Structural gene

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A structural gene is a gene that codes for any RNA or protein product other than a regulatory factor (i.e. regulatory protein). Structural genes are typically viewed as those containing sequences of DNA corresponding to the amino acids of a protein that will be produced, as long as said protein does not function to regulate gene expression. Structural gene products include enzymes and structural proteins. Also encoded by structural genes are non-coding RNAs, such as rRNAs and tRNAs (but excluding any regulatory miRNAs and siRNAs).

Contents

The distinction between structural and regulatory genes can be traced back to 1959 and work by Pardee, Jacob, and Monod—the so-called PaJaMo experiment—on the lac operon and the synthesis of proteins in E. coli . In that system, a single regulatory protein was detected that affected the transcription of the other proteins now known to compose the lac operon. [1]

Placement in the genome

In prokaryotes, structural genes of related function are typically adjacent to one another on a single strand of DNA, forming an operon. This permits simpler regulation of gene expression, as a single regulatory factor can affect transcription of all associated genes. This is best illustrated by the well-studied lac operon, in which three structural genes ( lacZ , lacY , and lacA ) are all regulated by a single promoter and a single operator. Prokaryotic structural genes are transcribed into a polycistronic mRNA and subsequently translated. [2]

In eukaryotes, structural genes are not sequentially placed. Each gene is instead composed of coding exons and interspersed non-coding introns. Regulatory sequences are typically found in non-coding regions upstream and downstream from the gene. Structural gene mRNAs must be spliced prior to translation to remove intronic sequences. This in turn lends itself to the eukaryotic phenomenon of alternative splicing, in which a single mRNA from a single structural gene can produce several different proteins based on which exons are included. Despite the complexity of this process, it is estimated that up to 94% of human genes are spliced in some way. [3] Furthermore, different splicing patterns occur in different tissue types. [4]

An exception to this layout in eukaryotes are genes for histone proteins, which lack introns entirely. [5] Also distinct are the rDNA clusters of structural genes, in which 28S, 5.8S, and 18S sequences are adjacent, separated by short internally transcribed spacers, and likewise the 45S rDNA occurs five distinct places on the genome, but is clustered into adjacent repeats. In eubacteria these genes are organized into operons. However, in archaebacteria these genes are non-adjacent and exhibit no linkage. [6]

Role in human disease

The identification of the genetic basis for the causative agent of a disease can be an important component of understanding its effects and spread. Location and content of structural genes can elucidate the evolution of virulence, [7] as well as provide necessary information for treatment. Likewise understanding the specific changes in structural gene sequences underlying a gain or loss of virulence aids in understanding the mechanism by which diseases affect their hosts. [8]

For example, Yersinia pestis (the bubonic plague) was found to carry several virulence and inflammation-related structural genes on plasmids. [9] Likewise, the structural gene responsible for tetanus was determined to be carried on a plasmid as well. [10] Diphtheria is caused by a bacterium, but only after that bacterium has been infected by a bacteriophage carrying the structural genes for the toxin. [11]

In Herpes simplex virus, the structural gene sequence responsible for virulence was found in two locations in the genome despite only one location actually producing the viral gene product. This was hypothesized to serve as a potential mechanism for strains to regain virulence if lost through mutation. [12]

Understanding the specific changes in structural genes underlying a gain or loss of virulence is a necessary step in the formation of specific treatments, as well the study of possible medicinal uses of toxins. [11]

Phylogenetics

As far back as 1974, DNA sequence similarity was recognized as a valuable tool for determining relationships among taxa. [13] Structural genes in general are more highly conserved due to functional constraint, and so can prove useful in examinations of more disparate taxa. Original analyses enriched samples for structural genes via hybridization to mRNA. [14]

More recent phylogenetic approaches focused on structural genes of known function, conserved to varying degrees. rRNA sequences frequent targets, as they are conserved in all species. [15] Microbiology has specifically targeted the 16S gene to determine species level differences. [16] In higher-order taxa, COI is now considered the “barcode of life,” and is applied for most biological identification. [17]

