Genetic organization in higher organisms.

During the past decade, investigations with microbial systems have provided a model of the structural and functional organization of the genetic material which permits a general understanding of transmissional and functional aspects of heredity in terms of the chemical structure of the genetic material. Of historical interest is the fact that one of the major paths of investigation which led to this state of knowledge was initiated with report of a specific deviation from Mendel’s Law of Segregation first seen in Drosophila melanogaster . Assay of meiotic products of females, heterozygous for different mutant alleles at the lozenge locus, yielded exceptions which were associated with recombination (Oliver 1940). Subsequent investigations of other multiple allelic loci in several higher organisms consistently yielded such exceptions. The term pseudo-alleles was used to describe mutants which formerly were called alleles, but which now yielded to recombination, and pseudo-allelic locus or complex locus were expressions used to describe a locus whose mutant alleles exhibited a low order of recombination. The use of these expressions reflects the classical conceptual framework within which these cases were interpreted. Thus, if a genetic unit is a unit of function and mutation within which there is no recombination, then the evidence of recombination requires that there be two such units in close proximity. Moreover, since mutation of these adjacent genetic units led to a similar array of phenotypic effects, it was inferred that these genes were functionally similar or related. Indeed, their phenotypic interactions in heterozygotes confirmed this interpretation. Thus was erected the notion of a pseudo-allelic locus as consisting of a small number of recombinationally separable units, whose recombinational distinction was paral­leled by functional distinction, and whose phenotypic interactions in heterozygotes reflected some relationship between their separable functions (see reviews by Carlson 1959; Green 1963). An accessory theorem (Lewis 1951) was based upon the observation that several pseudo-allelic systems in Drosophila were associated with salivary chromosome doublet structures, long believed to represent small duplica­tions. This notion suggested that pseudo-alleles were cases of gene duplicates in various stages of evolution, and the investigation of such systems was believed to be concerned essentially with the evolution of new genes and new gene functions. In summation, most of the work with higher organisms has been interpreted in a fashion entirely consistent with classical notions concerning genetic organization, with pseudo-allelism taken as a special situation. In contrast, the work with microbial systems has led to a considerable revision of classical notions concerning genetic organization. From these studies, there emerges a concept of the hereditary material as consisting of a linear order of units called cistrons, which are defined in terms of function (Benzer 1957). Each such unit possesses numerous, separable, linearly ordered sites capable of undergoing independent mutation (Benzer 1959, 1961). Moreover, it now is possible to relate the linear order of recombinational sites within a cistron to the genetic code which determines the linear order of amino acids in a polypeptide (Helinski & Yanofsky 1962; Yanofsky 1963). The microbial evidence has revealed still another order of genetic organization. Cistrons which control physiologically related polypeptides are found to be located adjacent to each other on the genetic map, and evidence is available which provides an understanding of the regulation of the function of these adjacent blocks of cistrons, now termed operons (Ames & Hartman 1963; Jacob & Monod 1961). Despite obvious parallels between the higher organism studies and the microbial work, considerable disagreement exists concerning the relevance of the microbial model of genetic organization for higher organisms. This paper is addressed to this point.