Genetic code
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Arbitrariness in the genetic code is one of the main reasons for a linguistic approach to molecular biology: the genetic code is usually understood as an arbitrary relation between amino acids and nucleobases. However, from a semiotic point of view, arbitrariness should not be the only condition for definition of a code, consequently it is not completely correct to talk about "code" in this case. Yet we suppose that there exist a code in the process of protein synthesis, but on a higher level than the nucleic bases chains. Semiotically, a code should be always associated with a function and we propose to define the genetic code not only relationally (in basis of relation between nucleobases and amino acids) but also in terms of function (function of a protein as meaning of the code). Even if the functional definition of meaning in the genetic code has been discussed in the field of biosemiotics, its further implications have not been considered. In fact, if the function of a protein represents the meaning of the genetic code (the sign's object), then it is crucial to reconsider the notion of its expression (the sign) as well. In our contribution, we will show that the actual model of the genetic code is not the only possible and we will propose a more appropriate model from a semiotic point of view.
Recent years have seen a great expansion in our understandings of how silent mutations can drive a disease and that mRNAs are not only mere messengers between the genome and the encoded proteins but also encompass regulatory activities. This review focuses on how silent mutations within open reading frames can affect the functional properties of the encoded protein. We describe how mRNAs exert control of cell biological processes governed by the encoded proteins via translation kinetics, protein folding, mRNA stability, spatio-temporal protein expression and by direct interactions with cellular factors. These examples illustrate how additional levels of information lie within the coding sequences and that the degenerative genetic code is not redundant and have co-evolved with the encoded proteins. Hence, so called synonymous mutations are not always silent but 'whisper'.
- MeSH
- genetický kód genetika MeSH
- kodon genetika MeSH
- lidé MeSH
- messenger RNA chemie genetika MeSH
- modely genetické MeSH
- mutace * MeSH
- otevřené čtecí rámce genetika MeSH
- proteiny chemie genetika metabolismus MeSH
- proteosyntéza genetika MeSH
- sbalování proteinů MeSH
- sbalování RNA MeSH
- stabilita RNA genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Almost all extant organisms use the same, so-called canonical, genetic code with departures from it being very rare. Even more exceptional are the instances when a eukaryote with non-canonical code can be easily cultivated and has its whole genome and transcriptome sequenced. This is the case of Blastocrithidia nonstop, a trypanosomatid flagellate that reassigned all three stop codons to encode amino acids. RESULTS: We in silico predicted the metabolism of B. nonstop and compared it with that of the well-studied human parasites Trypanosoma brucei and Leishmania major. The mapped mitochondrial, glycosomal and cytosolic metabolism contains all typical features of these diverse and important parasites. We also provided experimental validation for some of the predicted observations, concerning, specifically presence of glycosomes, cellular respiration, and assembly of the respiratory complexes. CONCLUSIONS: In an unusual comparison of metabolism between a parasitic protist with a massively altered genetic code and its close relatives that rely on a canonical code we showed that the dramatic differences on the level of nucleic acids do not seem to be reflected in the metabolisms. Moreover, although the genome of B. nonstop is extremely AT-rich, we could not find any alterations of its pyrimidine synthesis pathway when compared to other trypanosomatids. Hence, we conclude that the dramatic alteration of the genetic code of B. nonstop has no significant repercussions on the metabolism of this flagellate.
- MeSH
- Eukaryota genetika MeSH
- genetický kód MeSH
- paraziti * genetika MeSH
- terminační kodon MeSH
- Trypanosoma brucei brucei * genetika MeSH
- Trypanosomatina * genetika MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The site-specific chemical modification of proteins through incorporation of noncanonical amino acids enables diverse applications, such as imaging, probing, and expanding protein functions, as well as to precisely engineer therapeutics. Here we report a general strategy that allows the incorporation of noncanonical amino acids into target proteins using the amber suppression method and their efficient secretion in the biotechnological relevant expression host Bacillus subtilis. This facilitates efficient purification of target proteins directly from the supernatant, followed by their functionalization using click chemistry. We used this strategy to site-specifically introduce norbornene lysine into a single chain antibody and functionalize it with fluorophores for the detection of human target proteins.
