Evolutionary Anthropology 14:6–11 (2005) CROTCHETS & QUIDDITIES “The” Genetic Code? KENNETH M. WEISS AND ANNE V. BUCHANAN The DNA-based code for protein through messenger and transfer RNA is widely themselves, that carry the informa- regarded as the code of life. But genomes are littered with other kinds of coding tion. elements as well, and all of them probably came after a supercode for the tRNA Your life depends on the fidelity of system itself. these many codes. Aberrant codes re- lated to cell behavior can lead to dys- genesis or various metabolic diseases. Evolution and the diversification of Everyone knows of “the” genetic Anomalous cell-surface proteins can organisms are made possible by code, by which nucleotide triplets in cause autoimmune destruction, and vi- codes, or arbitrary assignments of DNA in the nucleus of cells specify the ruses are the Alan Turings of life that “meaning,” in multiple ways. Many amino acid (aa) sequence of proteins. evolve ways to break their receptor are not widely appreciated. Codes al- This is the code described in text- codes to gain illicit entry into cells (Fig. low the same system of components books as the heart of the genetic the- 1). to be used for multiple purposes. ory of life and its evolution. Discover- But there is an additional code, a These can be open-ended, the way the ies in recent years have made things code of codes, that makes all of this alphabet and vocabulary make this more complicated by showing that ge- possible, including “the” genetic code column possible, but the flexibility of nomes are littered with all sorts of itself, and may be the oldest and most a code can become constrained once a other kinds of coding elements. An ex- fundamental one of all. Protein-cod- system with many components that ample is DNA sequences located near ing (Figure 2) works via two interme- must work in concert, if an organism to protein-coding segments—“genes” diaries: messenger RNA (mRNA), a is to develop and survive—or evolve— proper—that are chemically recog- complementary copy of code tran- is in place. Codes are highly efficient nized by regulatory proteins, which scribed from a coding region of DNA, ways to carry uncorrupted informa- bind there to cause the nearby gene to and transfer RNA (tRNA), which car- tion from one place to enable indirect be expressed (or repressed) in specific ries aa’s to ribosomes to be linked to- action elsewhere. But this requires a cells or under specific conditions.1,2 gether to form a chain (polypeptide) decryption system at the receiving This gene-expression mechanism is as that becomes a protein, thus translat- end. fundamental as the classical genetic ing “the” genetic code. If mRNA takes Fidelity at both ends is vital. In code, because it allows cells to differ- a message to ribosomes, tRNA is the World War II, the Germans had their entiate into organs and tissues, en- Enigma decrypter that turns the code Enigma encryption machine, whose abling organisms from plants to peo- into action (a protein). As important use by U-boats caused chaos for Brit- ple to exist. The cells in the eyes you’re as the genetic protein code itself is, ish shipping, until the eccentric com- reading with and in the fingers that this decryption system may be the puter pioneer Alan Turing learned hold this page all have the same ge- most deeply fundamental aspect of how to break the code. That led to nome, but eyes and fingers are differ- the coding system, itself a kind of doom for Germany. For organisms, ent because they use different subsets code, and probably the first code. the price for code breakdown in the of those genes. This is specified by In 1953 Watson and Crick solved Battle of Life is similarly unremorse- tissue-specific developmental codes. the basic structure of DNA as a set of ful. Other DNA sequence elements are parallel chains connected by specific used to package, protect, or copy pairing of nucleotides, A with T and C DNA. Embryos develop and adult or- with G, the famous double helix. It ganisms respond to their environ- was not until 1967 that the use of DNA Ken Weiss is Evan Pugh Professor and Anne ments by using extensive arbitrary to code for aa sequences—our friend Buchanan is Senior Research Scientist in the codes in the form of combinations of the protein code, shown in Table Department of Anthropology at Penn State chemical signaling molecules that are 1—was deciphered (see3). Remark- University. E-mail: [email protected] produced by specific genes and are ably, this protein-coding process was released to be detected by other cells found to be based on the same © 2005 Wiley-Liss, Inc. whose