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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
With 3.2 billion pairs of nucleotides in the haploid human genome, about 20 million genes could be encoded. However, there are about 1,000 times fewer protein-coding genes than this estimate. But there are many more proteins than the 20,465 protein-coding sequences currently recognized in the human genome. The higher number of encoded proteins, for which the absolute number is still a matter of debate, is explained mainly by DNA-coding sequences producing more than one mRNA transcript, called a transcript variant. The disparity between the number of genes and gene transcripts results most frequently from alternative promoters and alternative splicing. As described above, splicing is the process by which introns are removed and exons sequences are fused together into an mRNA. Alternative splicing refers to a situation in which a single gene produces multiple messenger RNAs through different combinations of exons (Figure 3.9). Approximately 75% of the human genes with multiple exons have alternative splice sites. Alternative splicing may cause either inclusion or exclusion of one or several exons.
Homeostasis of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
The human DDC gene exists as a single copy, located on chromosome 7p12.1 (Table 1.1). The gene extends over 107.6 kb, and consists of 15 exons. Alternative splicing generates several mRNA isoforms. Tissue-specific expression of the DDC gene is controlled by two spatially distinct promoters—neuronal and nonneuronal—with the mRNA isoforms differing in the composition of the 5′ UTR and the presence of alternative exons. In humans, a deficiency in DDC synthesis, due to frameshift mutations, or alterations in its activity due to single amino acid substitutions, result in impaired cognitive and physiological homeostasis, and/or in some neuropsychiatric disorders [11].
Molecular Biology
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Michael Kuo, Richard M. Irving, Eric K. Parkinson
A gene is a region of the chromosomal DNA that produces a functional ribonucleic acid molecule (RNA). It comprises regulatory DNA sequences that determine when and in which cell types that gene is expressed, exons that are coding sequences and interspersed introns that are non-coding DNA sequences. These regulatory sequences often consist of CpG islands, short stretches of DNA rich in dinucleotides of cytosine and guanine. The methylation status of these CpG islands determines whether that gene is expressed in a particular cell or tissue, being unmethylated in tissues where the genes are expressed. As will be discussed later, aberration of this control is one of the mechanisms of tumour suppressor gene inactivation. However, these same genes can also be regulated by proteins that recognize methylated sequences called histones2 and these in turn can be regulated by polycomb genes such as BMI1.3 Transcription is the intra-nuclear process driven by RNA polymerase whereby one of the two DNA strands acts as a template for the synthesis of a single RNA strand which is complementary to the DNA, except that uracil replaces thymine in RNA. This primary RNA transcript then undergoes post-transcriptional processing, or splicing.4 Traditional dogma held that one gene produces one protein and therefore splicing was considered to occur simply in order to remove the non-coding intronic sequences, producing messenger RNA (mRNA). It is now known that by ‘alternative splicing’, one gene can result in the production of several different but often related proteins in different tissues.5
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.
Investigation of CEP290 genotype-phenotype correlations in a patient with retinitis pigmentosa, infertility, end-stage renal disease, and a novel mutation
Published in Ophthalmic Genetics, 2020
Madeline Williamson, Elias Traboulsi, Meghan DeBenedictis
There is no consensus view that explains why mutations in a single gene, such as CEP290, result in such varied disease phenotypes. It was recently proposed that disease severity correlates with total protein levels of CEP290. In a process known as nonsense-mediated alternative splicing (NAS), exons harboring nonsense mutations are selectively skipped from the final transcript. Alternatively, the mutation harboring exons in CEP290 may be spliced by basal exon skipping. In either case, the result is increased expression of higher-functioning gene transcripts due to nonsense-mediated decay of the transcripts containing the premature stop codons (14). Whether the process is better described as NAS or basal exon skipping is irrelevant to the fact that therapies utilizing alternative splicing to exclude exons containing nonsense mutations could be of great benefit to patients and warrants further investigation (15). However, alternative splicing and compensatory expression of functioning gene products cannot explain the difference in phenotypes of patients with identical genotypes, such as those homozygous for the c.4723A>T mutation. One possible explanation for the additional variation in phenotype severity would be existence of modifying variants in other genes involved in the pathway of proper cilia function (16).
SPLICELECT™: an adaptable cell surface display technology based on alternative splicing allowing the qualitative and quantitative prediction of secreted product at a single-cell level
Published in mAbs, 2020
Christel Aebischer-Gumy, Pierre Moretti, Romain Ollier, Christelle Ries Fecourt, François Rousseau, Martin Bertschinger
Interestingly, the human immune system provides an additional and elegant way to link cell surface display and secretion. B cells are the antibody producers in the human immune system. Each B cell expresses a single antibody specifically binding a single antigen. In resting B cells (memory cells), the antibody is predominantly membrane-bound. Upon recognition of its antigen, a B cell will proliferate into plasma cells expressing a huge amount of secreted antibody.44 The only difference between the two antibody isoforms is a C-terminal extension of the membrane-bound version with a transmembrane region.45 The controlled transition between the two isoforms of antibody (membrane-bound and secreted) is achieved by alternative splicing.45,46 Splicing describes the precise excision of the introns of the mRNA, accomplished by a protein complex called spliceosome that is able to recognize consensus sequences: the 5ʹ splice donor (5ʹ SD) and 3ʹ splice acceptor (3’SA) sites at the intron/exon borders and the branch point and the poly pyrimidines (poly(Y)) tract in the intron. The efficiency of the splicing depends largely on the different consensus sequences, but also on so-called splicing enhancer and repressor sequences present in both introns and exons. Alternative splicing describes the mechanisms by which a single pre-mRNA is matured into different mRNA, a process that is usually highly regulated by interaction of many different factors.47–58