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Genetics and exercise: an introduction
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Claude Bouchard, Henning Wackerhage
A typical gene (Figure 3.8) consists of coding sequences termed exons (i.e. exons encode the amino acid sequence of a protein), interrupted by noncoding regions termed introns. Additionally, there are regulatory DNA sequences located upwards and downwards and at times far from the gene whose transcription depends on the regulatory DNA. The number of exons is highly variable, with a range from one (e.g. G-protein-coupled receptor genes, GPCRs, with no introns) to a few hundred exons, such as titin (gene symbol TTN), a gene with 363 exons.
The Genetic Risk of a Couple Aiming to Conceive
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Joe Leigh Simpson, Svetlana Rechitsky, Anver Kuliev
The protein-coding regions are defined as exons, and code for 21,000 genes in the human genome. This constitutes 1.5% of the genome. At least 5,000 Mendelian disorders are exonic in origin (1) The other 98.5% of the genome contains non-coding DNA, believed to be responsible for gene regulation. Non-coding regions (introns) may separate coding genes or be interspersed among exons of a clinically significant gene. At a single genetic locus, many different nuclear mutations may arise. In compound heterozygosity, two different alleles may show different base mutations, each deleterious. Causative mutant alleles influencing a single phenotype may exist in two different genetic loci (mixed heterozygosity). It follows that both genes are necessary for a normal phenotype.
Basic genetics and patterns of inheritance
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Genes are composed of deoxyribonucleic acid (DNA) and are contained on the chromosomes. Each strand of DNA has a specific sequence of four nucleotides, each containing a different base, adenine, thymine, cytosine, or guanine. Adenine pairs with thymine and cytosine pairs with guanine as two complementary strands of DNA are wound together to form a double helix. Genes have a common basic structure (Fig. 20). First, there are upstream sequences that regulate transcription, known as promoters and enhancers. Then, there is a transcription initiation site, followed by a series of alternating exons and introns. The DNA sequence serves as a template from which messenger RNA (mRNA) is made; this process is known as transcription. As transcription proceeds, a primary mRNA is made from the DNA sequence of the gene, which includes the introns. The intron sequences are then spliced out and the exons are linked together to form the mature mRNA molecule. Thus, the exons are the only portions of the gene that specify the final protein product. The mature mRNA molecule is used to make the protein product by the process of translation. Groups of three nucleotides, called codons, code for specific amino acids. Transfer RNA (tRNA) and ribosomal RNA (rRNA) interact with the mRNA to assemble the amino acids into a polypeptide chain to form the final protein molecule.
Interplay of heavy chain introns influences efficient transcript splicing and affects product quality of recombinant biotherapeutic antibodies from CHO cells
Published in mAbs, 2023
Emma Kelsall, Claire Harris, Titash Sen, Diane Hatton, Sarah Dunn, Suzanne Gibson
Interestingly, sequence optimization failed to improve the expression from two of the best-performing plasmids (gDNA∆2 and cDNA +1). This is likely due to the highly optimized arrangement of other expression elements in these plasmids. It would be interesting to investigate if sequence optimization improved the expression of a completely intron-less-HC cassette as our study has revealed that introns in the HC have minimal influence on expression and can be removed without significantly affecting antibody titers. This was surprising due to the well-documented role of introns in enhancing gene expression. A possible explanation of the benefits seen by including introns is that these are context specific and are brought about by crosstalk of splicing with transcription, mRNA decay, and transcript stability. In the context of biotherapeutic mAb expression plasmids, because a very strong heterologous promoter is driving HC expression and typically it is the HC expression that dictates mAb expression levels,37 the promoter’s activity likely supersedes everything else. It is possible that the interplay between the endogenous HC promoter and introns would be different with introns playing a more significant role in HC expression.
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
RNA splicing is a complicated key regulatory step in the generation of the diverse repertoire of human proteins from the limited protein-coding genome. The splicing process is carried out in the spliceosome, a large complex consisting of hundreds of proteins, snRNAs, and five small nuclear ribonucleoproteins (snRNP) which act in concert to bind and remove intronic sequences [63]. The vast majority of protein-coding transcripts undergo such carefully orchestrated splicing events. However, when pre-mRNA processing and splicing deviate from the norm, splicing disorders can occur. Because every intron-containing gene requires a certain level of processing and splicing, mutations falling within a canonical splice site can lead to aberrant gene translation and potentially to disease. Two such well-explored diseases concerning small molecule RNA targeting are familial dysautonomia (FD) and spinal muscular atrophy (SMA).
Myeloid neoplasm with ETV6::ACSl6 fusion: landscape of molecular and clinical features
Published in Hematology, 2022
Zhan Su, Xin Liu, Weiyu Hu, Jie Yang, Xiangcong Yin, Fang Hou, Yaqi Wang, Jinglian Zhang
The vast majority of cases showed characteristic t(5;12)(q31;p13) chromosomal abnormalities or t(5;12)(q23-31;p13) (n = 2) and t(5;12)(q31-33;p13) (n = 1). Two cases harboring t(5;12) have been reported, but the authors supplied no detailed information about the translocation breakpoint. One case had a complex karyotype involving 5q and 12p [9]. To date, a total of six ETV6::ACSL6 variants and three reciprocal variants of ACSL6::ETV6 have been reported, which are summarized in Figure 2. The coexistence of two reciprocal chimeric genes was observed (n = 2). There were also cases in which two ETV6::ACSL6 variants coexisted (n = 2). The most commonly reported variant (n = 6) is ETV6::ACSL6, the breakpoint of which is flanked by exon 1 of ETV6 and exon 2 of ACSL6. Intron retention and truncated exons (or alternative splicing) may be found in some variants.