84 Martynas Ycas 



an important mutually complementary relation to each other which enables 

 them to be retained by the cells. This is shown by experiments with injected 

 catalase. Homologous catalase injected into guinea pigs is absorbed by the 

 tissues, but heterologous catalase is rejected (108). Similarly, homologous 

 antibodies readily pass the fetal barriers in rabbits, heterologous pass much 

 less readily (109). This phenomenon is probably connected with the anti- 

 genicity of proteins. The antigenically active sites of proteins are probably 

 also small, and therefore the exact sequence and composition of the major 

 part of the protein m.ay be irrelevant to function. It might be expected, then, 

 that the exact structure of small parts of a protein molecule would be rigidly 

 determined, and any mutation affecting this portion would be eliminated by 

 selection. Mutations affecting the 'irrelevant' portions may not affect the 

 viabihty of the organism, and the same protein in different species may therefore 

 diverge by a process of 'evolutionary drift.' That this process is real is strongly 

 suggested by the facts known about cytochrome c. This enzyme serves the 

 same function and has the same prosthetic group in both yeast and mammalian 

 tissues, but the two cytochromes have very different elution volumes from 

 ion exchange resin columns (110), almost certainly indicating a large difference 

 in amino acid composition. 



If for each kind of residue there is a characteristic rate of replacement by 

 mutation, the proteins should approach a definite equilibrium composition, 

 if selection is a minor factor. More definitely, each protein will constitute 

 a 'random grab' from a universe of amino acids, the frequencies of the amino 

 acids in this universe being determined by the equilibrium condition. 



Qualitative considerations suggest that there is something other than selection 

 which tends to make a given amino acid occur with a certain frequency. Certain 

 amino acids, alanine, leucine, isoleucine and valine have aliphatic side chains 

 lacking any obvious reactive functional group. The data on replacements 

 (Table II) indicate, apparently, that one is as good as another, as far as their 

 function in a protein is concerned. Yet leucine is systematically more abundant 

 than isoleucine. These two amino acids are so similar that it is difficult to 

 separate them by paper chromatography. Each of the other aliphatic amino 

 acids has its own characteristic frequency, likewise. 



Quantitatively, if a sample of « items is drawn at random from a population 

 where an item of type A occurs with frequency p, the distribution of A in a 

 large series of samples is given by the binomial (p + q)", where q = \ — p. 

 In particular, the variance cr^ of the distribution of A is given by 



o- == npq (4) 



If the hypothesis of a 'random grab' is correct, then in a collection of proteins 

 the variances of amino acids should be related to the mean value of their 

 frequencies and to the size of the proteins, expressed as the number of residues 

 per molecule. 



An immediate difficulty is that the sizes of the proteins listed in Table V 

 are not known, and these certainly differ one from another. It should be 

 particularly noted that the relevant size is not necessarily that obtained from 

 physical measurements of diffusion, osmotic pressure and sedimentation. This 

 is because there is ample evidence that physical molecules can be the result of 



