Deck 24: Neurogenetics

Question 1

Huntington disease (HD) is a dominantly inherited, adult-onset neurodegenerative disorder that affects about 1 in 10,000 people. Onset is around 50 years of age, there is no treatment, and the disorder inevitably causes dementia and loss of motor control, and is fatal. To study the cellular and molecular mechanisms associated with HD, animal models, including mice and Drosophila , have been created by transferring mutant human HD genes into these organisms. However, some of the behavioral changes seen in HD mice and fruit flies are difficult to correlate with those seen in affected humans. To more closely replicate the cognitive and motor changes in HD, researchers have created a primate model using rhesus macaques, which are one of our closest relatives and share many similarities with humans, including life span, cellular metabolism, as well as endocrine and reproductive functions. However, their use raises several important questions.
What are the ethical concerns related to research with primate models of human disease?

Answer 1

There are ethical concerns using primates as models of human disease. The animal would suffer and possibly die for human gain. We would not inject a disease into a human to study the disease. Primates are similar biologically to humans and that also questions the ethical reasoning. Again, we would not inject a disease into a human but scientists have injected primates that are similar to us.

Question 2

In this chapter we focused on how genes that control the development, structure, and function of the nervous system and interactions with environmental factors produce behavior. At the same time, we found many opportunities to consider the methods and reasoning by which much of this information was acquired. From the explanations given in the chapter, what answers would you propose to the following fundamental questions:
(a) How do we know there is genetic variation for a specific behavior that is present in strains of a species?
(b) How do we know that Drosophila can learn and remember?
(c) How do we know how the mutant gene product in Huntington disease functions?
(d) How do we know that schizophrenia has genetic components?

Answer 2

Genes which control the structure, function and development of the nervous system and other interactions with environmental factors, are the causes of producing behavior. Thus, behavior is a multifactorial trait which is controlled by genes.
(a)Several evidences point out that there are genetic variations for a specific behavior that is present in a species. Species-specific behaviors which are observable, like artificial selection and courtship rituals can help in establishing populations with differences in behavior which are heritable. In the case of humans, twin studies have helped establish the role of heredity for a specific behavior.
(b)Drosophila is used as an animal model for learning and remembering. An olfactory-based shock-avoidance learning system is used in fruit flies which help in identifying genes which are responsible for controlling memory and learning. In this learning system, pair of odors is presented to flies, in which one of the odors is associated with electric shock. The fruit flies learn quickly to avoid the odor which is associated with the shock.
(c)Huntington disease is a neurodegenerative behavioral disorder. It is an autosomal dominant late-onset disorder. There is a gradual loss of motor function and coordination by the cells. It is caused by the death of brain cells in certain parts of the brain. Normal HD gene present on chromosome 4 encodes a large protein called huntingtin (HTT) which is essential for survival of adult brain cell neurons. Mutant alleles have increased number of CAG (cytosine-adenine-guanine) repeats in exon 1 whereas normal alleles carry only 7-34 CAG repeats. In mutant alleles, additional glutamine residues are placed into the encoded protein due to expansion of CAG repeats. Since, the numbers of repeats are more in mutant alleles; this causes toxicity, leading to death of cells in various regions of the brain, resulting in behavioral abnormalities.
To know how the mutant gene product in Huntington disease functions, animal models of Drosophila and mice have been created by the transfer of mutant HD genes from humans to these models. But in case of these models, the behavioral changes are difficult to correlate with that of affected humans. Therefore, most recently a primate model of rhesus macaques has been used as they are one of our closest relatives and thus have many similarities with humans, though lots of opposition is there regarding the use of rhesus macaques as a model.
(d)Schizophrenia is a term which is used to describe a set of mental disorders. Individuals who are affected have psychotic symptoms, delusions, antisocial behavior and thought disorders. It is a familial disorder, as the closely the person is related to the schizophrenic patient; the more likely he is to develop the disease. Twin studies have helped establish a genetic relation with schizophrenia. If both express the trait then they are concordant for it, if one does and the other does not; then they are discordant for it.
Monohybrid and dihybrid inheritance have been stated as causes of schizophrenia. The knowledge that schizophrenia has genetic components has been obtained by the Human Genome Project which used high-throughput sequencing and haplotype mapping methods for studying schizophrenia. Genome-wide association studies (GWAS) have provided us with evidence that hundreds of genes contribute to this disorder and not any single allele or gene.

