Tugas genetika

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Stimulation.The response may be positive or negative, and the sources of stimulation may include chemical, gravity, light, and so on. The investigation of geotaxis ( response to gravity ) in Drosophila illustrates this general behavior response as well as the selection technique. In addition, this investigation used a novel approach that detemines the genetic influences of specific chromosomes on geotaxis.
Jerry hirsch and his colleagues designed a mass screening device that allows about 200 files to be tested per trial, as shown in figure 24.4. The maze is placed vertically, a fluorescent light illuminates the side opposite the entry point, and flies are added.
Those that continue to turn up at each junction will finally arrive at the top ; those that always turn down will arrive at bottom; and those making both “ up “ and : down “ decisions along the way will ultimately reside somewhere in between. It was found that flies could be selected for both positive and negative geotropism, establishing the genetic influence on this behavioral response.

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As shown in figure 24.5, mean scores may vary from + 4.0 to – 6.0, corresponding to the number of T-junctions the encounters going up or down. These data show that the extreme of negative geot-ropism is stronger than the extreme of positive geotropism. The two lines have now undergone selections, and the testingof more than 80,000 files.througt the experiment, clearcut but fluctuating differences were observed. Such results indicate the additive effects of polygenic inheritance.
Hirsch and his colleagues also perfomed an analysis of the importance of genes located on different chromosomes to geotaxis. Hey were able to differentiate between genes located on chromosomes 2 and 3 and the X in a rather ingenious way. They carried out a set of crosses that produced files that wereeither heterozygous or homozygous for a given chromosome.
Figure 24.6 shows how this


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Some is back-crossed to a male from the original line. The resulting female offspring contain all combinations of chromosome. The dominant mutations make it possible to recognize which chromosomes from the selected lines are present in homozygous or heterozygous configurations. For example, combinations O and X (Figure 24.6) differ by being homozygous and heterozygous, respectively, for the X chromosome 2 (0 and 2) and chromosome 3 (0 and 3). Thus, by subjecting these flies to the geotaxic maze, it is possible to assess the influence of genes on any given chromosome on the bahavioral response.
Many flies of each genotype have been tasted, and the chromosomal effects have been complied individually and in all combinations. For the negatively geotactic lines (flies that go up in the maze), genes on the second chromosome are the most important, followed by loci on chromosome 3 and the X (2 > 3 > X). For the positive lines (flies that go down in the maze), the reverse arranngement (X > 3 > 2) indicates the relative effects of chromosomes in controlling this trait. Thus, the overall result indicate that geotaxis is under polygenic control, and that the responsible loci are distributed on all three major chromosomes of Drosophilia.
Further genetic testing in which each chromosome from a selected line has been isolated in homozygous form in an unselected background has been used to estimate the number of genes that control the geotaxic response in Drosophilia. While this work has not yet produced definitive resukts, it does indicate that a small number of genes, perhaps two to four loci, are responsible for this behavior.


SINGLE-GENE EFFECTS ON BEHAVIOR
By far the most definitive information about the genetic influence on behavior has come from the study of effect of single genes on behavior. In this more recent approach, either spontaneous or, more often, induced mutations are analyzed in order to infer general pronciples about how normal behavior is created and regulated.
There are obvious advantages to thid approch. By and large, in these laboratory studies the environmental effct on the behavioral response is minimized or eliminated. Thus, the genetic influence is more straightforward and easier to define than in studies where the environment is a major factor. As a result, it is theoretically possible to dissect a behavioral pattern into its components.
In this section we shall look at a number of the large amount of information resulting from such studies, we shall be selective in our discussion.


