GENETICS AS A TOOL IN THE STUDY OF BEHAVIOR BENSON E. GINSBURG, Ph.D.* I. Introduction Some twelve years ago a geneticist introduced a summary of the now classic investigations on the physiological genetics ofNeurospora by borrowing a page from the annals ofbehavioral abnormalities as the prototype for his own work: the genetic control ofmetabolic reactions was put forward as the key concept in understanding gene action (i). Turned back upon itself, this concept provided a methodology for identifying and distinguishing some ofthe "natural" pathways taken by organisms to achieve their structural and functional characteristics, all the way from the intracellular level to the extra-organismic. In its barest essentials, this involves defining "natural units" in a genetic-evolutionary sense and analyzing them from this point ofview. Justas the parsing ofa sentence gives us only a certain kind ofunderstanding about it, so the analysis ofsome aspect of an organism into gene-controlled reactions tells a limited story, but it is a story that adds immeasurably to our understanding of living systems in their behavioral, as well as morphological and physiological, capacities. The illustration chosen as the introduction to the principles underlying the Neurospora investigations was tyrosine-phenylalanine metabolism, involving : a)Phenylketonuria, a recessive condition characterized by inability to oxidize phenylpyruvic acid, which is therefore accumulated and excreted in the urine—an interesting but unimportant incapacity, were it not for the fact that it is associated with a serious decrement in mental function. b)Tyrosinosis, an extremely rare condition in which phenylpyruvic * The author is professor ofnatural sciences at the University ofChicago. Experimentalwork ofthe author has been aided by grants from the Office ofNaval Research, the U.S. Public Health Service, and the National Science Foundation. 397 acid is presumably oxidized normally, but its product, parahydroxyphenylpyruvic acid, cannot be metabolized and is excreted in the urine. c) Alkaptonuria, inherited as a recessive, in which a further intermediate ofphenylalanine metabolism—homogentisic acid—accumulates and is excreted in the urine by virtue of lack of an enzyme, present in normal genotypes, which catalyzes its breakdown. Any ofthese three genetic conditions is incompatible with the normal metabolism of phenylalanine. Each of these mutations, by stopping the process at different points in the normal metabolic sequence, when taken together with the others, helps reveal what that sequence is and the number of places at which "errors" are possible. That the concomitants may involve mental events is not surprising, since the nervous system, no less than other systems, depends upon the intactness ofits metabolic machinery for normal function. (Evidence on phenylketonuria itselfsuggests that the accumulation ofphenylalanine bears a share ofthe responsibility for many of the symptoms, since clinical improvement has been noted as a result of phenylalanine-free diets [2].) II. Gene Structure Physiological genetics has come a long way since Garrod enunciated the principle ofinborn metabolic errors in connection with alkaptonuria (3). We now have a tenable notion ofthe structure ofthe gene that provides a model for its replication and, through its autosynthetic properties, of its manner of control over the events in relation to which genes stand as executive agents (4, 5,6). The nuclear genes ofhigher organisms are situated on the threadlike chromosomes and are identified with particular positions on the chromosomes, although chromosomal rearrangements do occur. Such rearrangements, involving no changes in the structural integrity ofa relocated gene or group ofgenes, may, nevertheless, produce phenotypic changes. Such changes have been reported for the fruit fly Drosophila and for the evening primrose Oenothera under conditions where experimental radiation was not involved in producing the rearrangement and where the structure ofthe relocated genes would, therefore, not have been affected (7). Position effects ofthis type are most commonly, but not invariably, manifested when the gene under study is moved from its normal position to one adjacent to a heterochromatic region ofthe chromosome . The chromosomal organization is a factor in genetic expression, as 398 Benson E. Ginsburg · Genetics as a Tool in the Study ofBehavior Perspectives in Biology and Medicine · Summer 1958 is, in fact, the entire genome. Since gene interactions are the rule, an individual gene is associated experimentally with a given trait relative to a specified range of genetic backgrounds and environmental influences. Analyses...