Question 3

Huntington disease (HD) is a dominantly inherited, adult-onset neurodegenerative disorder that affects about 1 in 10,000 people. Onset is around 50 years of age, there is no treatment, and the disorder inevitably causes dementia and loss of motor control, and is fatal. To study the cellular and molecular mechanisms associated with HD, animal models, including mice and Drosophila , have been created by transferring mutant human HD genes into these organisms. However, some of the behavioral changes seen in HD mice and fruit flies are difficult to correlate with those seen in affected humans. To more closely replicate the cognitive and motor changes in HD, researchers have created a primate model using rhesus macaques, which are one of our closest relatives and share many similarities with humans, including life span, cellular metabolism, as well as endocrine and reproductive functions. However, their use raises several important questions.
Does it seem likely that results from using rhesus macaques will translate directly to an understanding of the disease process in humans and lead to treatment?

Answer 3

Think of a drug that has gone through trials using a model organism like a mouse and it worked. Then, it was tested on humans and did not treat the disease. This is because on a cellular level, a mouse is different from humans and a drug may function differently in them. A model organism that was more similar to humans would be more likely to produce the same results that the drug would in humans. Therefore, it could be likely that results from using primates would directly lead to an understanding of a disease and lead to treatment. Primates have a similar cellular metabolism, life span, endocrine function and reproductive functions making them one of the best model organisms to use.

Question 4

Review the Chapter Concepts list. One of these concepts describes the focus of genetics and molecular biology on the structure and function of the nervous system. Write a short essay on the role of the synapse, neurotransmitters, and receptors in human behavioral disorders.
▪Behavior is a complex response to stimuli that is mediated both by genes and by the environment.
▪Lines of evidence including observations on species-specific behaviors and the use of artificial selection have established the role of genetics in behavior. In humans, studies of families, twins, and adoptions confirm that many forms of behavior in our species have a genetic basis.
▪Genetic and molecular studies of behavior in model organisms and in humans are centered on understanding the role of genes and environment in shaping the development, structure, and function of the nervous system, and its components, especially the synapse.
▪Genetic and genomic approaches to the study of behavior have been successfully used in Drosophila and the mouse, making them useful model organisms for the study of nervous system function and the mechanisms that underlie human behavioral disorders.
▪Many human behavioral disorders are complex responses to stimuli. These responses are mediated by genes, environmental factors, and interactions among genes and the environment. More recently, newly developed genomic techniques are being used to study the role of genes in human behavior.

Question 5

Huntington disease (HD) is a dominantly inherited, adult-onset neurodegenerative disorder that affects about 1 in 10,000 people. Onset is around 50 years of age, there is no treatment, and the disorder inevitably causes dementia and loss of motor control, and is fatal. To study the cellular and molecular mechanisms associated with HD, animal models, including mice and Drosophila , have been created by transferring mutant human HD genes into these organisms. However, some of the behavioral changes seen in HD mice and fruit flies are difficult to correlate with those seen in affected humans. To more closely replicate the cognitive and motor changes in HD, researchers have created a primate model using rhesus macaques, which are one of our closest relatives and share many similarities with humans, including life span, cellular metabolism, as well as endocrine and reproductive functions. However, their use raises several important questions.
If the primate HD model is successful, should it be used for other human behavioral disorders such as Alzheimer or Parkinson disease?

Question 6

In humans, the chemical phenylthiocarbamide (PTC) is either tasted or not. When the offspring of various combinations of taster and nontaster parents are examined, the following data are obtained:
Based on these data, how is PTC tasting behavior inherited?

Question 7

Various approaches have been applied to study the genetics of problem and pathological gambling (PG), and within-family vulnerability has been well documented. However, family studies, while showing clusters within blood relatives, cannot separate genetic from environmental influences. Eisen (2001) applied "twin studies" using 3359 twin pairs from the Vietnam-era Twin Registry and found that a substantial portion of the variance associated with PG can be attributed to inherited factors. How might twin studies be used to distinguish environmental from genetic factors in complex behavioral traits such as PG?

Question 8

Caenorhabditis elegans has become a valuable model organism for the study of development and genetics for a variety of reasons. The developmental fate of each cell (1031 in males and 959 in hermaphrodites) has been mapped. C. elegans has only 302 neurons whose pattern of connectivity is known, and it displays a variety of interesting behaviors including chemo-taxis, thermotaxis, and mating behavior, to name a few. In addition, isogenic lines have been established. What advantage would the use of C. elegans have over other model organisms in the study of animal behavior? What are likely disadvantages?

