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A M . ZOOLOGIST, 4:101-109(1964). PHYSIOLOGICAL A N D POPULATION ASPECTS OF BEHAVIOR GENETICS JOHN L. FULLER The Jackson Laboratory Bar Harbor, Maine and express themselves clearly enough to permit localization in linkage groups (Gruneberg, 1952; Green, 1963). The occurrence of so many neurological mutants reflects the complex determination of the central nervous system. Interference with any one of many gene-controlled processes can disrupt differentiation, and produce effects ranging from severe malformations which shorten life span to a few days through functional aberrations compatible, in the sheltered conditions of a well-run animal room, with essentially normal life span and reproduction. Some genes which affect behavior through the nervous system and receptors also have pleiotropic effects upon such characters as coat color. The dilute lethal gene (d1) in the mouse lightens the coat color of homozygotes, and produces extreme myelin degeneration at an early age (Kelton and Rauch, 1962). Dogs heterozygous for gene M have a dappled or merle coat. When homozygous, the gene produces deafness and microphthalmia. One can raise the question of behavioral pleiotropy of other Formal genetics—single genes genes which modify coat color, but do not Formal genetics always precedes the in- produce obvious neurological defects. Some vestigation of gene action and of the dis- evidence has been presented in favor of tribution of genes within populations, for it such pleiotropy (Keeler and King, 1942; is necessary to demonstrate that genes con- Keeler, 1948) in rats and other mammals. tribute to a particular phenotypic variation Most studies purporting to yield positive before embarking on more elaborate stud- correlations with behavior have employed ies. Many gene-controlled behavioral syn- stocks segregating at many loci besides the dromes can be detected without the need of one of interest. Hence, the effects of a formal behavioral tests. Over fifty neuro- given gene substitution may be swamped logical mutants have been described in Mus by variation at other loci; also in such mamusculus; so many that considerable in- terial it is difficult to separate effects caused genuity must be expended in assigning new, by pleiotropic effects of one gene from descriptive names which already range from those produced by closely linked genes. agitans to zigzag. Most behave as recessives Rigorous proof of pleiotropic effects of substitutions at single loci is best obtained This investigation was supported in part by Pub- from stocks maintained co-isogenic except lic Health Service Grant MH-01775 from the Na- for segregation at the locus of interest. Behavior genetics defines a field in terms of a class of phenotypes, and is thus coordinate with pigment or immunological genetics. As such it has three major programs: formal genetics, physiological genetics, and population genetics. Behavioral phenotypes are not particularly convenient for any of these, and the high current level of interest in the field reflects concern with the phenotype itself, rather than with advancement of pure genetics. However, the flow of information between behavioral science and genetics goes in both directions. Behavior is one of the important ways in which animals adapt to environmental challenges, and any consideration of the means by which genes affect fitness must involve behavior genetics. It is my task in this refresher course to give one individual's view of some central problems of this branch of science. Because my own experience has been predominantly with mammals, I shall select most of my examples from this class. tional Institutes of Health. (101) 102 JOHN L. FULLER We have been looking in the mouse for behavioral pleiotropism in a number of coat color mutants on a C57BL/6J or DBA/2J background without much success, though our search has not been systematic. Yellow mice (Ava) were found to be less able to maintain balance on a rotorod, but we consider this to be a secondary result of obesity. Similarly the reduced activity of yellow mice in a tilt cage (Les, 1958) may well be an outcome of increased weight. Though such explanations are not very exciting, they are at least plausible. Sometimes there is no good basis for speculation regarding mechanism. For example, pintail mice were found to extinguish more slowly than normals on a shock avoidance task (Denenberg, Ross, and Blumenfield, 1963). When the correlated characters are as different as pigmentation and timidity or length of tail and avoidance extinction, they do not immediately contribute to understanding of gene-phenotype relationships. Nevertheless, more such studies should be done and part of the description of all new genes (and old ones) should include behavioral effects. Much can be done with unit characters which is not possible when variation is controlled by multiple factors.1 This raises the question whether "cryptic" genes ascertainable only by their behavioral effects exist. Calling a gene cryptic does not imply that it has no structural effect, but only that its morphological effects have not been detected. As knowledge of the physiological basis of behavior increases, one would expect that many cryptic genes would be found to alter molecular structure or influence patterns of histogenesis.2 It has been difficult to prove rigorously in 1 An example of pleiotropic action of a gene with visible effects on behavior in an insect is