gene expression they alter. Watson-Crick complementary base- DOI 10.1002/evan.20033 Published online in Wiley InterScience These are codes because it is the com- pairing phenomenon that made DNA (www.interscience.wiley.com). bination of factors, not the factors itself. Experiments that synthesized CROTCHETS & QUIDDITIES “The” Genetic Code? 7 be much more difficult to maintain or ature as the second genetic code or modify the code by natural selection. the RNA code). Like the protein code, Too many mutations would change a the supercode involves RNA-aa asso- codon’s specification from an aa to ciations, but unlike the protein code, “nothing,” causing a skip in the the supercode is far from universal mRNA, and translating into nothing. and includes aspects of tRNA that have nothing to do with its nucleotide sequence or base-pairing. Instead, en- ATALEWITHIN,ORUPONA zymes called aminoacyl-tRNA syn- TALE thetases (aaRS’s) first “charge,” or aminoacylate the tRNA by attaching So far so good. But if genes code for proteins by specifying their aa se- its cognate aa, and then accompany it quence, then the translation mecha- to the ribosomes where the aa is dis- nism has to be just as specific! Sur- charged to the growing aa string. prisingly, how this codon-tRNA-aa There are specific aaRS’s for each aa. specifity, with its multiplicities of tRNA’s are small molecules 73 to 95 codons and tRNA genes with the same nucleotides in length that use comple- specificity, is managed and main- mentary base-pairing to fold into a Figure 1. Alan Turing. tained has little to do with the protein four-armed cloverleaf structure (Fig- code. Instead, there is an independent ure 3A), the D stem-loop, the central tRNA “supercode” (known in the liter- arm containing the anticodon, the template RNA strings in bacterial ex- tracts to see what aa strings were pro- duced showed that specific nucleotide triplets in DNA, that we now call codons, through a mRNA copy, bind with nucleotide triplet anticodons in tRNA (i.e., the anticodon is a string of 3 nucleotides complementary to those at the corresponding codon position in the mRNA). This system entirely depends on the fact that, when activated, distinct tRNA molecules bind a specific aa which they carry to the mRNA during translation, and that the aa they carry corresponds to their anticodon se- quence. As the mRNA moves through a ribosome, each of its triplets is se- quentially bound, again by base-pair- ing, to a tRNA with the complemen- tary anticodon; this juxtaposes the tRNA’s aa to the end of the building string of aa’s (Figure 2B). The 64 nucleotide triplets made possible by four options (A,C,T,G) in each of three successive positions, code for only 20 aa’s because most amino acids are represented by more than one codon, and hence more than one type of tRNA specifies a given aa, as shown in Table 1. The table also shows that the genome has many cop- ies of most types of tRNA (each coded for and transcribed from its own loca- tion in the genome). It is crucial that the code and its supporting tRNA sys- Figure 2. The main steps in DNA as a protein code. A. Transcription: mRNA copied from the tem be degenerate. Were this not so, template DNA. B. Translation: amino acids carried to the ribosome by tRNAs for incorpo- more than 40 nucleotide triplets ration into the growing polypeptide chain, with mRNA as template. The aaRS’s are would code for nothing, and it would explained below. 8 Weiss and Buchanan CROTCHETS & QUIDDITIES TABLE 1. GENETIC CODE: CODON TRIPLETS, AA NAME FOR WHICH EACH tRNA-aa part of the story would have TRIPLET CODES, AND IN PARENTHESES THE NUMBER OF GENES IN THE HUMAN nothing to do with coding. The triplet GENOME THAT PRODUCE tRNA THAT USES THAT CODON codes for each aa are identical in all species—there is only one codebook, that (with minor exceptions) pre- serves vital aspects of evolution and the coherence of all life. But the way in which tRNA’s pair with aa’s is not universal at all. Gene duplication events are respon- sible for the multiple copies of genes specifying tRNA’s that use each aa (Table 1). Like any other gene, each tRNA gene experiences mutation and varies. Similarly, the aaRS genes are also subject to mutation. Though all aaRSs have the same function, they are otherwise characterized by their diversity among species. Since there are only 20 aaRS genes, one for each aa, but the code is degenerate, an aaRS for a specific aa must recognize and charge the set of tRNAs (with dif- ferent anticodons and multiple inde- pendent, varying copies in the ge- T␺C stem-loop, and the acceptor stem at the other end where its aa is at- tached.