Fine structure of chromosomes.

Mendel discovered the particulate nature of hereditary factors and the rules of their transmission without knowledge of chromosomes. Indeed, much of the classical knowledge of heredity was obtained without reference to any cell structure. When, in the 1920’s, chromosomes were established as the carriers of the linear order of genes, many questions beyond the formal analysis of order and transmission could be tackled. Structural analysis, it was hoped, would soon reveal the mechanism of genetic crossing-over and chromosome replication and chemical studies of chromosomes were expected to give information on the nature of the gene. It turned out, however, that the light microscope could not reveal the organization of chromosomes and that their chemical nature was so complex that it prevented the recognition of the substance of the gene. Progress in chemical genetics became possible only after genetic analysis was extended to viruses and bacteria, organisms which do not have true chromosomes but a much simpler genetic system. Now DNA , already suspected of having something to do with the gene because of its constant association with chromosomes, could be established as the molecular basis of heredity. Above all, it was the recognition of the molecular structure of DNA which provided the understanding of the nature of genetic specificity and its expression in cellular synthesis, and suggested mechanisms for its replication. Viruses and bacteria provided the ideal material for analysis of the basic properties of a genetic system since here the genome consists of a single DNA molecule. It has been recognized for some time that bacteria and the related blue-green algae possess an unusual nuclear organization. The term prokaryotes has been used to distinguish these organisms, from the eukaryote animal and plant cells with typical chromosomes and mitotic division (Dougherty 1957; Ris & Chandler 1963). These terms are useful since they stress a real difference in the complexity of the genetic systems of the two cell types. How has the knowledge gained from the study of micro-organisms helped us in understanding the chromosome? It appears that the basic properties of the genetic system such as the coding for amino acids by the nucleotide sequence of the DNA and its transcription into RNA are alike in prokaryotes and eukaryotes. Nevertheless, the great difference in structural complexity of the two kinds of nuclei must signify some interesting modifications in their operations. It seems to me Important that this difference be recognized in terminology. Since the term chromosome' has been applied to the complex nucleoprotein structure of the ekaryote nucleus, it is unwise to use it also for the DNA molecule of viruses or cteria. I have, therefore, suggested ‘genophore’ as a general term to designate e physical counterpart of a linkage group (Ris 1961). How does a chromosome ffer from the genophore of a bacterial cell? From chemical studies, we know at in addition to DNA a chromosome contains considerable amounts of protein, particularly basic proteins of relatively small molecular weight (histones). In most nuclei, more complex proteins are also associated with chromosomes in variable amounts. What are the roles of these proteins? The chromosome complement of mammals contains about a thousand times as much DNA as a bacterial genophore. Does the histone serve to reversibly coil and condense the long DNA read into a manageable form? It has been suggested that histones act to repress ecific genes. What controls their specific association with DNA and how does is affect chromosome structure? In the light microscope, the chromosome appears ultistranded, and yet during replication it seems to behave in a semi-concervative manner analogous to a single DNA molecule. How can the DNA in a chromosome replicate in the same way as a bacterial genophore since it is many mes longer and in a complex association with protein? Obviously, before we can understand the basic processes of chromosomes, such as their replication and conformational changes during activation of RNA synthesis, we must have a clear understanding of chromosome organization at the molecular level. When the ectron microscope began to reveal the fine structure of cytoplasmic organelles, was hoped that it would soon solve the problems of chromosome organization. While it has shown some interesting details, we must admit that it has not yet answered any of the basic questions. As Porter said some years ago: ‘The nucleus both during interphase and mitosis has come to be regarded as one of the most difficult of biological objects to study by methods of electron microscopy' (Porter 1960). Other methods such as X-ray diffraction and polarizing microscopy have also offered promise here or there without giving final answers to the basic questions. Even though it is as yet impossible to propose a satisfactory model for the chromosome, it might prove useful to review what sort of structures have been revealed by these techniques, how these structures might be related to chromosome function, and what major problems remain unsolved.