- MeSH
- Bacillus subtilis genetika metabolismus MeSH
- click chemie MeSH
- CRISPR-Cas systémy MeSH
- ELISA MeSH
- genetické vektory MeSH
- genetický kód MeSH
- isopropylthiogalaktosid farmakologie MeSH
- kreatinkinasa, forma MM metabolismus MeSH
- lidé MeSH
- lysin chemie MeSH
- norbornany chemie MeSH
- proteinové inženýrství metody MeSH
- regulace genové exprese u bakterií účinky léků MeSH
- rekombinantní proteiny chemie genetika izolace a purifikace metabolismus MeSH
- zelené fluorescenční proteiny genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A limited number of non-canonical genetic codes have been described in eukaryotic nuclear genomes. Most involve reassignment of one or two termination codons as sense ones [1-4], but no code variant is known that would have reassigned all three termination codons. Here, we describe such a variant that we discovered in a clade of trypanosomatids comprising nominal Blastocrithidia species. In these protists, UGA has been reassigned to encode tryptophan, while UAG and UAA (UAR) have become glutamate encoding. Strikingly, UAA and, less frequently, UAG also serve as bona fide termination codons. The release factor eRF1 in Blastocrithidia contains a substitution of a conserved serine residue predicted to decrease its affinity to UGA, which explains why this triplet can be read as a sense codon. However, the molecular basis for the dual interpretation of UAR codons remains elusive. Our findings expand the limits of comprehension of one of the fundamental processes in molecular biology.
- MeSH
- buněčné jádro genetika MeSH
- fylogeneze MeSH
- genetický kód genetika MeSH
- kodon chemie genetika MeSH
- protozoální proteiny chemie genetika MeSH
- sekvence aminokyselin MeSH
- terminační kodon chemie genetika MeSH
- Trypanosomatina genetika MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Zvýšené hladiny lipoproteinu(a) jsou považovány za nezávislý rizikový faktor v procesu aterogeneze. Strukturní i funkční charakteristika částice lipoproteinu(a) je určena přítomností apolipoproteinu(a). Přestože jsou plazmatické hladiny tohoto lipoproteinu téměř zcela pod genetickou kontrolou genu pro apolipoprotein(a), vykazují značnou populační variabilitu. Velká část této variability je způsobena délkovým polymorfizmem genu pro apolipoprotein(a). Zbývající variabilita může být dána jak přítomností sekvenčních polymorfizmů v kódující sekvenci zmíněného genu, tak v jeho regulačních elementech. V kódující oblasti genu pro apolipoprotein(a) bylo zatím odhaleno jen málo polymorfních variant s funkčním významem. Rovněž analýza tří oblastí schopných regulovat expresi genu (promotor, zesilovače DHII a DHIII) prokázala nižší variabilitu, než se očekávalo. I přes dominantní úlohu jediného genu je genetická determinace hladin Lp(a) velice komplexní. Hlavní úlohu zde hraje délkový polymorfizmus genu pro apolipoprotein(a) a celá řada sekvenčních variant ovlivňujících jeho expresi a efektivitu tvorby lipoproteinové částice. Svou roli mají pravděpodobně i další genetické lokusy s minoritním účinkem a modulace negenetickými faktory.
Increased levels of lipoprotein(a) are supposed to be an independent risk factor for atherosclerosis. Apolipoprotein(a) determines structural and functional characteristics of the lipoprotein particle. The lipoprotein(a) concentration is almost entirely genetically determined at the apolipoprotein(a) gene locus, nevertheless it varies widely between individuals in all populations studied so far. Large part of the variance is correlated to the apolipoprotein(a) gene length polymorphism. Some of the variance could be additionally related to polymorphic sites either in the coding sequence or in the transcription regulatory regions. Only a few functional variants were discovered in the coding sequence of apolipoprotein(a) gene so far. Moreover, analyses of relevant regulatory regions (promoter, DHII and DHIII enhancers) have revealed less variability than was expected. Despite the lipoprotein(a) levels are under dominant control of a single locus its genetic determination is quite complex. The basic role belongs to the apolipoprotein(a) gene length polymorphism and to a panel of sequence variants affecting apolipoprotein(a) gene expression and lipoprotein(a) particle production rate. Besides, minor impact of other locuses and modulation by non–genetic factors should be considered.