presented b) Cotter in this refresher course. [Ed.] 2 "Cr\ptic" genes in insects have been repeatedly described. The contribution of Rothenbuhler in this refresher course deals with several instances in the honey bee. Others have been described in the wasp Habrobracon (A. R. Whiting, Adv. in Genetics 10, p. 309 310, 1961) and in Drosnphila (Gill, Am. Zoologist j , p. 507, l'J6'Sj. [LU.j mammals that single-locus substitutions which do not profoundly alter structure or chemistry have behavioral effects. Perhaps this is because behavior is so buffered by neural and endocrine mechanisms that major effects can only be produced by large perturbations at the molecular or tissue levels. However, in man such well established genes as red-green color blindness and phenylthiourea taste sensitivity are known only from their behavioral effects, and there seems no reason to suppose that our species is unique except in its adaptability to measurement of sensory differences. The existence of some unit characters detectable only, or primarily, by their behavioral effects is likely. Investigators should be aware, however, of the statistical and genetical problems involved in identifying unit factors. Polygenic systems can simulate Mendelian ratios (Wright, 1934; Fuller, Easier, and Smith, 1950; Edwards, 1960) under certain conditions. Problems also arise because of the blurring of classification of phenotypes as one relies on characters more remotely related to primary gene products. This can be illustrated by the syndrome of phenylketonuria in man which occurs in individuals homozygous for a gene which has a frequency of about 1% in our population. There is no overlap between homozygotes and wild type in the phenylalanine content of blood plasma, slight overlap in Binet I.Q., and marked overlap in head size and hair color (Penrose, 1951). To a behavior geneticist this outcome is pleasing, for the effects of this gene upon the psychological phenotype are more predictable than its effects upon the morphological phenotype. Formal genetics—biometrical methods I should now like to turn the currently more popular approach of considering behavior as a polygenically determined character and using biometric methods for its formal analysis. We shall hear examples of such work later today and I shall simply try to relate such studies to the developmental and populational aspects of behav- 103 PHYSIOLOGICAL BEHAVIOR GENETICS TABLE 1. Methods of biometrical studies in behavior genetics. Method 1. Selection 2. Intrafamily correlation 3. Crosses between two selected lines 4. Crosses between two inbred lines 5. Multiple Intercrosses or Diallel Crosses Example Reference Heritability of fighting ability in fowl estimated as .20 Heritability of avoidance learning within swine breeds = .45 Maze errors scores of hybrids between "bright" and "dull" lines were intermediate to parents. Variances not interpretable. Wheel running in mice—heterosis in Fx; dominance of genes for high scores: variances inconsistent; probably parents differ at 2-3 loci. Estimates obtained for additive effects, dominance, epistasis, maternal effects, etc. for ambulation and defecation scores of rats. Guhl, Craig and Mueller (1960) Willham, Cox and Karas (1963) Tryon (1940) ior genetics. When biometrical techniques are employed, genetic groups are characterized by their means and variances on standardized tests of behavior. The raw scores from the test instrument are often transformed into square roots, logarithms, reciprocals, or the like, in order to meet certain scaling requirements (Bruell, 1962). Table I briefly summarizes examples of five methods which have found use in behavior genetics. Selection and intrafamily correlation are carried out on genetically variable populations. Crosses between selected lines must await reliable separation and reasonable stabilization of the phenotype. The last two methods require highly inbred lines in which genetic variability is reduced to a minimum. The diallel method introduced into behavior genetics by Broadhurst (1960) seems particularly promising. The use of a variety of unrelated lines permits broader generalization to a species as a whole than any arbitrarily selected pair of strains.3 I found in a study of the inheritance of alcohol preference (Fuller, 1964) that knowledge of the outcome of one interstrain cross gave no indication of the results of another cross. In Figure 1 are plotted alcohol preference scores of four inbred strains and the six hybrids between them. Each line corresponds to one constant-parent group; the mean scores of the variable-parents are 3 This problem is further developed in the contribution by Bruell in this refresher course. [Ed.] Bruell (1962) Broadhurst (1960) 1.8 C57BL/6 1.7 1.6 ui O 1.5 oin a <r 1.4 f 1.3 1.2 I.I 1.0 1.0 I.I 0BA/2J 1.2 1.3 1.4 A/J 1.5 1.6 1.7 1-8 C3HeB/J C57BL/J Variable Parent Score FIG. 1. Alcohol scores of constant-parent groups as a function of scores o£ the variable parents. shown on the abscissa. Each hybrid is represented twice, on the curves of each parent; the pure strains are shown only once. Groups with a C57BL/6J parent had high alcohol preference scores; those with a DBA/2J parent (except for C57BL/6J x DBA/2J) were low. The offspring of A/J or C3HeB/J mice resembled the variable rather than the constant parent. The important conclusion from this experiment is that high preference for alcohol is dominant, recessive, or neither, depending upon the particular mating. Such variety in genetic determination suggests variability in the physiological underpinning of apparently similar behavioral phenotypes. 