Functions of noncoding sequences in mammalian genomes

Patrushev, Lev I.; Kovalenko, T. F.

doi:10.1134/s0006297914130021

Cited by 49 publications

(41 citation statements)

References 220 publications

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“…The rs480414 G/A SNP is located in the intron of the DDAH1 gene on chromosome 1p22. Although the intron is a noncoding region, recent studies have shown that mutations in noncoding parts of the genome can be associated with disease progression (27). Introns can work to positively regulate gene expression by stimulating mRNA accumulation through a process known as intron-mediated enhancement (28).…”

Section: Discussionmentioning

confidence: 99%

A single nucleotide polymorphism in the dimethylarginine dimethylaminohydrolase gene is associated with lower risk of pulmonary hypertension in bronchopulmonary dysplasia

et al. 2016

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Aim Pulmonary hypertension (PH) develops in 25–40% of bronchopulmonary dysplasia (BPD) patients, substantially increasing mortality. We have previously found that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) production, is elevated in patients with BPD-associated PH. ADMA is metabolized by NG,NG- dimethylarginine dimethylaminohydrolase (DDAH). Presently, we test the hypothesis that there are single nucleotide polymorphisms (SNPs) in DDAH1 and/or DDAH2 associated with the development of PH in BPD patients. Methods BPD patients were enrolled (n=98) at Nationwide Children’s Hospital. Clinical characteristics and 36 SNPs in DDAH1 and DDAH2 were compared between BPD-associated PH patients (cases) and BPD-alone patients (controls). Results In BPD patients, 25 (26%) had echocardiographic evidence of PH (cases). In this cohort, DDAH1 wildtype rs480414 was 92% sensitive and 53% specific for PH in BPD, and the DDAH1 SNP rs480414 decreased the risk of PH in an additive model of inheritance (OR=0.39; 95% CI [0.18–0.88], p=0.01). Conclusion The rs480414 SNP in DDAH1 may be protective against the development of PH in patients with BPD. Furthermore, the DDAH1 rs480414 may be a useful biomarker in developing predictive models for PH in patients with BPD.

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Section: Discussionmentioning

confidence: 99%

A single nucleotide polymorphism in the dimethylarginine dimethylaminohydrolase gene is associated with lower risk of pulmonary hypertension in bronchopulmonary dysplasia

et al. 2016

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“…Moreover, the sequences of introns do not represent junk DNA, but actually play a key role in gene expression and regulation [14]. Thus, whether the expression of these genes is disturbed will form the basis of subsequent studies from our laboratory.…”

Section: Discussionmentioning

confidence: 99%

Prolonged Integration Site Selection of a Lentiviral Vector in the Genome of Human Keratinocytes

Qian

Wang

et al. 2017

Med Sci Monit

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BackgroundLentiviral vectors have been successfully used for human skin cell gene transfer studies. Defining the selection of integration sites for retroviral vectors in the host genome is crucial in risk assessment analysis of gene therapy. However, genome-wide analyses of lentiviral integration sites in human keratinocytes, especially after prolonged growth, are poorly understood.Material/MethodsIn this study, 874 unique lentiviral vector integration sites in human HaCaT keratinocytes after long-term culture were identified and analyzed with the online tool GTSG-QuickMap and SPSS software.ResultsThe data indicated that lentiviral vectors showed integration site preferences for genes and gene-rich regions.ConclusionsThis study will likely assist in determining the relative risks of the lentiviral vector system and in the design of a safe lentiviral vector system in the gene therapy of skin diseases.

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“…The typing strategy described here utilizes long-range PCR to amplify full-length sequences of class I genes (HLA-A, B, C), and uninterrupted sequences from exon 2 to beginning of exon 4 of class II (HLA-DRB1 and DQB1), thereby providing valuable intron information involving previously unmapped regions. Intron sequences constitute approximately 30% of the human genome [30]; however, the function of introns is not completely understood. Recent NGS studies have shown that noncoding RNAs (ncRNAs), including miRNA, siRNA, long noncoding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs) found in intron regions of the human genome may play an important role in regulating gene expression [31,32].…”

Section: Discussionmentioning

confidence: 99%

Application of High-Throughput Next-Generation Sequencing for HLA Typing on Buccal Extracted DNA: Results from over 10,000 Donor Recruitment Samples

Yin¹,

Lan

Nguyen³

et al. 2016

PLoS ONE

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BackgroundUnambiguous HLA typing is important in hematopoietic stem cell transplantation (HSCT), HLA disease association studies, and solid organ transplantation. However, current molecular typing methods only interrogate the antigen recognition site (ARS) of HLA genes, resulting in many cis-trans ambiguities that require additional typing methods to resolve. Here we report high-resolution HLA typing of 10,063 National Marrow Donor Program (NMDP) registry donors using long-range PCR by next generation sequencing (NGS) approach on buccal swab DNA.MethodsMultiplex long-range PCR primers amplified the full-length of HLA class I genes (A, B, C) from promotor to 3’ UTR. Class II genes (DRB1, DQB1) were amplified from exon 2 through part of exon 4. PCR amplicons were pooled and sheared using Covaris fragmentation. Library preparation was performed using the Illumina TruSeq Nano kit on the Beckman FX automated platform. Each sample was tagged with a unique barcode, followed by 2×250 bp paired-end sequencing on the Illumina MiSeq. HLA typing was assigned using Omixon Twin software that combines two independent computational algorithms to ensure high confidence in allele calling. Consensus sequence and typing results were reported in Histoimmunogenetics Markup Language (HML) format. All homozygous alleles were confirmed by Luminex SSO typing and exon novelties were confirmed by Sanger sequencing.ResultsUsing this automated workflow, over 10,063 NMDP registry donors were successfully typed under high-resolution by NGS. Despite known challenges of nucleic acid degradation and low DNA concentration commonly associated with buccal-based specimens, 97.8% of samples were successfully amplified using long-range PCR. Among these, 98.2% were successfully reported by NGS, with an accuracy rate of 99.84% in an independent blind Quality Control audit performed by the NDMP. In this study, NGS-HLA typing identified 23 null alleles (0.023%), 92 rare alleles (0.091%) and 42 exon novelties (0.042%).ConclusionLong-range, unambiguous HLA genotyping is achievable on clinical buccal swab-extracted DNA. Importantly, full-length gene sequencing and the ability to curate full sequence data will permit future interrogation of the impact of introns, expanded exons, and other gene regulatory sequences on clinical outcomes in transplantation.

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Functions of noncoding sequences in mammalian genomes

Cited by 49 publications

References 220 publications

A single nucleotide polymorphism in the dimethylarginine dimethylaminohydrolase gene is associated with lower risk of pulmonary hypertension in bronchopulmonary dysplasia

A single nucleotide polymorphism in the dimethylarginine dimethylaminohydrolase gene is associated with lower risk of pulmonary hypertension in bronchopulmonary dysplasia

Prolonged Integration Site Selection of a Lentiviral Vector in the Genome of Human Keratinocytes

Application of High-Throughput Next-Generation Sequencing for HLA Typing on Buccal Extracted DNA: Results from over 10,000 Donor Recruitment Samples

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