Debate

Despite the widespread classification of genes as either structural or regulatory, these categories are not an absolute division. Recent genetic discoveries call into question the distinction between regulatory and structural genes, [18] suggesting greater complexity. Structural gene expression is regulated by numerous factors including epigenetics (e.g. methylation) and RNA interference (RNAi). Structural genes and even regulatory genes themselves can be epigenetically regulated identically, so not all regulation is coded for by “regulatory genes”. [18]

There are also examples of proteins that do not decidedly fit either category, such as chaperone proteins. These proteins aid in the folding of other proteins, a seemingly regulatory role. [19] [20] Yet these same proteins also aid in the movement of their chaperoned proteins across membranes, [21] and have now been implicated in immune responses (see Hsp60) [22] and in the apoptotic pathway (see Hsp70). [23]

More recently, microRNAs were found to be produced from the internal transcribed spacers of rRNA genes. [24] Thus an internal component of a structural gene is, in fact, regulatory. Binding sites for microRNAs were also detected within coding sequences of genes. Typically interfering RNAs target the 3’UTR, but inclusion of binding sites within the sequence of the protein itself allows the transcripts of these proteins to effectively regulate the microRNAs within the cell. This interaction was demonstrated to have an effect on expression, and thus again a structural gene contains a regulatory component. [25]

