Reading Frame

Almost all organisms translate their genes into protein structures using an identical, universal codon dictionary in which each amino acid in the protein is represented by a combination of only three nucleotides. For example, the sequence AAA in a gene is transcribed into the sequence UUU in messenger RNA (mRNA) and is then translated as the amino acid phenylalanine. A group of several codons that, taken together, provide the code for an amino acid, is called a reading frame. There are no "spaces" in the mRNA to denote the end of one codon and the start of another. Instead, the reading frame, or group of triplets, is determined solely by initial position of the pattern-making machinery at the start of the translation. In order for correct translation to occur, this reading frame must be maintained throughout the transcription and translation process.

Any single or double base insertions or deletions in the DNA or RNA sequence will throw off the reading frame and result in aberrant gene expression. Mutations that result in such insertions or deletions are termed "frameshift mutations." The insertion of three nucleotides, on the other hand, will only extend the length of the protein without affecting the reading frame, although it may affect the function of the protein. Several genetic diseases, including Huntington's disease, contain such trinucleotide repeats.

Because DNA consists of four possible bases and each codon consists of only a three-base sequence, there are 4³, or sixty-four possible codons for the twenty common amino acids. In the codon dictionary, sixty-one of the codons code for amino acids, with the remaining three codons marking the end of the reading frame. The codon AUG denotes both the amino acid methionine and the start of the reading frame. In several cases, more than one codon can result in the creation of the same amino acid. For example CAC and CAU both code for histidine. This condition is termed "degeneracy," and it means that some mutations may still result in the same amino acid being inserted at that point into the protein. The above example also explains the "wobble hypothesis," put forward by Francis Crick, which states that substitutions in the terminal nucleotide of a codon have little or no effect on the proper insertion of amino acids during translation.

Medically important frameshift mutations include an insertion in the gene for a rare form of Gaucher disease preventing glycolipid breakdown. Charcot-Marie-Tooth disease, which results in numbness in hands and feet, is caused by the repetitive insertion of 1.5 million base pairs into the gene. A frameshift mutation of four bases in the gene coding for the low-density lipid receptor near one end causes the receptor to improperly anchor itself in the cell membrane, resulting in the faulty turnover of cholesterol that causes hypercholesteroiemia, or high blood levels of cholesterol. A single nucleotide pair deletion in codon 55 of the gene coding for phenylalanine hydroxylase (PAH) results in a form of phenylketonuria. Frameshift mutations are denoted by listing the location and specific change in the DNA. For example, 55delT indicates a thymidine was deleted in the 55th codon of the PAH gene.

see also Crick, Francis; Genetic Code; Mutation; Transcription; Translation.

Paul K. Small

Bibliography

Fairbanks, Daniel J., and W. Ralph Anderson. Genetics: The Continuity of Life. Pacific Grove, CA: Brooks/Cole, 1999.

Lewis, Ricki. Human Genetics: Concepts and Applications, 4th ed. New York: McGraw-Hill, 2001.

Lodish, Harvey, et al. Molecular Cell Biology, 4th ed. New York: W. H. Freeman, 2000.

Pasternak, Jack J. Human Molecular Genetics: Mechanisms of Inherited Diseases. Bethesda, MD: Fitzgerald Science Press, 1999.

reading-frame shift (genetics) In the normal transcription of a cistron, nucleotides are read in threes, the ‘reading frame’ being determined by the starting-point. Each triplet codes a specific amino acid; the sequence of codons therefore dictates the amino acids and their order in a given protein. Certain mutagens (e.g. acridine dyes), which incorporate themselves between the complementary strands of the DNA, may cause errors in replication such that the daughter DNA gains or loses a nucleotide. When this daughter DNA is transcribed (see TRANSCRIPTION), the nucleotides will be read in the correct triplets up to the point of mutation, but the extra or missing nucleotide will cause a shift in the reading frame (to left or right) thereafter, such that all subsequent nucleotides will be read in wrong triplets. The result might be a protein with the wrong amino acids (often it is terminated early) but in any case it is dysfunctional.

reading-frame shift A change in the grouping of nucleotides so they are transcribed incorrectly. In the normal transcription of a cistron, nucleotides are read in threes, the ‘reading frame’ being determined by the starting-point. Each triplet codes a specific amino acid; the sequence of codons therefore dictates the amino acids and their order in a given protein. Certain mutagens (e.g. acridine dyes), which incorporate themselves between the complementary strands of the DNA, may cause errors in replication such that the daughter DNA gains or loses a nucleotide. When this daughter DNA is transcribed, the nucleotides will be read in the correct triplets up to the point of mutation, but the extra or missing nucleotide will cause a shift in the reading frame (to left or right) thereafter, such that all subsequent nucleotides will be read in wrong triplets. The result might be a protein with the wrong amino acids (often it is terminated early) but in any case it is dysfunctional.

reading frame A sequence of bases in messenger RNA (or deduced from DNA) that encodes for a polypeptide. Since each coding unit (codon) of the genetic code consists of three consecutive bases, the reading frame is established according to precisely where translation starts. For example, if translation starts one base either side of the correct base, an entirely different sequence of codons will be read, resulting in a faulty polypeptide or none at all. The hallmark of a functional gene is that it is transcribed to produce an open reading frame (ORF), consisting of a start codon to pinpoint exactly where translation should start, a stop codon to signal termination of translation, and typically a long sequence of codons that specify the constituent amino acids of the polypeptide (as well as introns in most eukaryote genes).