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Codon Reiteration and the Evolution of Proteins Proc. Nati. Acad. Sci. USA Vol. 91, pp. 4298-4302, May 1994 Evolution Codon reiteration and the evolution of proteins HOWARD GREEN AND NORMAN WANG Department of Cell Biology, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115 Contributed by Howard Green, January 18, 1994 ABSTRACT Sequence data banks have been searched for dropped out, leaving few reiterants of hydrophobic amino proteins possessing uninterrupted reiterations of any amino acids. There is no reiterant of arginine. acid. Hydrophilic amino acids, and particularly glutamine, Among reiterants containing 20 or more residues, gluta- account for a large proportion of the longer reiterants. In the mine is clearly dominant and accounts for half of all reiter- genes for these proteins, the most common reiterants are those ants. The other nine amino acid residues found in reiterants that contain poly(CAG), even out-of-frame or, to a lesser are mainly hydrophilic. degree, those that contain repeated doublets ofCA, AG, or GC. The preferential generation of such reiterants requires that Codons Responsible for Reiterants of 10 or More Amino DNA strand-specific signals predispose to reiteration and thus Acid Residues to the extension of coding regions. Of the 229 reiterants, there are only 48 that are encoded by Sequences consisting of multiple consecutive residues of a uninterrupted reiterations of a single codon; most of the single amino acid (reiterants) are not rare in proteins. For amino acid reiterants are the result of mixed synonymous example, reiterants consisting of glutamine residues, most codons. Probably some of these were originally reiterants of often encoded by CAG, were first discovered in homeotic a single codon, but nucleotide substitutions have since oc- proteins (1-3) and later in other transcription factors. In the curred within the sequence. In examining the frequency of case of the gene for involucrin, CAG reiteration seems to codons responsible for amino acid reiterants, we have con- have been the means by which the coding region was gen- sidered only the uninterrupted codon reiterants (Fig. 2). Of erated (4-6). Human genetic diseases due to triplet reitera- these, only 1 is in a prokaryote (Mycoplasma). tion are the result of uncontrolled action of the reiteration The reiterants may be divided into two classes according to mechanism used in evolution (7). whether the reiterated codon does or does not bear some To see what rules govern the reiteration process, we have resemblance to the codon CAG (Table 1). Of the total of 48 analyzed the available data on the amino acid reiterants that reiterants, CAG accounts for 15. Two codons, AGC (Ser) and have been introduced into proteins and on the nature of the GCA (Ala), are permutations of CAG and, when reiterated, responsible codons. We describe here the preferential reit- give rise to out-of-frame reiterations of CAG; these two eration of trinucleotides resembling the glutamine codon codons account for 6 reiterants. CAG. The six serine reiterants are encoded by only two of its six synonymous codons. Of these two, only AGC, when reiter- Incidence of Amino Acid Reiterants of Different Lengths ated, gives rise to out-of-frame poly(CAG), and this codon is responsible for five of the six examples of reiterated serine. A search was made of three sequence data banks (GenBank, This is so even though AGC is not particularly prominent GenBank Update, and the Brookhaven Protein Data Bank) among the serine codons used for a range of microbial, using BLAST (8) for sequences consisting of uninterrupted Drosophila, and human proteins (11). The only other serine amino acid reiterants of different length. The frequency of codon found to be reiterated, TCA, contains the dinucleotide reiterants containing five to nine identical amino acid resi- CA. Of the four nonreiterated serine codons, three lack any dues is shown in Fig. 1A. In general, the frequency of resemblance to CAG. Similarly, GCA is the only alanine reiterants ofeach amino acid correlates with its abundance in codon (of four) whose reiteration gives rise to out-of-frame proteins: leucine and alanine, the most abundant, are the poly(CAG) and is the only codon responsible for an alanine most frequently reiterated, whereas tryptophan and cysteine, reiterant. Accumulation of clusters of CAG and of permuta- the least abundant, are virtually not reiterated. This suggests tions of that trinucleotide have been noted earlier in the gene that for some amino acids, the principal factor affecting the for hunchback (hb) in one of two lineages ofDrosophila (12) frequency of