Somatic mutations and proteins

Abstract

A large body of data has now been accumulated concerning the ways in which heritable mutations can affect protein structure. Such mutations are usually presumed to arise in the germ line, and are studied by progeny analyses of various types. Today, I would like to consider how somatic mutations might be genetically predisposed and thereby made available to an organism during its adaptation to environmental hazards or during its development. The highly specialized immune system of higher animals can profitably be discussed from this viewpoint, and I shall describe a possible molecular mechanism (Smithies 1965) for implementing the immune response, and then consider very briefly its relevance to other adaptive and developmental processes. The immune response The essential questions which are posed by the immune system can be stated simply: (i) How can many different antibodies be specified by an initially fixed genetic endowment? (ii) How can selection be made against anti-self antibodies and for anti-foreign antibodies? (iii) How can an antigen instruct the organism to respond more effectively to repeated encounters with the same foreign substance? (i) Antibody variability could be the consequence of the organism having a relatively large number of related but not identical genes in the initial zygote from which to select combinations forming useful antibodies. This possibility is un­attractive for reasons of economy, and such a system would probably be genetic­ally unstable. I have consequently preferred to explore one of many alternative possibilities, namely that there are a limited number of genetic loci determining antibody structure which have evolved so that they can provide many different proteins as a result of genetically predisposed somatic mutations.