Genetics Problem Spaces

Introduction Problem Spaces Behavioral Genetics Overview Intro Exercise Research Questions Literature Resources Assignments Student Projects

Behavioral Genetics Overview The behavior of animals is the focus of several different scientific disciplines (e.g. psychology, ethology, neurobiology). These fields have made great progress describing the complex array of behaviors that animals exhibit, how behaviors are modified by the environment and how evolution shapes behavior. A common theme of this research is the underlying cellular and chemical complexity of behavior. Even the simplest of behavior involves the interactions of sensory cells, muscles and complex neuronal networks. One approach to deciphering complex phenomena like behavior is to “genetically dissect” them. Genetic dissection is an experimental approach for understanding the role of genes in a process. It has been tremendously successful in providing the frame work of our current understanding of complex biological phenomena such as animal development and cancer. Genetic dissection is outline in more detail below. Behavioral genetics is the subdiscipline of genetics focusing on animal behavior. The goal of behavioral genetics is to understand the genetic basis of behavior, to understand how genes and the environment interact to influence behavior, and to understand how evolution has shaped the genes that control behavior. History of Caenorhabditis elegans as a Research Organism. Since Mendel, the use of model research organisms may be more important to genetics than any other field of biology. The choice of the nematode Caenorhabditis elegans as a model research organism can be credited to one person, Sydney Brenner. After studying medicine in his native South Africa, Dr. Brenner decided to go to England to conduct basic research. He arrived in England just before Watson and Crick discovered the double helical structure of DNA. In the early 1960’s he established one of the most productive and influential genetics laboratories in the world. His research contributed to our understanding of the triplet nature of the genetic code and provided evidence for the existence of mRNA. In the mid-1960’s, he and his officemate, Francis Crick both concluded that “most of the classical problems of molecular biology have been solved and that the future lay in more complex problems.” They decided to change their research focus and to tackle two of the most complex phenomena in biology, animal development and the nervous system. Dr. Brenner planned to use a genetic approach to study these phenomena. Therefore, he sought a new model research organism appropriate to the problem. He rapidly settled on Caenorhabditis elegans. Since the 1960’s, C. elegans has become one of the most important organisms in Biology. It is worth considering several advantages it offers over other organisms. Ease of Cultivation. C. elegans can be cultured in the laboratory at room temperature. It feeds on a standard strain of E. coli. Adults are only about 1 mm long and it is possible to grow thousands on a single Petri dish. Hermaphrodites mature in less than three days and lay hundreds of eggs. Therefore, a single week is sufficient for a single hermaphrodite to generate a culture with thousands of worms. Simple Genetics. It is possible to conduct controlled matings with C. elegans. Self-fertilizations are conducted with the hermaphrodites. Cross matings can be conducted with males and hermaphrodites. Thousands of mutant strains of C. elegans have been generated and they are available for free from the Caenorhabditis Genetics Center. Detailed Development Described. An adult C. elegans is transparent and all of its 951 cells are visible under a microscope. A complete cell fate map describing how the single cell zygote give rise to all of the cells in an adult is known. Genome Sequenced. C. elegans was the first animal to have its genome completely sequenced. It has about 19,000 genes, about 40% of which are related to genes in humans. Genetic Dissection Genetic or mutational dissection is an experimental approach for understanding the role of genes in complex biological processes. This approach has been effective in understanding complex processes such as the development of body plans, the initiation and progression of cancer, and animal behavior. In fact, genetics has been so important in the biology of these topics, that your textbook devotes an entire chapter to each. Mutational dissection of any complex biological process can be broken down into five steps. Step 1: Generate mutants for the process being studied. For example if you were interested in the role of genes in wing formation in Drosophila, you would begin by isolating mutant strains of flies that lack wings or had malformed wings. Typically, mutations are created by exposing the flies to chemical mutagens. Next, several generations of the fly are examined for altered wing phenotypes. If flies with altered wings are found, they will be used to generate true-breeding strains. At the end of this process, there will be a series of independent mutant strains with altered wings. Careful analysis of the mutations may indicate they belong to different phenotypic classes. For example there may be several mutant strains without wings, several mutant strains with misshaped wings and several mutant strains with nearly normal wings except for the veining pattern. The different classes of phenotypes suggest different sub processes involved in wing formation. Step 2: Classify mutant genes. Analyze each mutation with standard Mendelian crosses and backcrosses. Using these crosses, determine if the mutant traits are controlled by a single Mendelian gene or are quantitative, if they are dominant or recessive to wildtype, if they are autosomal or sex linked, if they are lethal, and if they are sex influenced. Some of the most useful mutations will be conditional. For example, they may be temperature sensitive, where the mutant phenotype is only expressed at high temperatures, but at normal temperatures a wildtype phenotype is expressed. Step 3: Count the genes involved in the process. Determine how many different genes are represented by the pool of mutant strains. This might be done by performing complementation test with the strains. In a complementation test, recessive mutant strains are interbred. If the mutations of two strains are in different genes, the offspring of the strains will be phenotypically wildtype. However, if the mutations of the two strains are in the same gene, then the strains offspring will be phenotypically mutant. Steps 1 through 3 will identify the minimum number of genes involved in the complex trait. However, it must be noted that this approach may not identify all the genes involved in the trait. Step 4: Structural and functional analysis. Identify the gene sequence associated with each mutation and study its expression. Determine the nucleotide sequence of the gene and of the mRNA, analyze the structure of the protein encoded by the gene, and determine the developmental timing and spatial expression of the gene. These observations will provide important insight into the genes involvement in the complex process. Step 5: Identify genetic interactions. Determine how the gene product interacts with other genes. An initial strategy may be to analyze of epistasis. Epistatic analysis provides insight into the hierarchy of the gene interactions. A second powerful strategy is to isolate modifier mutations. Modifier mutations are mutations in one gene that ameliorates (suppresses) or worsens (enhances) a mutation in a second gene. Modifier mutations by themselves might not affect the phenotype. They can only be detected in the context of other mutation. Modifier mutations also indicate that the modifier and affected genes participate in the same process.