104 JOHN L. FULLER Behavior-phenotype correlations Physiological and population geneticists sometimes question the value for their purposes of estimating heritabilities, dominance, and additive components which are specific for particular populations or crosses tested in a prescribed fashion. What can one do with the numbers derived from the analysis except use them as guides for efficient selection? Physiologically minded behaviorists tend to shortcut biometry and to use selected strains and behaviorally differentiated inbred strains as raw material for functional analysis. The general approach is through correlation of behavioral and morphological or chemical phenotypes. If significant correlations can be established, one may ascribe both aspects of the phenotype to a common dependence upon the genotype. For example C57BL/1O mice fight over food more than BALB/c mice (Fredericson and Birnbaum, 1954), and BALB/c's are more emotional by the open field defecation test (Lindzey, 1951). Maas (1962, 1963) has found that the concentration of serotonin in the brain stem is reliably higher in the BALB/c strain. He has also shown that the two strains differ in behavioral response to Parnate, a monoamine oxidase inhibitor; injected with reserpine, which depletes serotonin, the strains become more alike. The picture is consistent with a hypothesis that naturally occurring variation in serotonin plays a role in the lower emotionality and higher aggressiveness of the C57BL/10 strain. It must be pointed out, however, that these two strains differ also in such obvious characters as pigment and such esoteric behaviors as preference for alcohol (McClearn and Rodgers, 1959), Many other associations could be found if searched for. The particular relationship suggested by Maas is plausible because serotonin is believed to have behavioral effects and because the chemical difference is localized in the brain stem, a region which is critical for the expression of emotionality. It is easy, however, to generate other plausible hypotheses. Big brains may function differently from little ones. In Figure 2 are shown relation- s so (5 BALB/c C) BALB/c z 2 SOO iX a CJCBA 4 e » 450 OC5TBL/6 r CfcOTBL/B * * " * . IL VCS7BR/ed d0Bfl/l MEAN BODY WEIGHT (GRAMS) FIG. 2. Brain weight of inbred lines of mice as a function of body weight. Each point is based upon 10 or more adult animals of the sex indicated. ships between brain weight and body weight for a number of inbred strains. I am indebted to Dr. J. B. Storer for the data upon which this figure is based- Strain BALB/c has a very large brain for its size; C57BL/1O is not shown, but other strains of the C57 group have relatively small brains. I consider the brain-weight' association with temperament rather unlikely, but by looking for it in a large number of unrelated strains one could test it- more adequately than with a single pair of strains. The point is that behavior-phenotype correlations should be based upon a wide sampling of strains in order that the general significance of the relationships can be evaluated. Endocrine glands and behavior The endocrine system has been a favorite hunting ground for mechanisms intermediary between genes and behavior, since the effects of hormones upon behavior are amply documented (Beach, 1948). Work on the thyroid gland in rodents provides a good example of efforts in this area. Rats selected for emotional defecation had heavier thyroids than a strain selected for low reactivity (Yeakel and Rhodes, 1941). This finding was confirmed using modern meth- PHYSIOLOGICAL BEHAVIOR GENETICS ods of studying thyroid physiology in strains of rats selected for high (reactive) and low (non-reactive) defecation in the open-field (Feuer and Broadhurst, 1962a, b,c). The heavier thyroids of the reactive strain were filled with colloid and had a lower rate of iodine uptake. Selection for emotional reactivity had apparently produced a mild hypothyroidism. Similarly the least active, and presumably fearful, strains of house mice observed by Thompson (1953) are also somewhat hypothyroid (Amin, Chai, and Reinecke, 1957; Chai, 1958). At higher levels of thyroid activity no correlation with activity is apparent. A relationship between low thyroid function (Eleftheriou and Zarrow, 1961) and fearful behavior (King, 1961) has been found in two substrains of the deermouse, Peromyscus maniculatus. The correlations between thyroid function and behavior are fairly consistent in this group of studies which have utilized comparisons among subspecies produced by natural selection (Peromyscus), strains developed by directed selection (rat), and inbred strains whose differentiation into active and inactive types is probably largely an accident of genotype fixation (mouse). It seems logical to conclude that variation in thyroid activity is one of the pathways through which genes influence behavior. Structural and regulator genes It will be noted that neither the serotonin mechanism nor the thyroid mechanism has been postulated to influence behavior through an altered gene product. The difference between the C57BL/6 and BALB/c strains with respect to serotonin is believed, in fact, to concern tissue binding of this substance rather than rate of synthesis (Maas, 1963). In the thyroid studies cited there is no evidence of mutations in structural genes directing the synthesis