Nest-Cleaning Behavior in Honeybees
Honeybee nests are frequently infected with Bacilluslarvae, the agent causing American foulbrood disease. The disease may be counteracted by what is called hygienic behavior by worker bees. The cells of infected larvae are opened, and the diseased organisms are removed from the hive. Hygienic hives are resistant to infection, while hives containing strains that do not display removal behavior are susceptible to the disease.
In 1964, Walter Rothenbuhler published results of his cross between a hygienic (Brown) line with a nonhygienic (Van Scoy) line. This work atrongly favors the hypothesis that two recessive indepen-dently assorting genes (u and r) or a gene complex are responsible for hygienic behavior.
The F1 hybrids were all nonhygienic. However when F1 drones were back-crossed to hygienic, queens, faur phenotypes were produced in roughly aqual proportions,as shown in Figure 24.7. While one group was hygienic and one group nonhygienic, the other two groups were most interesting. One could uncap cells but not remove infected larvae. The fourth group, which at first appaered nonhygienic, was shown to be able to remove larvae if the cells were artificially uncapped. Thus, they were not able to uncap.
It appears that one gene pair (ulu) or a linked complex of genes determines uncapping behavior, and second gene pair (r/r) or complex determines removal ability. We have begun with this axampke to illustrate the way a genetic study has allowed components of a more complex behavior to be disected. Nest cleaning inhoneybees is also one of the most striking examples of the far-reaching effects of genes on behavioral responses.




TAXES IN BACTERIA
Behavioral responses exits evev in single-celled or ganisms such as bacteria.These responses are in the form of taxes (plural of taxis) and are mediated by flegella or cillia. Bacteria demonstrate chemotaxis and are attrated to or avoid a variety of stimuli. These responses have now been isolated that discrupt normal behavior.
Motile bacteria such as E, coli and Salmonella are capable of monitoring gradients of chemicals and moving along the gradient by controlling flagellar

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Action. Cells exhibit periods of smooth swimming called runs caused by counterclockwise (CCW) rotation of flagella, which act much like propellers, driving the bacteria through the medium. During runs, the flagella form a cohesive bundle, leading to movement in a single direction. Runs, which have an average duration of 1 second, alternate with avents called tumbles during which the flagella switch direction and rotate clockwise (CW). In clockwise rotation, the flagella become dispersed, and each acts independently. As a result, during tumbles, the cell achieves little net displacement (Figure 24.8). Tumbles, which last only about 0.1 second, serve to change the direction of the cell. In the presence of an attractant, runs that carry the cell up the gradient are extended, while those that move the cell down the gradient are not (Figure 24.9). In the presence of a repellent, the parameters are inverted.
Although molecular details of the chemo tactic response in bacteria are not yet available, the major components of the system have been identified, and the role of several gene products have been described. E. coli contains at least four different Tran membrane receptor proteins that bind to effectors and initiate an intracellular response, These proteins, called transducers, are members of a gene family that contains divergent periplasmic domains that bind chemical effectors, and conserved cytoplasmic domains involved in transmitting signals to the flagella. The intracellular pathways involve a set of cytoplasmic chemo taxis proteins that includes cheA, CheB, CheR, CheW, CheY, and CheZ.
The excitation pathway involves interaction of the transducer protein with CheW and CheA (figure 24.10), resulting in phosphorylation of CheA. Signal transmission from CheA to CheB and CheY involves transfer of phosphate groups to these gene products. Che A apparently integrates the response of the cell to chemical stimuli, as Che A mutans are nonchemotactic. It is thought that activated CheY bind directly to the base of the flagellar apparatus and favors CW rotation by changing the rates of transition between CW and CCW ration. CheZ acts to dephosphorylate Chey and inactivate its signal. Mutans of CheZ are apparently unable to inactivate the signal, with the result that runs are extended by a factor of three. A second pathway, called the adaptations pathway, involves Che R and Che W. this pathway apparently to enhances the sencitiviti of the transducer protein to the changing environmental conditions by mutilations mediated by CheB. Thus, the chemotactic behavior of E. coil involves a number of genes that receive and process signals and generate a response trhough a methabolic network involving protein phosphorylation and methylation. At the present time, the analysis of chemotaxis in bacteria represents the best-known example of the relation – ship between a behavioral response and its underlying molecular mechanisms.

