(JO ERWIN CHARGAFF 



opposite that directs the incorporation." This remarkable phenomenon — 

 the high tendency of methylcytosine to be next to guanine— was again 

 touched upon in our study on the sequence characteristics of the de- 

 oxyribonucleic acid of rye germ [37]. Several analogous observations also 

 were discussed there of which one may be mentioned. When, in this 

 nucleic acid, the coupled dipyrimidine units are surveyed, it is found that 

 methylcytosine has a greater tendency to be linked to either thymine or 

 cytosine than the latter has to associate with itself or with thymine ; and 

 there is a definite bias in favour of methylcytosine-cytosine units. In our 

 recent investigation of the bromouracil-containing nucleic acid of E. colt 

 [42] a more general formulation of the neighbour problem was attempted : 

 "One gains the impression that, after the selection of equal numbers of 

 6-aminopurines and 6-ketopyrimidines, on one hand, and of 6-keto 

 purines and 6-aminopyrimidines on the other, a second mechanism — an 

 exclusion principle, as it were — comes into play, so that certain neighbours 

 are tolerated and others not, or rarely." 



Somewhat similar observations have also been made in the case of the 

 ribonucleic acids in which the analysis of neighbouring tendencies is 

 easier because of the facility of obtaining any given nucleoside as either 

 the 3' or the 5' phosphate. An examination of this type has, for instance, 

 been made with ribonucleic acid preparations from different cellular 

 portions of rat liver [55]. A particularly instructive example of the neigh- 

 bour principle is offered by the "soluble" ribonucleic acids of the cyto- 

 plasm concerned with the specific transfer of amino acids [56], in which the 

 terminal sequence adenine-cytosine-cytosine is required ; a sequence that 

 can apparently be enforced by a specific enzymic mechanism. 



The manner in which a growing deoxypolynucleotide chain could 

 guarantee the quality of its continuation is not yet a topic encouraging 

 speculation.* Our present ideas about the enzymes taking part in the bio- 

 synthesis of specific polymers will probably have to undergo a stringent 

 revision before the directed synthesis of complicated sequences will 

 begin to be understood. For this, more than a biological form of Scotch 

 tape is required. Certain sequential restrictions could, incidentally, be 

 explained if, under circumstances, runs of more than one nucleotide were 

 the immediate precursors of the polymer chain. We have, for instance, 

 discussed the evidence, in rye germ nucleic acid, of the two dinucleotides 

 cytosine-guanine and methylcytosine-guanine being able to substitute 

 each other at random [37]. 



In considering the problem of the nucleotide sequence in deoxyribonu- 

 cleic acids we have barely turned the corner. There is a long road before 

 us ; and we shall not see its end. 



* "Whereof one cannot speak, thereof one must be silent," Wittgenstein, 

 Tractatus Logico-Philosophicus. 



