Download PHYSIOLOGICAL AND POPULATION ASPECTS OF BEHAVIOR

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. Hopefully, modification
of the nervous system by genetic means can
provide another tool for understanding the
causes of individual variation, and the
mechanisms of behavior regulation.
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