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Avoidance Rections in Paramecium
Agreat deal is know about the neuropisiologi of ciliary action in paramecium. This organism swims in a more coordinated fasion than a bacterium. Upon encountering a physical barrier or noxious stimulus, it reverses the direction in which all cilia are beating, causing it to back up. A reversal again ocruos, and it swims off in a new direction.
The close coordination of ciliari direction is controlled by changes in electrical potential associated with the outer membrane. This depolaritations passes along the membrane across the cell, leading to a calcium influx. The increased Ca++ inside the cell is thought to initiate the reversal of direction of beating cilia.
Several mutants unable to execute this avoidance reaction jave been identified. The Pawn mutant, named after its chess counterpart, cannot swim backward under normal conditions. However, if the membrane is disrupted with detergent and the calcium ion concentration is increased sufficiently, backward swimming is observed. Thus, the ciliary apparatus is completely functional. The pattern shown in Figure 24.11 confirms that the mutation has eliminated electrical conductance essential to reversal. A second mutation, Paranoic, is also aptly named. Its electrical discharge patterns are compared with those of Pawn and wild type in Figure 24.11. A Paranoic mutant showns random reversals of ciliary direction and backing up in the presence of increased sodium ions, even in the absence of barriers.
In these and other mutants, behavioral responses are mediated by changes in the electrical potential of the cell membrane. The transducer are a class of integral membrane proteins known as ion channels. Because ions will not pass through lipid bilayer in the plasma membrane, they move through io channels in order to flow into and out of the cell. Ion channels can be open, allowing ions to move passively in response to a gradient, or they can be closed, preventing the flow of ions and electricsl impulses. Such channels act as switches, transducing chemical or mechanical signals into electrical impulses that control the direction of ciliary beat.
In Paramecium, mutants in seven different complementation groups affect Ca++ current. In one such mutant, pantophobiac (pnt), the action potential is reversed and the cell exhibits a prolonged period of backward swimming when exposed to various stimuli. The defective protein responsible for this mutation has been identified by microinjecting mutant cells with wild-type cytoplasm before injection has identified calmodulin, a Ca++ binding protein as the defective gene product in this mutant. Calmodulin binds to the Ca++ ion, and this complex in turn binda to and activates a number of enzymes. In the pnt A mutant, there is an amino acid substitution of serine for phenylalamine at position 101, and the mutant protein binds Ca++ weakly or not at all. Because ion channels in Paramecium and humans are identical in structure and function, further work on ion channels in Paramecium will not only shed light on genetic control of behavior in this organism, but also on he mechanisms that underlie taste, hearing, smelling, and the action of neurotransmitters in humans and other higher organisms.


Behavior Genetics of a Nematode
In 1968, in one of the boldest attempts to define the total genetic influence on the behavior of a single organism, Sidney Brenner began an investigation of te nematode Caenorhabditis elegans. Brenner had previously made valuable contributions in the field of molecular genetics, including studies of DNA replication, F factor, mRNA, and the genetic code. When he turned to the study of behavior, he hopoed that it would be possible to dissect genetically the nervous system of C. elegan using techniques previously applied successfully to other organisms.
He chose thus nematode because it was possible to determine the complete structure of the nervous system. Adult worms are about 1 mm long and are




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Composed of only 959 cells, about 300 of which are neurons. As a result, it is possible to cut serial sections of an embedded organism and its nervous system in a three – dimensional model. Brenner then hoped to induce large number of behavioral mutations and to cheminal alteration in the nervous system. Because of the vast scope of this ressearch endeavor,work is still underway. Some progress has been made, particularly in isolating large number of mutstions. Three types of behavioral mutants have been characterized. The worms are positively chemotactic to a variety of stimuli ( cyclic AMP and GMP; anions such as CI-,Br-,and I-;and cations such as Na+,Li+,K+,and Mg++).As shown in figure 24.12, positive attracton can be tracked in gradients on agar plates. The study of mutants has shown that sensory receptors in the head alone mediate the orientation responses to attractants.
A second clss of behavior studied involves ther motaxis. Cryophilic mutants move toward cooler temperatures, and thermophilic mutants move to ward warmer temperatures. However. This behavior has not yet been correlated with the responsible component of the nervous system.
The third clss of behavior involves generalized movement on the surface of an agar palte. Of 300 induced mutations, 77 affected the movement of the animal. While wild-type worms with a smooth, sinuous pattern, mutants are either uncoordinated (unc) or rollers (rol). Those that are uncoordinated vary from the display of partial paralysis to small aberrations of movement, including twitching. Roll-ers move been correlated with defects in the dorsal or ventral nerve cord or in the body musculature.
Linkage mapping has also begun. All mutants are distributed on six linkage graups, corresponding to the haploid number of chromosomes characeristic of this organism. Numeraus unc mutants are faund on each of the six chromosomes, indicating extensive genetic control of nervous system development.
Brenner’s work is being extended in many laboratories throughout the wold. In fach, an international congress now meets regularly to discuss work on C. Elegans. Research now includes genetic analysis of development, and nongenetic probelms are also being approached. This organism promises to rank with Drosophila in the amount of information acquired abaut it. It is hoped that study of C. Elegans will unloch the mysteries of how genes control the structure of the nervous system.
Single-Gene Effects in Mice
Surely the oldest recorded behavior mutant is the watzer mutation inthe mouse, recorded in 80 B.C. in