of hormone. Instead, the variations seem to be matters of the rate of synthesis or liberation or binding of hormone, or perhaps the effectiveness of a hormone as a regulator of function within a particular cell. 105 I suggest that the genetic model based on the concept of metabolic errors leading to inappropriate enzymes or structural molecules is inappropriate to much of the observed heritable variation in behavior. Instead, we should perhaps select as our model the regulator genes (Jacob and Monod, 1962), which in microorganisms control the transfer of genetic information in DNA to the sites of protein synthesis in in the ribosomes. Extending the concept of regulator genes to multicellular organisms is not too difficult, but the experimental validation of such a hypothesis presents formidable difficulties (Monod and Jacob, 1961). Perhaps, however, there is more than coincidence in the fact that these authors, whose concern is with transmission of information back and forth between cytoplasm and gene, and Miller (1963), whose interest is in the transfer of environmental information to the nervous system (the phenomenon of memory), both suggest that differentiation of cells in culture may provide a key to regulatory mechanisms. Certainly there is a formal resemblance between the induction of an enzyme in colon bacillus, and learning in an animal. Something from the outside must elicit the genetic potential (cf. Hyden, 1962). Pertinent here also is the finding that the regional distribution of cholinesterase in the brains of rats reared in a complex environment differs from that of rats reared in isolation (Rosenzweig et al., 1962). Implicit in the discussion thus far is the hypothesis that genetic effects on behavior are mediated at the molecular level, either through an effect on structure of a gene product, or through regulation of the output of gene product. To some this view may seem too restricting as it seems to leave no opportunity for genes to operate through control of the arrangement of cells which are biochemically and physiologically identical, but connected in a different fashion. When quantitative neurological techniques have been applied to "normal" mammalian brains, variation has been found. We do not know, however, that the differences in cell number and arrangement found by 106 JOHN L. FULLER Lashley and Clark (1946) have any behavioral significance, nor do we know that the characters are heritable. If they are heritable, we have no satisfactory hypothesis for the control of cell growth patterns by genes. Regulator genes may well be involved, their action during the period of growth and differentiation being more or less irrevocably impressed upon the organism as an individualistic arrangement of structurally normal cells. In the face of lack of data it is pointless to speculate further at this time. Sometime in the not too distant future some inspired investigator is going to synthesize concepts of regulative genetics, differentiation, and behavior, and design experiments to test his hypotheses. However, there are some implications of this point of view, that the most interesting part of behavior genetics is related to regulatory rather than structural genes, which can influence our choice of behavioral phenotypes in any genetic experiment. Regulative functions as phenotypes Commonly in genetic research we select as a phenotype some character which is easy to measure accurately and proceed to define the conditions under which it is to be measured. This is the usual procedure in behavior genetics, and investigators are pleased if their methods maximize genotypic effects. But such a strategy is not suitable for studying the genetics of regulatory systems, as the work of Jacob and Monod (loc. cit.) has shown. The enzyme beta-galactosidase in the wild type colon bacillus is an inducible enzyme; that is enzyme is produced only in the presence of a suitable substrate such as galactose. Thus, to discover whether there is a mutation in the structural gene which carries information for the synthesis of /J-galactosidase, one must grow organisms in the presence of galactose. Mutants (the constitutives) are known, however, which synthesize enzyme in the absence of galactose. By ingenious experiments Jacob and Monod showed that these mutants had occurred at another locus, a regulator locus, and that the constitutive effect resulted from the absence of an inhibitor which normally blocked the structural gene's transfer of information. I propose that we should measure behavioral phenotypes under a set of environments and search for the function which expresses the rate of behavior (B) change as environment (E) is modified. In very general terms this might be written as a differential equation: dB/dE = F (G) where (G) stands for a genotype. The function F would be expected to assume different values as genotype is varied. For some purposes E may symbolize experience rather than environment. Slopes of learning curves, psychophysical functions, behavioral responses to varying population density, or to injected drugs are representative of functions which might be studied. From my own work I shall cite one example of this approach. The data on alcohol preference shown in Figure 1 were computed by a method illustrated in Figure 2. Alcohol preference was scored by comparing the amount of fluid taken from each of six tubes of differing concentration presented simultaneously. A cumulative curve of consumption was drawn