Question 9

Using the behavioral phenotypes of a series of 18 mutants falling into five phenotypic classes, Thomas (1990) described the genetic program that controls the cyclic defecation motor program in Caenorhabditis elegans. The first step in each cycle is contraction of the posterior body muscles, followed by contraction of the anterior body muscles. Finally, anal muscles open and expel the intestinal contents. Below is a list of selected mutants (simplified) that cause defects in defecation.
Present a simple schematic that illustrates genetic involvement in C. elegans defecation. Account for the action of the aex gene and speculate on the involvement and placement of the cha gene.

Question 10

Discuss why the study of human behavior genetics has lagged behind that of other organisms.

Question 11

P. Scott and J. L. Fuller studied 50 traits in five pure breeds of dogs. Almost all the traits varied significantly in the five breeds, but very few bred true in crosses. What can you conclude with respect to the genetic control of these behavioral traits?

Question 12

Although not discussed in this chapter, C. elegans is a model system whose life cycle makes it an excellent choice for the genetic dissection of many biological processes. C. elegans has two natural sexes: hermaphrodite and male. The hermaphrodite is essentially a female that can generate sperm as well as oocytes, so reproduction can occur by hermaphrodite self-fertilization or hermaphrodite-male mating. In the context of studying mutations in the nervous system, what is the advantage of hermaphrodite self-fertilization with respect to the identification of recessive mutations and the propagation of mutant strains?

Question 13

In July 2006, a population of flies, Drosophila melanogaster , rode the space shuttle Discovery to the International Space Station (ISS) where a number of graviperception experiments and observations were conducted over a nine-generation period. Frozen specimens were collected by astronauts and returned to Earth. Researchers correlated behavioral and physiological responses to microgravity with changes in gene activity by analyzing RNA and protein profiles. The title of the project is " Drosophila Behavior and Gene Expression in Microgravity." If you were in a position to conduct three experiments on the behavioral aspects of these flies, what would they be? How would you go about assaying changes in gene expression in response to microgravity? Given that humans share over half of the genome and proteins of Drosophila , how would you justify the expense of such a project in terms of improving human health?

Question 14

Of a variety of investigational approaches that have been applied to the study of schizophrenia, two separate approaches, twin studies and genomic analysis, have provided strong support for a genetic component.
(a) Provide a summary of the contribution that each has played in understanding schizophrenia.
(b) Speculate on the value that genomic analysis using samples from monozygotic and dizygotic twins might have for enhancing research on schizophrenia.

Question 15

Describe the use of single-nucleotide polymorphisms (SNPs) in the study of genetic causes of schizophrenia.

Question 16

Autism, a relatively common complex of human disorders, can range from severe to mild. What evidence indicates a possible link between genetics and autism?

Question 17

An interesting and controversial finding by Wedekind and colleagues (1995) suggested that a sense of smell, flavored with various HLA (human leukocyte antigen) haplotypes, plays a role in mate selection in humans. Women preferred T-shirts from men with HLA haplotypes unlike their own. The HLA haplotypes are components of the major histocompatibility complex (MHC) and are known to have significant immunological functions. In addition to humans, mice and fish also condition mate preference on MHC constitution. The three-spined stickleback ( Gasterosteus aculeatus ) has recently been studied to determine whether females use an MHC odor-based system to select males as mates. Examine the following data (modified from Milinski et al., 2005) and provide a summary conclusion. Why might organisms evolve a mate selection scheme for assessing and optimizing MHC diversity?
The table compares odor-based choices made by gravid females for males with optimal MHC alleles and males with nonoptimal MHC alleles. Gravid females chose different amounts of time (seconds) for exposure to males with optimal MHC alleles versus those with nonoptimal MHC alleles. The number of females spawning when exposed to different males with different MHC complements is also presented in the table.

Question 18

Describe studies indicating that the degree of DNA methylation (removal or addition), coupled with changes in trinucleotide repeats, can play a role in mental illness. How have twin studies aided our understanding of the role of DNA methylation in the study of mental illness?

Question 19

Fragile-X syndrome is characterized by intellectual deficits, some dysmorphia, and hyperactivity. It is caused by abnormal expansion of a (CGG) n repeat in the 5'-untranslated region of the FMR1 gene and as such results in hypermethylation of CpGs. Considering the role of the FMR1 gene in expression of fragile-X syndrome, what is the relationship between hypermethylation and FMR1 gene expression?

Question 20

There are at least eight known progressive neuronal dysfunction diseases in humans that are caused by abnormal numbers of CAG repeats within the coding regions of specific genes. Genes carrying such mutations are typically of the gain-of-function class and often share a common mechanism of progressive pathogenesis. Why are such genes "gain-of-function"? Speculate on why such diseases are probably caused by a common mechanism of pathogenesis.