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China and described as a mouse “found dancing with its tail in its mouth.” Waltzing mice run in a tinght circle and demonstrate both horizontal and vertical head shaking as well as hyperirritability. Some waltzers are also deaf.
Genetic crosses between mutant and normal house mice ( mus musculus ) reveal a simple recessive inher-itance pattern characteristic of Mendel’s monohybrid matings. Investigation of the inner ear of mutants has reveled degeneration of both the cochlea and semi circular canals, accounting for the deafness and circling behavior. This is an example of a mutation causing a structural anomaly which, in turn, alters bahavior.
Many other single-gene behavior effect are know in the mouse, an organism particularly well characterized genetically. Of over 300 mutants discovered representing about 250 loci, over 90 are neurological in nature and alter behavior. These are classified into three groups of syindromes, as shown in table 24.2. The neurological basis of many of these has now been determined.
The incoordination mutants quaking and jumping are due to faulty myelination of of nervous tissue. Quaking is an autosomal recessive mutation, and jumping is inherited as a sex-linked recessive. The former cannot synthesize adequate myelin, while the latter demonstrates a degenerative process involving myelin. Cerebral degeneration is a mutant exhibiting progressive deterioration of behavior. As its name implies, part of the brain deteriorates.
The study of such mutants clearly establieshes the genetic basis of normal development. Additionally and more germane to this chapter, abnormal development is linked directly to altered behavior by these findings
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DROSOPHILA BEHAVIOR GENETICS
Genes an Mating Behavior in Drosophilia
We have already discussed geotaxis in Drosophiliaas an example of the selection methodology, but much more information on the behavior genetics of this organism is available. This is not at all surprising because of our extensive knowledge of its genetics and the ease with which it can be manipulated experimentally. Advances made beginning in the 1970s, particularly by Seymour Benzer and his colleagues, represent significant strides in the field of behavior genetics.
As early as 1915, Alfred Sturtevant observed that the sex-linked recessive gene yellow affects maiting preference, besides conferring the more obvious pigmentation difference. Recall that such a situation is an example of pleiotropic gene expression ( seechapter 4 ). Sturtevant found that both wild-type and yellow females, when given the choice of wild-type or yellow males, prefer to mate with wild type. Wild-type and yellow males prefer to mate with yellow females. These conclusions were based on quantitative measurement of success in mating between all combinations of yellow and wild-type (gray-bodied) males and females.
In 1956, Margaret Bastock extended these observations by investigating which, if any, component of courtship behavior was affected by the yellow nutant gene. Courtship in wild-type Drosophilia is a complex ritual. The male first undergoes orientation, where he follows the female, perhaps circles her, and then orients ussually at right angles and taps her on the abdomen. Once he has her attention, male wing display or vibration occurs. The wing closest to the female is raised and vibrates rapidly for several second. He then moves behind her, and contact is made between the male proboscis and female genitalia, described as “ licking “. Following this phase, if she has signaled acceptance by remaining in place, he mounts her and copulation occurs.
Bastock compared wild-type and yellow males for courtship rituals. What she observed was that yellow males prolong orientation but spend much less time in the vibrating and licking phases. Courtship patterns displayed by wild-type and yellow males are represented in Figure 24.13.
It appears that the yellow mutation has disrupted the intricate sequences of male courtship. Differences in the finer aspect of courtship have also been noted between related species of Drosophilia. In these instances, the behavioral differences are thought to server as possible isolating mechanisms during evolution.