References

  1. ↑ Pardee, Arthur B.; Jacob, François; Monod, Jacques (1959-06-01). "The genetic control and cytoplasmic expression of "Inducibility" in the synthesis of β-galactosidase by E. coli". Journal of Molecular Biology. 1 (2): 165–178. doi:10.1016/S0022-2836(59)80045-0.
  2. ↑ Müller-Hill, Benno (1996-01-01). The Lac Operon: A Short History of a Genetic Paradigm. Walter de Gruyter. ISBN   9783110148305.
  3. ↑ Wang, Eric T.; Sandberg, Rickard; Luo, Shujun; Khrebtukova, Irina; Zhang, Lu; Mayr, Christine; Kingsmore, Stephen F.; Schroth, Gary P.; Burge, Christopher B. (2008). "Alternative isoform regulation in human tissue transcriptomes". Nature. 456 (7221): 470–476. Bibcode:2008Natur.456..470W. doi:10.1038/nature07509. PMC   2593745 . PMID   18978772.
  4. ↑ Yeo, Gene; Holste, Dirk; Kreiman, Gabriel; Burge, Christopher B. (2004-01-01). "Variation in alternative splicing across human tissues". Genome Biology. 5 (10): R74. doi: 10.1186/gb-2004-5-10-r74 . ISSN   1474-760X. PMC   545594 . PMID   15461793.
  5. ↑ Makałowski, W. (2001-01-01). "The human genome structure and organization". Acta Biochimica Polonica. 48 (3): 587–598. doi: 10.18388/abp.2001_3893 . ISSN   0001-527X. PMID   11833767.
  6. ↑ Tu, J; Zillig, W (1982-11-25). "Organization of rRNA structural genes in the archaebacterium Thermoplasma acidophilum". Nucleic Acids Research. 10 (22): 7231–7245. doi:10.1093/nar/10.22.7231. ISSN   0305-1048. PMC   327000 . PMID   7155894.
  7. ↑ Sreevatsan, Srinand; Pan, Xi; Stockbauer, Kathryn E.; Connell, Nancy D.; Kreiswirth, Barry N.; Whittam, Thomas S.; Musser, James M. (1997-09-02). "Restricted structural gene polymorphism in the Mycobacterium tuberculosis complex indicates evolutionarily recent global dissemination". Proceedings of the National Academy of Sciences. 94 (18): 9869–9874. Bibcode:1997PNAS...94.9869S. doi: 10.1073/pnas.94.18.9869 . ISSN   0027-8424. PMC   23284 . PMID   9275218.
  8. ↑ Maharaj, Payal D.; Anishchenko, Michael; Langevin, Stanley A.; Fang, Ying; Reisen, William K.; Brault, Aaron C. (2012-01-01). "Structural gene (prME) chimeras of St Louis encephalitis virus and West Nile virus exhibit altered in vitro cytopathic and growth phenotypes". Journal of General Virology. 93 (1): 39–49. doi:10.1099/vir.0.033159-0. PMC   3352334 . PMID   21940408.
  9. ↑ Brubaker, Robert R. (2007-08-01). "How the structural gene products of Yersinia pestis relate to virulence". Future Microbiology. 2 (4): 377–385. doi:10.2217/17460913.2.4.377. ISSN   1746-0921. PMID   17683274.
  10. ↑ Finn, C. W.; Silver, R. P.; Habig, W. H.; Hardegree, M. C.; Zon, G.; Garon, C. F. (1984-05-25). "The structural gene for tetanus neurotoxin is on a plasmid". Science. 224 (4651): 881–884. Bibcode:1984Sci...224..881F. doi:10.1126/science.6326263. ISSN   0036-8075. PMID   6326263.
  11. 1 2 Greenfield, L.; Bjorn, M. J.; Horn, G.; Fong, D.; Buck, G. A.; Collier, R. J.; Kaplan, D. A. (1983-11-01). "Nucleotide sequence of the structural gene for diphtheria toxin carried by corynebacteriophage beta". Proceedings of the National Academy of Sciences of the United States of America. 80 (22): 6853–6857. Bibcode:1983PNAS...80.6853G. doi: 10.1073/pnas.80.22.6853 . ISSN   0027-8424. PMC   390084 . PMID   6316330.
  12. ↑ Knipe, David; Ruyechan, William; Honess, Robert; Roizman, Bernard (1979). "Molecular genetics of Herpes Simplex Virus: The terminal sequences of the L and S components are obligatorily identical and constitute a part of structural gene mapping predominantly in the S component" (PDF). Proceedings of the National Academy of Sciences of the United States of America. 76 (9): 4534–4538. Bibcode:1979PNAS...76.4534K. doi: 10.1073/pnas.76.9.4534 . PMC   411612 . PMID   228300.
  13. ↑ Moore, R. L. (1974-01-01). "Nucleic Acid Reassociation as a Guide to Genetic Relatedness among Bacteria". Modern Aspects of Electrochemistry. Current Topics in Microbiology and Immunology. Vol. 64. pp. 105–128. doi:10.1007/978-3-642-65848-8_4. ISBN   978-3-642-65850-1. ISSN   0070-217X. PMID   4602647.
