagen VI ␣5 chain contains an additional von Willebrand factor A domain and a unique domain. The size of the collagenous domains and the position of the structurally important cysteine residues within these domains are identical between the collagen VI ␣3, ␣4, ␣5, and ␣6 chains. In mouse, the new chains are found in or close to basement membranes. Collagen VI ␣1 chain-deficient mice lack expression of the new collagen VI chains implicating that the new chains may substitute for the ␣3 chain, probably forming ␣1␣2␣4, ␣1␣2␣5, or ␣1␣2␣6 heterotrimers. Due to a large scale pericentric inversion, the human COL6A4 gene on chromosome 3 was broken into two pieces and became a non-processed pseudogene. Recently COL6A5 was linked to atopic dermatitis and designated COL29A1. The identification of novel collagen VI chains carries implications for the etiology of atopic dermatitis as well as Bethlem myopathy and Ullrich congenital muscular dystrophy.Members of the collagen protein superfamily play important roles in maintaining extracellular matrix structure and function. To date 28 family members are known (1, 2), among which the fibril-forming collagens and the FACIT collagens form large subgroups. In addition, several collagens exist that have highly specific functions. Among these, collagen VI forms a distinct network of microfibrils in most connective tissues. Electron microscopy revealed a beaded filament structure of the microfibrils (3). The ␣1, ␣2, and ␣3 chains of collagen VI form heterotrimeric monomers that already intracellularly assemble to dimers and tetramers (4, 5). After secretion, filaments are formed by end to end interactions of the preassembled tetramers.The three previously known collagen VI chains contain a relatively short collagenous domain of about 335 residues together with VWA 3 domains, which are the characteristic non-collagenous domains of collagen VI. A common feature of VWA domains is their involvement in the formation of multiprotein complexes (6). Whereas all three collagen VI chains contain two C-terminal VWA domains, the ␣1 and ␣2 chains carry only one and the ␣3 chain ten VWA domains at the N terminus (7,8). In addition, the ␣3 chain contains a unique domain with similarities to salivary gland proteins, a fibronectin type III repeat, and a bovine pancreatic trypsin inhibitor/ Kunitz family of serine protease inhibitor domain (Kunitz domain) at the C terminus (8). It was suggested that the VWA domains play a role in the assembly of collagen VI (9 -11). However, recently the analysis of lysyl hydroxylase 3-deficient mouse embryos indicated...

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Section: Discussionmentioning

confidence: 92%

Three Novel Collagen VI Chains with High Homology to the α3 Chain

Gara

Grumati

Urciuolo

et al. 2008

Journal of Biological Chemistry

154

182

View full text Add to dashboard Cite

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“…6,[61][62][63] The very high throughput of NGS makes it ideal for large-scale projects and will make genotyping of large ADPKD cohorts feasible (e.g., in association with large ADPKD clinical trials or ADPKD population studies). The NGS deep sequencing of the entire genomic structure of both the PKD1 and PKD2 genes holds the potential of discovering atypical mutations like the ones we describe here, and helps to clarify the genetic basis of the 10% of ADPKD pedigrees in which no mutation is detectable through conventional Sanger sequencing.…”

Section: Discussionmentioning

confidence: 99%

“…6 GCs have been previously described in ADPKD 7,8 but their exact genomic origin and extent have not been characterized.…”

mentioning

confidence: 99%

Identification of Gene Mutations in Autosomal Dominant Polycystic Kidney Disease through Targeted Resequencing

Rossetti

Hopp

Sikkink

et al. 2012

Journal of the American Society of Nephrology

155

146

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Mutations in two large multi-exon genes, PKD1 and PKD2, cause autosomal dominant polycystic kidney disease (ADPKD). The duplication of PKD1 exons 1-32 as six pseudogenes on chromosome 16, the high level of allelic heterogeneity, and the cost of Sanger sequencing complicate mutation analysis, which can aid diagnostics of ADPKD. We developed and validated a strategy to analyze both the PKD1 and PKD2 genes using next-generation sequencing by pooling long-range PCR amplicons and multiplexing barcoded libraries. We used this approach to characterize a cohort of 230 patients with ADPKD. This process detected definitely and likely pathogenic variants in 115 (63%) of 183 patients with typical ADPKD. In addition, we identified atypical mutations, a gene conversion, and one missed mutation resulting from allele dropout, and we characterized the pattern of deep intronic variation for both genes. In summary, this strategy involving next-generation sequencing is a model for future genetic characterization of large ADPKD populations.

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“…La grande majorité du temps, ces conversions géniques ont peu d'impacts fonctionnels parce que celles qui ont un effet délétère sont éliminées par sélection naturelle (Noonan et al 2004;Hiwatashi et al 2011;Petronella et Drouin 2011, 2014. Par contre, chez les humains, plusieurs maladies génétiques sont néanmoins causées par des conversions gé-niques entre gènes dupliqués (Bischof et al 2006;Chen et al 2007). …”

Section: Introductionunclassified

Haute fréquence de conversions géniques entre les gènes codant pour la phosphatase du 2-déoxyglucose 6-phosphate chez trois espèces du genreSaccharomyces

Piscopo

Drouin

2014

Genome

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Résumé : Les conversions géniques sont des échanges non réciproques de séquences entre gènes. Elles sont relativement fréquentes chez Saccharomyces cerevisiae, mais peu d'études ont analysé le destin évolutif des conversions géniques ou leur impact fonctionnel chez les gènes de levures. Ici, nous analysons l'évolution et l'impact des conversions géniques entre les deux gènes codant pour la phosphatase du 2-déoxyglucose-6-phosphate chez S. cerevisiae, Saccharomyces paradoxus et Saccharomyces mikatae. Nos résultats démontrent que la dernière moitié de ces gènes est sujette à des conversions géniques chez ces trois espèces. La grande similarité et le plus grand pourcentage de nucléotides G et C dans les régions converties, ainsi que l'absence de longues régions de sites convertis communs adjacents, suggèrent que ces conversions géniques se produisent fréquemment et de façon indépendante chez ces trois espèces. La haute fréquence de ces conversions résulte probablement du fait qu'elles ont peu d'impact sur les séquences protéiques codées par ces gènes. Mots-clés :Saccharomyce cerevisiae, Saccharomyces paradoxus, Saccharomyces mikatae, conversions géniques, phosphatase du 2-déoxyglucose 6-phosphate.Abstract: Gene conversions are nonreciprocal sequence exchanges between genes. They are relatively common in Saccharomyces cerevisiae, but few studies have investigated the evolutionary fate of gene conversions or their functional impacts. Here, we analyze the evolution and impact of gene conversions between the two genes encoding 2-deoxyglucose-6-phosphate phosphatase in S. cerevisiae, Saccharomyces paradoxus and Saccharomyces mikatae. Our results demonstrate that the last half of these genes are subject to gene conversions among these three species. The greater similarity and the greater percentage of GC nucleotides in the converted regions, as well as the absence of long regions of adjacent common converted sites, suggest that these gene conversions are frequent and occur independently in all three species. The high frequency of these conversions probably result from the fact that they have little impact on the protein sequences encoded by these genes.

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Genome-wide identification of pseudogenes capable of disease-causing gene conversion

Cited by 83 publications

References 38 publications

Three Novel Collagen VI Chains with High Homology to the α3 Chain

Three Novel Collagen VI Chains with High Homology to the α3 Chain

Identification of Gene Mutations in Autosomal Dominant Polycystic Kidney Disease through Targeted Resequencing

Haute fréquence de conversions géniques entre les gènes codant pour la phosphatase du 2-déoxyglucose 6-phosphate chez trois espèces du genreSaccharomyces

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