The Genetic Dissection of
Behavior in Drosophilia
In 1967, Seymour Benzer and his colleagues initiated a comprehensive study of behavior genetics in Dro

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philia. Benzer’s approach is an excellent example of the use of genetic techniques to “ disset “ a complex biological phenomenon into its simpler components. Furthermore, the use of such techniques allows geneticists to study the underlying basis of the phenomenon – in this case, behavior. Benzer’s goals in this research illustrate the “ genetic dissection “ approach :
1. To discern the genetic components of behavioral responses by the isolation of mutations that disrupt normal behavior.
2. To identify the mutant genes by chromosome localization and mapping.
3. To determine the actual site within the organism at which the gene expression influences the behavioral renpone.
4. To learn, if possible, how the particular gene expression influences behavior.
All four steps are illustrade in a discussion of phototaxis, one of the first behavior studied by Benzer. Normal flies are positively phototactic; that is, they move toward a light source. Mutations are induced by feeding male flies sugar water containing EMS (ethymethanesulfonate, a potent mutagen) and mating them to attached-X virgin females. As shown in Figure 24.14, the F males receive their X chromosome from their father. Because they are hemizygous, any sex-linked recessive mutations are expressed.
The F males must be tested for their respone to light, and those that are not attracted to it are isolated. Benzer found runner mutants, which move quickly to and from light; negatively phototactic mutants, which move away from light; and nonphototatic mutant, which show no preference for light or darkness. He establised that the behavior changes were due to mutation by mating these F males to attached-X virgin females. Male progeny of this cross also showed the abnormal phototactic responses, comfirming them as products of sex-linked recessive mutations.
We shall now delve into work cocerning just one group, the nonphototactic mutants. Such flies behave in the light as normal flies do in dark. They can walk normally, but respond to light as if they were blind. Benzer and Yoshiki Hotta tested the alectrical activity at the surface of mutant eyes in respone to a flash of light. The pattern of electrical activity was recorded as an electroretinigram.Vari-







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ous types of abnormal responses were detected, and in none of the mutanta was a normal pattern observed. When these mutations were not all allelic; instead, they were shown to occupy several loci an the X chromosome. Thus, it can be concluded that several gene products contribute to the formation of behavioral respone to light.
Where, within the fly, must adequate gene expression occur to yield a normal pattern ? In an ingenious approach aimed at answering this question, Benzer turned to the use of mosaics. In mosaic flies, some tissues are mutant and others are wild type. If it can be ascertained which part must be mutant in order to yield the abnormal behavior, the primary focus of the genetic alteration can be determined.
To facilitate the production of mosaic flies, Benzer used a strain that has one of its X chromosomes in an unstable ring shape. When present in a zygote undergoing cell division, the ring-X is frequently lost by nondisjunction. If the zygote is female and has two X chromosomes (one normal and one ring-X), loss of the ring-X at the first mitotic division will result in two cells – one with a single X (normal X) and one with two X chromosomes (one normal and one ring-X). The former cell goes on to produce male tissue (XO) and expresses all alleles on the remaining X, while the latter produces female tissue and does not express heterozygous recessive X-linked genes. Such an occurrence is illustrated in Figure 24.15. One can see that loss of the ring-X will produce mosaic flies with male and female parts that express or do not express sex-linked recessive genes, respectively.
In the embryo, when and where the ring-X is lost determines the pattern of mosaicism. The loss ussually occurs early in development, before the cells migrate to the surface of the blastula to form the blastoderm. As shown in Figure 24.16, depending on the orientation of the spindle when the loss occurs, different types of mosaics will be created. If the stable X chromosome contains the behavior mutation and anobvious mutant gene (yellow, for example), the pat-