starting with the most concentrated alcohol, and the concentration of alcohol corresponding to one-half the total volume was determined graphically (or by arithmetical interpolation). The concept employed is that alcohol is a regulator of drinking behavior and the scores obtained are measures of the environmental pressure needed to produce a standard modification of that behavior. The technique confirms the pioneer work of McClearn and Rodgers (1959, 1961) on alcohol preference of inbred strains of mice, and has better scaling properties for genetic analysis. Observing behavior under several conditions often yields a dividend of differentiating phenotypes which look alike in one particular situation. For example, HS and DBA/2 mice show close to 100% susceptibility to audiogenic seizuies in the standaul PHYSIOLOGICAL BEHAVIOR GENETICS test procedures. Ginsburg (1954) found that Diamox, a carbonic anhydrase inhibitor, reduced susceptibility sharply in both strains. In contrast, glutamic acid gave effective protection only in DBA/2s. Such results suggest that the genotypic determinants of susceptibility are operating through different channels in the two strains. Another example from audiogenic seizure genetics involves separation of phenotypes by comparing the effects of prestimulation (Fuller and Smith, 1953). Under standard test conditions hybrids of DBA/2J mice with A/J or C57BL/6 mice are 95-100% susceptible, with an average convulsion latency of approximately 30 seconds. When prestimulated by a short burst of sound, latency is greatly decreased in the DBA/2 x A hybrids but not in the C57BL/6 hybrids. Viewing behavioral phenotypes as functions of a changing environment creates more work for the investigator, but increases insight into the mechanisms of gene action. It is conceivable that some gene systems are tightly linked with behavioral regulation through a hormone or a neural transmitter or modulator, and might be readily detectable. More often the relationships between the two will be difficult to follow, and perhaps not amenable to experimental validation. But even though the regulator concept is loosely applied, I think it helps to counteract a view that genetic information operates to structure behavior independently of environmental information. We behavior geneticists give lip service to the idea of heredity-environment complementarity, but when we design our experiments only to maximize phenotypic effects of genie variation we lose the opportunity to discover how genes operate in behavioral differentiation. Behavior genetics and populations As with physiological genetics, the most powerful methods of population genetics depend upon the identification of alleles at specific loci. The thesis of this paper has been that structural gene substitutions seem for the most part to be so disruptive of 107 neural organization that behavior is grossly distorted, or so benign that their effect, if any, is obscured by non-controlled genetic and environmentally produced variation. An argument has been presented for the importance of regulatory genes in endowing behavior with its adaptive characteristics, but no techniques for studying these in populations have been suggested, and it may be impossible ever to do so. Yet the situation is not hopeless. A clear demonstration that selection for a behavioral phenotype forces changes in specific components of the genotype has been provided by Dobzhansky and Spassky (1962). In lines of Drosophila pseudoobscura, selected for negative geotaxis, the proportion of AR/ CH heterokaryotypes of the third chromosome increased. In lines selected for positive geotaxis, the AR chromosome was favored. Even failing locus or chromosome identification, one can work with quantitative traits using biometrical methods. Particular interest attaches to the special case in which one end of a fundamentally normal distribution is set off by a threshold. It has been shown (Edwards, 1960) that if the population probability of being in the threshold class is p, the probability that a first degree relative of an index case will also fall in the theshold class is p&. The model roughly fits the family expectation for schizophrenia. The population incidence of the disease is about .01, and the risk in first degree relatives is approximately .10. Such considerations might also apply to the familial occurrence of social dominance in species in which a few individuals dominate large groups. Scott (1944) has proposed that social behavior determines social organization and has called for a social genetics. In our joint research with dogs we were forced to adopt the concept of breeds as populations varying in the frequency and intensity of behavioral phenotypes, rather than as sets of typical individuals. The population concept is easier to apply to morphological characters than to behavior, but the investigation of genetic control of social structure in natural 108 JOHN L. FULLER and semi-natural societies should be most rewarding. Such work is still largely in the future, though Freedman's (1959) study of breeds of pups reared under disciplined or permissive conditions has shown the possibilities. The genetics of behavioral phenotypes shares all the problems of the formal, physiological, and populational genetics of other complex characters. It should have much to gain from continued close association with developmental genetics and with regulatory physiology. 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