reiterants of five to nine residues is the abun- and in vertebrate and Drosophila genes for the TATA-binding dance of the amino acid; but even for this length of reiterant, protein (TBP) (13). there are amino acids, such as valine and isoleucine, that are Of the remaining reiterated codons listed in Table 1, 20 underreiterated in relation to their abundance in proteins. possess the doublets CA, AG, or GC. Of the 10-codon Reiterants containing 10-14 residues (Fig. 1B) are quite reiterants that do not possess at least one of these dinucle- different from those containing 5-9 residues. Glutamine, otides, there are 6 examples of poly(AAT) (Asn), found only which is not a very abundant amino acid, is the most in microorganisms, and 1 example ofpoly(GAT) (Asp). Ifthe frequently reiterated. Leucine, the most abundant amino rules ofreiteration are somewhat different in microorganisms acid, is infrequently reiterated, and there are no reiterants of and this group is eliminated, there is left in animals and plants valine, isoleucine, tyrosine, methionine, cysteine, and tryp- only a single reiterant of >10 codons lacking all of the three tophan. There are also no lysine reiterants. dinucleotides [poly(GAT)]. None ofthe reiterated codons are Among reiterants containing 15-19 residues (Fig. 1C), triplets of a single nucleotide. glutamine is still the most frequent; phenylalanine has A summary of the relation between the frequency of reiterants and the resemblance of their codons to CAG is in Table 2. The three codons giving rise to reiterated The publication costs ofthis article were defrayed in part by page charge given payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. Abbreviation: TBP, TATA-binding protein. 4298 Downloaded by guest on September 30, 2021 Evolution: Green and Wang Proc. Natl. Acad. Sci. USA 91 (1994) 4299 A B 10-14 1400 T 5-9 1o 1000 800 6600 4 400 E 2000 0 L A G S V E T I R D K P N F Q Y M H C W L A G S V E T I R D K P N F Q Y M H C W C D 25 T 15-19 25 T 220 20 t w 20 n qp 15 + O 15 -- C.42 410 0 10 6 10 .. t .0 0 z 5 Z 5 -, M. l .i.i.i . l.'...,.. m .N -_-._ .II L A G S V E T I R D K P N F Q Y M H C W L A G S V E T I R D K P N F Q Y M H C W FIG. 1. Amino acid reiterants in proteins. The protein data banks were searched for uninterrupted reiterants of each amino acid. Each panel gives a different range of reiterant lengths. (A) Frequency of reiterants of five to nine identical amino acid residues, uncorrected for duplicate entries. Included is the abundance ofeach amino acid in a large number ofproteins ofmolecular mass 20-50 kDa taken from ref. 9. For reiterants of greater length (B-D), duplicates have been removed. Note scale changes on ordinates. CAG codons account for 21 of the reiterants or 44% of the at the 5' end of the reiterated CAA codons, this CAG, rather total. These three codons have a frequency of reiteration per than the adjacent CAA codons, was reiterated. codon that is 30 times higher than codons lacking any Mixed Reiterations. In the glucose repression mediator resemblance to CAG. The reiteration frequency of codons SSN6 or CYC8 (20) of Saccharomyces cerevisiae, there is a containing two nucleotides of the three is intermediate, CA stretch of 64 residues consisting almost entirely of alternating being most important and GC the least. If microbial forms glutamine and alanine residues. In the encoding DNA, (GCA- were excluded from the comparisons, the ratio of reiterants CAA-GCA-CAA, etc.), 184 nucleotides (95%) of the total of containing CAG to reiterants lacking CA, AG, and GC would 192 form CA, AG, or GC doublets. This sequence lies imme- be much higher. diately 5' of a sequence of 27 codons of almost homogeneous poly(CAA). It seems clear that near the 5' end of this stretch, Multiple Codon Reiterants in a Single Gene two events of substitution or of insertion/deletion led to the formation of the codon GCA. The pair of codons GCA-CAA Near a reiterant in a coding region, there may be a second was then reiterated, extending the alternation in the 5' direc- reiterant. For example, in the Drosophila notch gene (2) and tion; the reiteration mechanism must have acted, not on a in the LPMC61 antigen of Eimeria tenella (14), poly(CAG) trinucleotide, but on the hexanucleotide or some multiple ofit. stretches may be separated from each other by as little as one Low Frequency of T. It was pointed out earlier that the triplet that diverges from CAG by a single nucleotide. This sense strand of the involucrin gene, whose evolution prob- suggests that the poly(CAG) stretches belong to a single longer ably began by CAG reiteration, has a low T content (4).
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