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tern of mosaicsim will be readily apparent. For example, the fly may consist of a mutant head on a wild-type body, a normal head on a mutant body, one normal and one mutant eye on a normal or mutant body, and so on.
When such mosaicsfor nonphototactic mutants were studied, it was found that the focus of the genetic defect was in the eye was normal, abnormal behavior was still detected. Even if only one eye was mutant, a modified abnormal behavior was observed. Instead of crawling straight up toward light as the normal fly does, the single mutant-eyed fly crawls upward to light in a spiral pattern. In the dark, such a fly will move in a staight line. Thus, mosaics studies have established that the focus of nonphototactic gene expression is in the eye itself. Additionally, the abnormal behavior is due to altered electrical conductance of the cells of the eye.
Benzer and other workers in the field have identified a large number of genes affecting behavior in Drosophilia. As shown in Table 24.3, mutant have been isolated that affect locomotion, response to stress, circadian rhythm, sexual behavior, visual behavior, and even learning. The mutations have received very descriptive and often humorous names.
Many mutations have been analyzed with the mosaic technique in order to localize the focus of gene expression. While it was easy to predict that the focus of the nonphototactic mutant would be in the eye, other mutant are not so predictable. For example, the focus of mutant affecting circadian rhythms has been located in the head, presumably in the brain. The wing up mutant might have a defect in the wings, articulation with the thorax, the thorax musculature, or the nervous system. Mosaic studies have pinpointed the indirect flight muscles of the the thorax as the focus. Cytological studies have comfirmed this finding, showing a complete lack of myofibrils in these muscles. Temperature-sensitive paralytic mutants are paralyzed at a raised temperature (29oC) but recover rapidly if the temperature is lowered. Mosaic studies have revealed that both the brain and thoracic ganglia represent the focus causing this abnormal behavior. More recent work has shown that mutant flies have defective sodium channels, and that the paralytic locus encodes a protein that controls movement of sodium across the membrane of nerve celld.
The drop-dead mutant is most interesting. Such mutant flies appear completely normal for the first few days of adult life. Then they begin to stagger, fall over, and die. The cause of death could be related to any vital function anywhere in the body. However, mosaic study revealed that the defect is in the head. Most flies with mutant heads and normal bodies drop dead, while most with normal heads and mutant bodies do not. As shown in Figure 24.17, the brain of the drop-dead mutant appears to be full of holes. Examination of the brain of mutants before death shows them to be normal.
The mosaic technique has also been used to determine which regions of the brain are associated with sex-specific aspects of courtship and mating behavior. Jeffery Hall and his associates have shown that mosaics with male cells in the most dorsal region of the brain, the protocerebrum, exhibit the initial stages of male courtship toward females. Later stages of of male sexual behavior including wing vibrations and attempted copulation require male cells in the thoracic ganglion. Similar studies of female-specific sexual behavior have shown that the ability of a mosaic to induce courtship by a male depends on female cells in the posterior thorax or abdominal region. A region of the brain within the protocerebrum must be female for receptivity to copulation. Anatomical studies have confirmed that there are fine structural differences in the brains of male and female.

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Drosophilia, indicating that some forms of behavior may be dependent on the development and maturation of specific part of the nervous system.

Learning in Drosophilia

To study the genetics of behavior such as learning, it would be advantageous to use an organism like Drosophilia, in which methods of genetic analysis are highly advanced. However, the first question is: Can Drosophilia learn? Recent work from a number of laboratories indicates that organisms such as Drosophilia are, in fact, capable of learning. Using a simple apparatus, flies are presented with a pair of olfactory cues, one of which is associated with an electrical shock. Flies quickly learn to avoid the odor assiciated with the sock. That this response is learned is indicated by a number of factors : firs, performance is indicated with the pairing of a stimulus/response with a reinforcer ; second, and flies exhibit short-term memory for the training they have received.
Other evidence suggests that more innate forms of behavior, such as courtship, are also associated with learning. Richard Siegel and his colleagues have foundthat following unsuccessful courtship of sexually unreceptive females, males show a reduction of courtship in abaut 3 hour, even in the presence of sexually receptive females. Memory deficient mutants, such as amnesiac , resume active courtship in about 1 hour, presumably because the previous experience has been forgotten.
The demonstration that Drosophila can learn opens the way to selecting mutants that are defective in learning and memory. To accomplish this, males from an inbread wild-type strain are mutagenized and mated to females from the same strain. Their progeny are recovered and mated to produce populations of flies, each of which carries a mutagenized X ahromosome. Mutants that affect learning are selected by testing the population for response in the olfactory/ shock apparatus. A number of learning-deficient mutants including dunse, turnip, rutabaga, and cabbage have been recovered. In addition, a memory-deficicient mutants, amnesiac (mentioned previously), that learns normally but forgets four times faster than normal. Each of these mutations represents a single gene defect that method used to recover them, all the mutants found so far are X-linked genes. Presumably similar genes controlling behavior are also located on auto-somes.

