Editing Codon usage bias (section)

=== Effect on transcription or gene expression ===
[[Heterologous expression|Heterologous gene expression]] is used in many biotechnological applications, including protein production and [[metabolic engineering]]. Because tRNA pools vary between different organisms, the rate of [[transcription (genetics)|transcription]] and translation of a particular coding sequence can be less efficient when placed in a non-native context. For an overexpressed [[transgene]], the corresponding mRNA makes a large percent of total cellular RNA, and the presence of rare codons along the [[primary transcript|transcript]] can lead to inefficient use and depletion of ribosomes and ultimately reduce levels of heterologous protein production. In addition, the composition of the gene (e.g. the total number of rare codons and the presence of consecutive rare codons) may also affect translation accuracy.<ref name = "pmid17017124">{{Cite journal | pmid = 17017124| pmc = 6032470| year = 2006|author1=Shu, P. |author2=Dai, H. |author3=Gao, W. |author4=Goldman, E. | title = Inhibition of translation by consecutive rare leucine codons in E. coli: absence of effect of varying mRNA stability. | journal = Gene Expr. | volume = 13| issue = 2| pages = 97–106| doi = 10.3727/000000006783991881}}</ref><ref name = "pmid31509345">{{Cite journal | pmid = 31509345 | year = 2019|author1=Correddu, D. |author2=Montaño López, J. d. J. |author3=Angermayr, S. A. |author4=Middleditch, M. J. |author5=Payne, L. S. |author6=Leung, I. K. H. | title = Effect of Consecutive Rare Codons on the Recombinant Production of Human Proteins in Escherichia coli. | journal = [[IUBMB Life]] | volume = 72| issue = 2| pages = 266–274| doi =10.1002/iub.2162 | hdl = 11343/286411| s2cid = 202555575| hdl-access = free}}</ref> However, using codons that are optimized for tRNA pools in a particular host to overexpress a heterologous gene may also cause amino acid starvation and alter the equilibrium of tRNA pools. This method of adjusting codons to match host tRNA abundances, called [[codon optimization]], has traditionally been used for expression of a heterologous gene. However, new strategies for optimization of heterologous expression consider global nucleotide content such as local mRNA folding, codon pair bias, a codon ramp, [[codon harmonization]] or codon correlations.<ref name = "pmid29624661">{{Cite journal | pmid = 29624661| year = 2018|author1=Mignon, C. |author2=Mariano, N. |author3=Stadthagen, G. |author4=Lugari, A. |author5=Lagoutte, P. |author6=Donnat, S. |author7=Chenavas, S. |author8=Perot, C. |author9=Sodoyer, R. |author10=Werle, B. | title = Codon harmonization - going beyond the speed limit for protein expression. | journal = [[FEBS Letters]] | volume = 592| issue = 9| pages = 1554–1564| doi = 10.1002/1873-3468.13046| doi-access = free}}</ref><ref name = "pmid21102527">{{Cite journal | pmid = 21102527| pmc = 3074964| year = 2011| last1 = Plotkin| first1 = J. B.| title = Synonymous but not the same: The causes and consequences of codon bias| journal = Nature Reviews Genetics| volume = 12| issue = 1| pages = 32–42| last2 = Kudla| first2 = G| doi = 10.1038/nrg2899}}</ref> With the number of nucleotide changes introduced, [[artificial gene synthesis]] is often necessary for the creation of such an optimized gene.

Specialized codon bias is further seen in some [[endogenous]] genes such as those involved in amino acid starvation. For example, [[amino acid synthesis|amino acid biosynthetic]] enzymes preferentially use codons that are poorly adapted to normal tRNA abundances, but have codons that are adapted to tRNA pools under starvation conditions. Thus, codon usage can introduce an additional level of transcriptional regulation for appropriate gene expression under specific cellular conditions.<ref name = "pmid21102527" />