2 wee ke Be a ee ee Errors in Human Hemoglobin as a Function of Age 217 1 glutamic residue and 1 isoleucine residue whose codons can mutate to valine codons by single base changes, whereas the tetrapeptide has only the isoleucine codon that can mutate to valine by a single base change. Assuming that the majority of valine at the position of coded isoleucine is incorporated through translational errors, that the valine substitution through transthat the other amino acids have properties so different from isoleucine and valine that complexes between them and isoleucyl-tRNA would be very infrequent indeed, it would seem that the sum ofthe contributions of somatic mutations at the codons for the 3-glycine and 1-glutamic acid positions could be equalto the contribution of translational errors at the isoleucine position in the octapeptide. Correlations and speculations given above are no substitute for experimental facts! However, it does seem clear that translational Variation can cause a small amountof a correctly coded mRNA to produce a chemically ajtered protein and that these alterations are chemically similar to those which can also arise by somatic mutations; to date, methods have not been judicially applied to distinguish between these alternatives in the analysis of errors in protein synthesis and ageing. Nevertheless, a combination of these errors can lead to a considerable amount of error-containing protein to be formed bycells. An average isoleucine substitution frequency per amino acid residue in human hemoglobin of 3 x 10-, where isoleucine is one of 20 amino acids each of which may show a similar frequency of amino acid substitution, suggests that a total of 8.5% of the polypeptide chains being synthesized contain one amino acid difference from correctly coded ones. For molecules composed of polymers of polypeptide chains, a large percentage of the molecules may contain one or more amino acid substitutions. If error-containing molecules are more prone to become enzymatically inactive but retain their antigenic properties, it is conceivable that the inactive enzyme molecules found in tissue culture [5] and liver [4] cells ate molecules which contain errors, References 1 Cresco, J.B.,; Nauciton, M.A., and WeaTHerazz, D.J.: Abnormal human haemoglobins. Separation and characterization of the « and @ chains by chromatography, and the determination of two new variants, Hb Chesapeake and Hb J (Bangkok). J. molec. Biol. 19: 91-108 (1966). iw fo 0} m3 Cricx, G.H.C.: The origin of the genetic code. J. molec. Biol. 38: 367-379 (1968). Daynorr, M.O.; Hunt, L.T.; McLavonun, P.J., and Barker, W.C.: Globins; in esi 2 3. 2 lational errors is similar for isoleucine in both the tetra- and octapeptides,