Molecular Biologi of Behavior
Since in many cases, mutation results in the alteration or abolition of a singe protein, biochemical study of the learning mutants described above can provide a link between behavior and molecular biology. The dunce mutation is one of the first for which this link has been established. The locus for dunce has been shown to encode the structural gene for the enzymecyclic AMP photosphodiesterase. It appears that rutabaga is a mutation is in thi gene for a GTP-binding protein associated with adenylate cyclase. The unexpected clustering of these independently derived mutations in the biochemical pathway of the adenyl cyclase system suggests a role for cyclic nucleotides in learning. This conclusion is consistent with work in the sea hare, Aplysia, indicating that

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Mental Disorder with a
Clearcut Genetic Bassis

Many genetis disorders in human in some behavioral abnormality. One of the most prominent examples in Huntington disease (HD). Inherited as an autosomal dominant disprder, it affect the nervous system, including the brain. Symptoms of HD usually appear in the fifth decade of life with a gradual loss of motor function and coordination. Degenaration of the nervous system is progressive, and personality changes occur. The affected individual soon is unable to care for himself. Most victims die within 10 to 15 years after onset of the disease. Since onset is usually after a family has been started, all children of an affected person must live with the knowlegde that they face a 50 percent probability of developing the disorder. The gene for HD maps to the tip of the short arm of chromosome 4 and is associated with elevated brain levels of quinolinic acid, a naturally occurring neurotoxin. Althought the gene has not yet been isolated, nearby molecular markers can be used in RFPL analysis (Chapter 16) to diagnose those carrying the dominant allele before symptoms appear.
The Lesch-Nyhan syndrome is inherited as a sex-linked recessive disorder. Onset is within the first year, and the disease is most often fatal early in childhood. The disorder is of a metabolic nature, involving purine biosynthesis. Affected individuals lack hypoxanthine-guanine phosphoribosyltransferase (HGPRT), and accumulate high levels of uric acid. Mental and physical retardation occurs, and these individuals demonstrate uncontrolled self-mutation. They also strike out at individuals attemping to care for them.
Other metabolic disorder are also known to affect mental function. For example, Tay-Sachs disease, an autosomal recessive disorder, involves severe mental retardation among other phenotypic characteristics. The disease is apparent soon after birth and is fatal.


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Porphyria, under the control of an autosomal dominant allele, ussually has a much later anset and is marked by recurring periods of dementia. The autosomal recessive disease phenylketonuria, unless detected and treated early, result in metal retardation. All of these disorders alter the normal biochemistry of the affected individuals and are inherited in a Mendelian fashion.
Chromosome abnormalities also produce syndromes with behavioral components. Down syndrome (trisomy 21) result in metal retardation. While there is a wide range of variability, the mean IQ of affected individuals is estimated to be 25 to 50. The onset of walking and talking is often delayed until four to five years of age. Both Klinefelter syndrome (XXY) and Turner syndrome (XO) may also result in diminished mental capacity.

Human Behavior Traits with
Less-Defined Genetic Bases
Other aspects of human behavior, notably schizophrenia and manic-depressive illness, have been the subject of extensive study. Investigations have sought to relate the development of the mental disorder or the display of intelligence to the closeness of family relationships or twin studies. In all cases, it has been concluded that a genetic component influences the trait, but that environmet also plays a substantial role.
A discussion of schizophrenia may server to illustrate the methodology used. This mental disorder is characterized by withdrawn, bizarre, and sometimes delusional behavior. Those affected by the disease are unable to lead organized lives and are periodecally disabled by the condition. It is clearly a family disease, with relatives of schizophrenics having a much higher incidenceof this disorder than the general population. Furthermore, the closer the relationship to the index case or proband, the greater is the the probability of the disorder occurring.
The concordance of schizophrenia in monozygotic and dizygotic twins has beenthe subject of many studies. In almost every investigation, concordance has been higher in monozygotic twins than in dizygotic twins reared together. Although these results suggest that a genetic component exists, they do not reveal the precise genetic basis of schizophrenia. Simple monohybrid and dihybrid inheritance as well as multiple gene control have been proposed for schizophrenia. However, it seems unlikely that onlyone or two loci are involed, nor is it likely that the control is stictly quantitative, as in polygenic inheritance. In both schizophrenia and manic-depressive illness, it is most sound to conclude that each individual is endowed with a genetic predisposition for normal or abnormal behavior and that environmental factors can sever to alter the final phenotype.
There ia a long-standing controversy about genetic differences in intelligence between races. While IQ testing has established intelligence differences in populations of different races, there is currently no strong evidence to support the conclusion that this is due to a genetic component. With regard to intelligence. The environment undoubtedly has a profound effect on the type of intelligence measured by the various forms of IQ test. It seems likely that the genetic component of intelligence does not differ any more significantly betweeen individuals within the same race.





