Principles of Biochemistry Volume 3 - A. Lehninger 1985

Molecular mechanisms of genetic information transfer
Protein synthesis and its regulation
Viral DNAs sometimes contain genes within other genes or overlapping genes

For a long time, a foundational tenet of molecular biology was the strict collinearity between The nucleotide sequence of a Gene, the mRNA transcribed from it, and the polypeptide chain it encodes. However, as we have seen, Many eukaryotic genes contain intervening, untranslated nucleotide sequences—introns—that disrupt this absolute collinearity between a gene and its encoded polypeptide (Sections 27.28 and 28.23).

Further questions regarding THE PRINCIPLE OF collinearity arose from another remarkable discovery. It was found that in certain Viruses, the exact same DNA nucleotide sequence encodes two different Proteins by utilizing two distinct reading frames for codons. The existence of such "genes within genes" was demonstrated during The Study of bacteriophage φX174 DNA, which consists of 5,386 nucleotide residues—an amount seemingly insufficient to encode the nine different proteins synthesized by the virus. Once Sanger and his colleagues determined the complete nucleotide sequence of the φX174 chromosome (p. 850), they analyzed it in detail and compared it with the Amino acid sequences of the proteins encoded by φX174 genes. As a result, several overlapping gene sequences were discovered in the φX174 DNA. As shown in Fig. 29-23, genes B and E are located within genes A and D, respectively, and in five instances, the start codon of one gene overlaps the stop codon of another. Fig. 29-24 illustrates how genes D and E occupy the same DNA segment while utilizing different reading frames; a similar situation occurs with genes A and B. The extent of these overlapping sequences and internal genes fully compensates for the apparent shortage of NUCLEOTIDES in the φX174 DNA, given the total number of amino acid residues contained in its nine encoded proteins.

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Fig. 29-23. Genes within genes. The DNA of phage φX174 contains nine genes (A-J). The proteins encoded by this DNA contain a greater number of amino acid residues than can possibly be coded by the 5,386 nucleotides found in the phage DNA. It was therefore hypothesized that a portion of the DNA must encode more than one gene. A comparison of the DNA nucleotide sequence with The amino acid sequences of its encoded proteins revealed that gene B is located within gene A, but these two genes utilize different reading frames. Similarly, gene E lies within gene D and also has a distinct reading frame (see Fig. 29-24). The "internal" genes are highlighted in red, while untranslated spacer DNA regions are shown in gray. In addition to genes B and E residing within genes A and D, the φX174 phage DNA features short overlap regions between other genes. In five cases, the initiation signal of one gene overlaps the termination signal of the preceding one, with both signals utilizing different reading frames.

This discovery was soon followed by similar observations in other viral DNAs, including those of phage λ, the oncogenic simian virus 40 (SV40), and phage G4, a close relative of φX174. Phage G4 is remarkable in that it possesses at least one codon utilized by three different genes. It has been suggested that overlapping genes or genes within genes exist exclusively in viral genomes. The fixed size of the viral capsid necessitates an exceptionally economical use of limited DNA, which must encode the proteins required to ensure the infectivity of the viral particle and sustain its Replication capacity.

Fig. 29-24. A segment of the nucleotide sequence of the gene D mRNA transcript in φX174 DNA. This illustrates how gene E, residing within gene D, is encoded by a reading frame distinct from that of gene D. The reading frames of the genes are indicated by different colors.