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Masters seminar on

codon usage bias and its utilizationSpeaker : Deshmukh AbasahebID: 49489

Content :IntroductionTheory behind the codon biasPattern of codon usage bias in speciesFactors affecting codon biasEffect of codon usage biasMeasurement of codon usage bias Application of codon usage biasConclusion

Codon usage bias The differences in the frequency of occurrence of synonymous codon in coding DNA or in mRNA transcript.What is codon?What is synonymous codon? Why there is differences in frequency of occurence of syn. Codon?GENETIC CODE

The genetic code is the set of rules by which information encoded in mRNA sequences is converted into proteins (amino acid sequences) by living cellsCodons are a triplet of bases which encodes a particular amino acidAs there are four bases, there are 64 different codon combinations (4 x 4 x 4 = 64)The order of the codons determines the amino acid sequence for a proteinThe coding region always starts with a START codon (AUG) and terminates with a STOP codon either by ( UAA/ UGA/ UAG).

The Genetic Code

DEGENARATEORDEREDCOMMA- FREENEARLY UNIVERSALCOMPOSED OF NUCLEOTIDE TRIPLETNON OVERLAPPING

6Because of the degeneracy of all genetic codes, 18-20 amino acids are encoded by more than one codon (2, 3, 4, or 6).

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Degeneracy of codon

TTT (Phenylalanine)CTT (leucine) ATT (Isoleucine) GTT (Valine).

GAT and GAC code for Aspartic acidGAA and GAG code for Glutamic acid

There is only 1 threefold degenerate site: the 3rd position of an isoleucine codon. ATT, ATC, or ATA all encode isoleucine, but ATG encodes methionine.

Fourfold degenerate sites: are codon positions where changing a nucleotide in any of the 3 alternatives has no effect on the amino acid.Five amino-acids are encoded by 4 codons which differ only in the third position. These sites are called fourfold degenerate sites

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Codon-usage bias

Codon bias is the probability that a given codon will be used to code for an amino acid over a different codon which codes for the same amino acid.

Brian Clark (1970)

10Biases in synonymous codon usage can be explained by: (1) mutational bias theory(2) selection favoring preferred codon theoryTheory for codon usage bias

11Mutational Bias theory (osawa et al.,1988)If the unequal codon-usage is due to biases in mutation patterns, then the expectation is that the magnitude and the direction of the bias will be more or less the same for all codon families and for all genes, regardless of function or expression levels. Let us assume that the mutation pattern in an organism tends to result in AT rich sequences. Under such a mutational regime, it is expected that all four-fold degenerate codon families will exhibit a preference for codons ending in A or T. Thus, the preferred codons for valine should be GTA and GTT and the preferred codons for arginine should be CGA and CGT.

Chemical decay of nucleotide bases (Kaufmann and Paules, 1996) Non-uniform DNA repair

Non-random replication errors

12Mutational BiasesSome bacterial genomes (e.g., Mycoplasma capricolum), exhibit this type of consistent codon-usage bias. Mycoplasma capricolum shows G+C rich mutational pattern.Codon familyAmino acidG/C in 3rd (%)A/T in 3rd (%)CULEU937GUVAL955UCSER982CCPRO955ACTHR982GCALA946CGARG1000GGGLY955

most amino acids allow synonymous GC content changing substitutions in the third codon position, the overall GC bias of a genome or genomic region is highly correlated with GC3, a measure of third position GC content.For individual amino acids as well, G/C ending codons usage generally increases with increasing GC bias and decreases with increasing AT bias

Principal Findings: Two G-ending codons, AGG (arginine) and TTG (leucine), unlike all other G/C-ending codons, show overall usage that decreases with increasing GC bias, contrary to the usual expectation that G/C-ending codon usage should increase with increasing genomic GC bias. Moreover, the usage of some codons appears nonlinear, as a function of GC bias. a continuous-time Markov chain model of GC-biased synonymous substitution. This model correctly predicts the qualitative usage patterns of all codons, including nonlinear codon usage in isoleucine, arginine and leucine.The model accounts for 72%, 64% and 52% of the observed variability of codon usage in prokaryotes, plants and human respectively.When codons are grouped based on common GC content, 87%, 80% and 68%of the variation in usage is explained for prokaryotes, plants and human respectivelyOct,2010

Theory of selection favoring preferred codon 15Two selective factors have been convincingly invoked to explain codon usage bias.

