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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
Every protein is encoded by a DNA sequence within a gene at a defined locus on a chromosome. Codons of three sequential nucleotides encode a single amino acid or a stop signal. Regulatory regions containing target sites for various DNA-binding proteins flank the coding sequence and control gene expression. These regions form a vital part of the gene and their loss can have profound effects on protein expression. Mutations in control regions can cause disease, as evidenced by some of the haemoglobin gene mutations that cause thalassaemia. An upstream promoter provides binding sites for RNA polymerase and transcription factors. Functionally related enhancer sequences are located further afield and recruit various DNA-binding proteins that can regulate the efficiency of gene transcription. The transcriptional unit contains exons of coding DNA separated by introns, which play no part in the finished protein. A large portion of our genome is composed of repetitive DNA of unclear function.
Molecular Biology and Gene Therapy
Published in R James A England, Eamon Shamil, Rajeev Mathew, Manohar Bance, Pavol Surda, Jemy Jose, Omar Hilmi, Adam J Donne, Scott-Brown's Essential Otorhinolaryngology, 2022
DNA mutation may occur as a result of base substitutions, as well as nucleotide insertions and deletions. Insertions and deletions of nucleotides are very rare in coding DNA. Base substitution is a more common form of mutation in coding DNA, which may have a range of consequences on the function of the gene: a loss of function; a gain in function, often due to stabilisation of the active protein or no net functional effect. An example of a silent substitution yielding no functional effect is seen when an amino acid may be encoded by different codons (e.g. GUA, GAC, GUG and GUU all encode valine), so a substitution of the third base results in no change to the amino acid. At the other extreme is the nonsense mutation, whereby a base substitution results in an early stop codon, which leads to truncation of the polypeptide and a dramatic reduction in function.
Transcriptionally Regulatory Sequences of Phylogenetic Significance
Published in S. K. Dutta, DNA Systematics, 2019
In most eukaryotic exons, a pentanucleotide AATAA is present, which is some 25 bp before the 3′ end of the coding DNA region. This consensus sequence has also been suggested as a signal for termination of transcription or for polyadenylation. Immediately after the 3′ end of coding sequence of several mRNAs there is often a tetranucleotide TTTT which is also a candidate signal for RNA polymerase II termination.237
RHOA G17V induces T follicular helper cell specification and involves angioimmunoblastic T-cell lymphoma via upregulating the expression of PON2 through an NF-κB-dependent mechanism
Published in OncoImmunology, 2022
Fenglian Que, Lihong Zhang, Taoli Wang, Meifang Xu, Wangen Li, Shengbing Zang
DNA was extracted from formalin-fixed paraffin-embedded tissues using a silica membrane–based DNA purification method (DNA Micro Kit, Sangon Biotech, and Shanghai, China). All extracted DNA samples were assessed for the quality using PCR amplification. Forty-six AITLs were assessed using targeted amplicon sequencing to detect the RHOA G17V mutation in exon 2 of the RHOA gene (NM_001664). A fragment of RHOA, including the p.Gly17Val site was amplified using DNA extracted from formalin-fixed paraffin-embedded tissue sections, with 5`-GCCCCATGGTTACCAAAGCA-3` and 5`-TATCGAGGTGGATGGAAAGC-3` as sense and antisense primers, respectively. A PCR-amplified product of 244 bp was obtained in all cases, and direct sequencing of these products was performed. The coding DNA position 50 G > T mutation of the RHOA gene predicted a change in the wild-type G (Gly) to the mutant type V (Val).
Antisense oligonucleotide therapeutics in clinical trials for the treatment of inherited retinal diseases
Published in Expert Opinion on Investigational Drugs, 2020
Kanmin Xue, Robert E. MacLaren
A noteworthy feature of ASO-based splicing-modulating therapy is that the clinical benefits may vary between patients with compound heterozygous mutations. For instance, most LCA10 patients are compound heterozygotes for the common c.2991 + 1655A>G mutation, and the clinical effect of ASO-mediated correction of this splicing defect may vary depending on the severity of the mutation on the second allele (e.g. whether it is a missense or nonsense mutation). A potential alternative therapeutic strategy, which could target both alleles, is to utilize spliceosome-mediated pre-mRNA trans-splicing. In this approach, an AAV vector is used to deliver a 5ʹ partial CEP290-coding DNA sequence containing a binding domain to intron 26–27 (between exon X and 27). Trans-splicing between the exogenous 5ʹ partial CEP290 pre-mRNA and the endogenous mutant pre-mRNA has been shown to produce hybrid full-length CEP290 transcripts in a mini-gene mouse model [49]. A similar trans-splicing therapeutic strategy for RHO-associated adRP has also been demonstrated in vitro using a 3ʹ partial RHO-coding sequence packaged within an AAV transgene construct [50].
Playing the genome card
Published in Journal of Neurogenetics, 2020
I suggest that these terms are fundamentally misleading as applied to genome sequencing. The implied analogy is to codes used in spycraft. Once you decode or decipher a coded message, you understand its meaning. The implication is that by sequencing a genome, we understand its meaning. But biologists knew in the 1990s and know now that this is not the case. To understand the meaning of a gene (i.e. a protein-coding DNA sequence), we would need to understand the function(s) of the protein it codes for, if not also how it carries out that function. To understand the meaning of a stretch of DNA that does not code for a protein, we would need to understand its function, such as what gene(s) it alters the expression of, via which nucleic acid and protein partners, and how. In most cases, simply having a DNA sequence does not convey such meaning. It is a sequence of basepairs, which, for protein-coding sequences, is also a sequence of amino acids. This is a starting point for exploring its meaning, which is what the protein does and how. Thus, DNA sequencing is more analogous to writing down a series of letters in a foreign language, without yet knowing what the sentence means, than it is to decoding or deciphering an encoded message.