CHAPTER SUMMARY
1 Behavioral genetics has emerged as an important specialty within the field of genetics because both genotype and environment have an impact in determining an organism’s behavioral response.
2 Since both genotype and environment play a role in the expression of behavioral traits, the production of purely objective data in this area is particularly difficult.
3 Three areas of genetically influenced behavior research are being pursued: the behavior of closely related organisms from similar environment whose survival needs appear to be identical; the laboratory modificarion of behavioral traits for evidence of heritability; and specific effects of a single gene on behavior strongly influenced by the genotype.
4 The studies of alcohol preference and open- field behavior in mice and mate selection in baboons illustrate behavior strongly influenced by the genotype.
5 Studies of maze learning in rats and geotaxis in Drosophilia have successfully established both bright and dull lines of rats and either positively or negatively geotaxis Drosophilia. These results have led researchers to ascribe the relative contributions of genes on specific chromosome to these behaviors.
6 By isolating mutations that cause deviations from normal behavior, the role of a corresponding wild-type allele in the respective response is established. Numerous examples have been examined, including honeybee hygenic behavior; chemotaxis, thermotaxis, and general movement in nematodes; neurological mutations in mice; and a vsriety of behaviors in Drosophilia.


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7 Any aspect of human behavior is difficult to study because the individual’s environment makes an important contribution toward trait development. In humans, studies using twins have shown that while a family may have a predisposition to schizophrenia, the expression of this disorder may be modified by the environment. Generel intelligence is also a product of both genetic and environmental influences.


Insights and Solutions

Manic depression is an affective disorder associated with recurring mood changes. It is estimated that one in four individuals will suffer from some form of affective disorder at least once in his lifetime. Genetic studies indicate that manic depression is familial, and that single genes may play a major role in controlling this behavioral disorder. In 1987 two separate studies using RFLP analysis and other genetic markers reported lingkage between manic depression and markers on the X chromosome and to the short arm of chromosome 11. At the time, these reports were hailed as landmarj discoveries, opening the way to the isolation and characterization of genes that control specific forms behavior, and the development of theraoeutic strategies based on knowledge of the nature of the gene product and its action. However, further work on the same populations reported in 1989 and 1990 demonstrated that the original result were invalid, and concluded that no linkage to markers on the X chromosome and to marlers on chromosome 11 could be established. These findings do not exclude the role of major genes on the X chromosome and autosomes in manic depression, but do exclude linkage to the markers used in the original reports.
This setback not only caused embarrassment and confusion, but it also forced a reexamination of the validity of the methods used in mapping human genes, and the analysis of data from linkage studiesinvolving complex behavioral traits. Seeveral factors have been proposed to explain the flawed conclusions reported in the original studies. What do you suppose some of these factors to be ?
ANSWER: while some of the criticisms were at the directed at the choice of markerrs, most of the factors at work in this situation appear to be related to the phenotype of manic depression. At least three confounding elements have been identified. One is age of onset. There is a positive correlation betwen age and appearance of manic depression. Therefore, at the time of a pedegree study , younger individuals who will be affected later in life may not show any signs of manic depression. Another confusing factor is that in the populations studied, there may in fact be more than one major ex-linked gene ang more than one major autosomal gene that cause manic depression. A third factor relates to the diagnosis of manic depression itself. The phenotype is complex and not as easily quantified as height or weight. In addition, swings in mood alterations and the role of enviromental factors from affective disorders having a biological and/or genetic basis.
These factors point up the difficulty in researching the genetic basis of complex behavioral traits. Individually or in combinations, the factors describe above might skew the results enough so that guidelines for proof that are adequate for other traits are not stringent enough for behavioral traits with complex phenotypes and complex underlying causes.