  14. ↑ Angerer, R. C.; Davidson, E. H.; Britten, R. J. (1976-07-08). "Single copy DNA and structural gene sequence relationships among four sea urchin species". Chromosoma. 56 (3): 213–226. doi:10.1007/bf00293186. ISSN   0009-5915. PMID   964102. S2CID   26007034.
  15. ↑ Pruesse, E.; Quast, C.; Knittel, K.; Fuchs, B. M.; Ludwig, W.; Peplies, J.; Glockner, F. O. (2007-12-01). "SILVA: a comprehensive online resource for quality checked and aligned ribosomal RNA sequence data compatible with ARB". Nucleic Acids Research. 35 (21): 7188–7196. doi:10.1093/nar/gkm864. ISSN   0305-1048. PMC   2175337 . PMID   17947321.
  16. ↑ Chun, Jongsik; Lee, Jae-Hak; Jung, Yoonyoung; Kim, Myungjin; Kim, Seil; Kim, Byung Kwon; Lim, Young-Woon (2007-01-01). "EzTaxon: a web-based tool for the identification of prokaryotes based on 16S ribosomal RNA gene sequences". International Journal of Systematic and Evolutionary Microbiology. 57 (10): 2259–2261. doi: 10.1099/ijs.0.64915-0 . PMID   17911292.
  17. ↑ Hebert, Paul D. N.; Cywinska, Alina; Ball, Shelley L.; deWaard, Jeremy R. (2003-02-07). "Biological identifications through DNA barcodes". Proceedings of the Royal Society of London B: Biological Sciences. 270 (1512): 313–321. doi:10.1098/rspb.2002.2218. ISSN   0962-8452. PMC   1691236 . PMID   12614582.
  18. 1 2 Piro, Rosario Michael (2011-03-29). "Are all genes regulatory genes?". Biology & Philosophy. 26 (4): 595–602. doi:10.1007/s10539-011-9251-9. ISSN   0169-3867. S2CID   16289510.
  19. ↑ Hendrick, J. P.; Hartl, F. U. (1995-12-01). "The role of molecular chaperones in protein folding". FASEB Journal. 9 (15): 1559–1569. doi: 10.1096/fasebj.9.15.8529835 . ISSN   0892-6638. PMID   8529835. S2CID   33498269.
  20. ↑ Saibil, Helen (2013-10-01). "Chaperone machines for protein folding, unfolding and disaggregation". Nature Reviews Molecular Cell Biology. 14 (10): 630–642. doi:10.1038/nrm3658. ISSN   1471-0072. PMC   4340576 . PMID   24026055.
  21. ↑ Koll, H.; Guiard, B.; Rassow, J.; Ostermann, J.; Horwich, A. L.; Neupert, W.; Hartl, F. U. (1992-03-20). "Antifolding activity of hsp60 couples protein import into the mitochondrial matrix with export to the intermembrane space" (PDF). Cell. 68 (6): 1163–1175. doi:10.1016/0092-8674(92)90086-r. ISSN   0092-8674. PMID   1347713. S2CID   7430067.
  22. ↑ Hansen, Jens J.; Bross, Peter; Westergaard, Majken; Nielsen, Marit Nyholm; Eiberg, Hans; Børglum, Anders D.; Mogensen, Jens; Kristiansen, Karsten; Bolund, Lars (2003-01-01). "Genomic structure of the human mitochondrial chaperonin genes: HSP60 and HSP10 are localised head to head on chromosome 2 separated by a bidirectional promoter". Human Genetics. 112 (1): 71–77. doi:10.1007/s00439-002-0837-9. ISSN   0340-6717. PMID   12483302. S2CID   25856774.
  23. ↑ Cappello, Francesco; Di Stefano, Antonino; David, Sabrina; Rappa, Francesco; Anzalone, Rita; La Rocca, Giampiero; D'Anna, Silvestro E.; Magno, Francesca; Donner, Claudio F. (2006-11-15). "Hsp60 and Hsp10 down-regulation predicts bronchial epithelial carcinogenesis in smokers with chronic obstructive pulmonary disease". Cancer. 107 (10): 2417–2424. doi: 10.1002/cncr.22265 . ISSN   0008-543X. PMID   17048249.
  24. ↑ Son, Dong Ju; Kumar, Sandeep; Takabe, Wakako; Kim, Chan Woo; Ni, Chih-Wen; Alberts-Grill, Noah; Jang, In-Hwan; Kim, Sangok; Kim, Wankyu (2013-12-18). "The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis". Nature Communications. 4: 3000. Bibcode:2013NatCo...4.3000S. doi:10.1038/ncomms4000. ISSN   2041-1723. PMC   3923891 . PMID   24346612.
  25. ↑ Forman, Joshua J.; Coller, Hilary A. (2010-04-15). "The code within the code: microRNAs target coding regions". Cell Cycle. 9 (8): 1533–1541. doi:10.4161/cc.9.8.11202. ISSN   1538-4101. PMC   2936675 . PMID   20372064.
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