(1) translation optimization(2) folding stability of the protein

Selection for translation efficiencyThe correlation between codon frequency and abundant cognate tRNAs was a compelling argument for natural selection choosing between synonymous codons

The three main parameters that affect translation efficiency are The maximum turnover of ribosomes, (ii) The efficiency of aminoacyl-tRNA matching (iii) Ternary complex concentrations (Kurland1991).

Ikemura (1981b) described an optimal codon as one that satisfied certain rules of codon choice; the predominant rule is that they are translated by the most abundant cognate tRNA.

Codons that are recognized by the major tRNAs are translated 36 fold faster than their synonyms (Sorensen, Kurland and Pedersen 1989).

The translation efficiency of a codon is related to the relative quantity of tRNA molecules that recognize the particular codon. -Ikemura (1981b)

Selection for translation accuracyThe rate of initial codon recognition can vary up to 25 fold with optimal codons being recognised most rapidly results into faster translation (Curran and Yarus 1988)

Since the number of ribosomes is often limiting; The consequence of faster translation is that ribosomes spend less time on the mRNA, thus increasing the number of free ribosomes and increasing the number of mRNAs translated per ribosome. (Ikemura 1985) It has been estimated that in E. coli the non-optimal Asn codon AAU can be mistranslated eight to ten times more often than its optimal synonym AAC (Parker et al. 1983; Percup and Parker 1987)

Similarly in some contexts the non-optimal codon UUU (Phe) is frequently misread as a leucine codon (Parker et al. 1992)

19 Is codon usage bias uniform along the length of the mRNA?

For many highly expressed genes, codons recognized by low abundance tRNAs are overrepresented in the 5 region of the coding region. This pattern suggests that ribosomes translate more slowly over the initial 50 codons or so (the so-called ramp stage) and then translate the remainder of the mRNA at full speed.

Ramp stage(Tuller et al. 2010)

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What purpose does the ramp play in translation?Faster translation elongation immediately after slower initiation effectively generates more uniform spacing between ribosomes further down the mRNA prevents ribosome congestion & translation stalling and termination.

21The length of the ramp corresponds well to the length of the polypeptide needed to fill the exit tunnel of the ribosome. so the nascent peptide chain should emerge from the ribosome as it transitions from the slow ramp stage to the fast stage of elongation. This raises the possibility that the slowdown in the ramp might increase the fraction of correctly folded product.

Another potential role for the ramp involves protein foldingSelection for stable protein folding

22Codon arrangement along the mRNA

The arrangement of different codons along the length of the mRNA influences translation efficiency. In the autocorrelated pattern, when an amino acid recurs in the protein, there is a strong propensity to use the same codon the second time as that for the first occurrence of the amino acid. In the anticorrelated pattern, when an amino acid recurs in the protein, there is a strong tendency to use a different codon the second time from that used in the first occurrence of the amino acid.

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Literature cited

2009

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Universal and species-specific patterns of codon usage

Jan C Biro 2008 ; studies on the origin & evolution of codon bias,

Codon usage in nuclear genes of four monocot ( rice, maize, wheat, barley) & three dicot species(Arabidopsis, Nicotiana tabacum & Pisum sativum) was analysed to find general pattern in codon choice of plant spp.

Codon bias was correlated with GC content at the third codon position.GC contents were higher in monocot species than in dicot spp at all codon positionThe high GC contents of monocot spp might be the result of relatively stronger mutational bias that occurred in lineage of poaceae spp.In both spp. ENC for most genes was similar to that for expected enc based on GC content at the third codon positions. G & C ending codons were detected as the preferred codons in monocot spp.Pyrimidine (C & T ) is used more frequently than purine (G & A) in four fold degenerate codon groups.

29The genome hypothesis All genes in a genome tend to have the same coding strategy. That is, they employ the codon catalog similarly and show similar choices between synonymous codons.

Different taxa have different coding strategies.

Richard Grantham

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Are there universal preferences?There are NO universally preferred or universally avoided codons.There may be some universal preferences and avoidances as far as codon neighbor pairs are concerned. For example, the pair NN

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