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Study Guide – Genotype vs. Phenotype 1. Over the years researchers working with Drosophila have obtained strains that are heterozygous for deletions that cover virtually all (but not all) of the genome. These deletions when homozygous are lethal. a. How would one see a deletion using polytene chromosomes in Drosophila? b. What does the lethality of the homozygous deletions say about the prevalence of genes that can be mutated to lethality? c. Deletions visible on the polytene chromosome cause the complete loss of several genes. What does the finding that deletions covering almost all the genome have been obtained say about the recessive or dominant nature of the loss of virtually all Drosophila genes (a similar result is found for C. elegans)? d. Deletions for some regions of the fly genome, however, have not been found. Why do you think this is so? e. Genes in such regions are termed “haploinsufficient.” Why? f. Answer question c with regard to the genes in the regions described in part d. g. We can diagram gene activity with two, one or no doses of the wild-type gene as shown in the figure. i. Where would you draw a line separating activity sufficient to give the wildtype phenotype from activity that gives rise to a mutant phenotype for most of the genes in Drosophila? ii. Where is the line for a gene discussed in d and e? h. What do these considerations say about the relationship of the loss of gene activity to whether the gene is expressed as recessive or dominant? i. For much of this class session we will try to derive the notion of the standard or average gene, i.e., a gene that exhibits the genetic properties of most genes in the genome. For example, would the loss of a standard gene be a recessive or dominant trait? 2. Herman Muller in classic paper in 1932 (see Extra Reading) described several different ways that genes could be mutated. He described an allele that gives the phenotype seen with the complete loss of the gene as an amorph. We now usually refer to such alleles as null alleles or complete loss-of-function alleles. He also described alleles that had reduced gene activity as hypomorphic. This term is still used but we also speak of these alleles as partial loss-of-function alleles. a. In the same diagram as in 1g, draw a box representing the activity of an organism that is heterozygous and an organism that is homozygous for a hypomorphic allele m. b. For a standard gene would m be a recessive or a dominant mutation? c. For most genes most alleles give the null phenotype, i.e. appear to act like complete loss-of-function alleles? Why would you expect more null than hypomorphic alleles for a standard gene? d. What is the relative frequency for dominant alleles in the average gene? in a haploinsufficient gene? e. If you were doing a mutagenesis of visible mutants (such as was done by Sydney Brenner), could you identify genes represented only by hypomorphic mutations? Why? f. Brenner estimated that the rate of mutation of the average gene was 1/2000. What would be the rate (higher, the same, lower) for a gene discussed in part e? g. Draw appropriate lines to demarcate the activity needed for a wild-type phenotype, a hypomorphic phenotype, and a null phenotype for the diagram in 1g. h. Given different hypomorphic alleles (m1, m2, etc.), would heterozygotes with a deletion of the region (e.g., m1/Δ, where Δ represents the deletion) give the hypomorphic phenotype or the null phenotype? How? Diagram this as before. i. Could the results in part h demonstrate that an allele m was indeed hypomorphic and not null? j. In parts e and h you developed criteria to hint that a given phenotype is null. What are these? k. Suppose you had sequence information that told you which alleles contained nonsense mutations. Would having a nonsense mutation signify that you have a null allele? l. Are the various criteria developed in this problem for identifying null alleles sufficient to demonstrate the null phenotype? 3. One type of hypomorphic allele is one that is expressed in a temperaturesensitive fashion, i.e. mutant expresses the mutant phenotype (the restrictive temperature) at one temperature and the wild-type phenotype at another (the permissive temperature). In C. elegans most heat-sensitive mutants are identified from screens at 25° (the highest growth temperature possible) and then found to be wild-type at 15°. a. C. elegans has a Q10 ~2. What is the Q10? What does this mean for the relative growth rate at 15° compared to 25°? b. One useful experiment that is done with temperature-sensitive strains is the determination of the temperature-sensitive period, the time that the gene needs to be active for adults to have the wild-type phenotype. Imagine that you have a heat-sensitive strain, which has been grown for a couple of generations at both the restrictive (25°) and permissive (15°) temperatures. Animals are switched to the opposite temperature at various times after hatching and then scored for the mutant phenotype when the animals become adults. Suppose that the gene is needed only during the L3 period for the adults to be wild type. i. Consider a graph of the up-shift experiment (moving animals from 15° to 25°). The x-axis is the time (in 25° equivalent hours) of the shift after hatching. The y-axis is the % animals that as adults show the wild-type phenotype. For various time points before and after the L3 period plot what percent of the animals are wild type. Connect the dots through the L3 period to complete the graph. ii. Using the same reasoning, deduce the curve for a down-shift experiment. The area of overlap of the two curves demarcates the temperature-sensitive period. c. How do the temperature-sensitive periods for the following two mutants differ? (Open squares are the down shift; closed diamonds are the up shift.) What could be the reason for this difference? Which gene is needed earlier for the adult phenotype? d. How would you interpret the following temperature-shift experiment? 4. a. Would you expect temperature-sensitive alleles to be rare or common for the average gene? b. A few genes are known for which all mutant alleles produce a temperaturesensitive phenotype, even alleles that are known to be completely deleted for the gene. How do you interpret the temperature-sensitive phenotype? What produces it? 5. Mutant phenotypes can also be produced by gain-of-function mutations. One of the first described by Muller is the hypermorph, where more activity of the gene is present. a. How could you diagram a hypermorphic allele in the figure for problem 1g? b. Would the phenotype of a hypermorphic mutation be recessive or dominant? c. We can often add an additional copy of the wild-type gene through a genetic duplication. i. What would happen if you added an extra wild-type gene to a haploinsufficient heterozygote (m/+)? ii. What would happen if you added an extra wild-type gene to a hypermorphic heterozygote (m/+)? iii. Can you use these results to distinguish these types of mutations. d. How frequently would you expect hypermorphic mutations in the average gene? Why? e. What are ways that hypermorphic alleles can be generated? 6. Another type of gain-of-function mutation is one in which a gene is inappropriately expressed either in space or in time. If a gene is expressed in inappropriate cells, then if can produce a new phenotype, e.g., the Antennapedia mutation in flies produces legs instead of antennae. Continued expression of the lin-14 in C. elegans, which is normally expressed in the L1 stage, results in the repeated expression of L1 stage cell divisions. Because of the new phenotypes produced by these mutations, they can be referred to as neomorphic mutations. I would refer to them as misexpression alleles. a. Are the misexpression mutations expressed as dominant or recessive mutations? b. What is the effect of an extra copy of the wild-type gene for one of the misexpression alleles? c. How would be the effect of a deletion of the gene? d. What, on average, is the expected relative number of such mutations in a gene? 7. The final Muller morph is the antimorph in which the mutation interferes with the wild-type function of the gene. These mutations are often said to produce toxic products. a. What sorts of defects could lead to antimorphic mutations b. Would an antimorphic mutation be expressed as a dominant or a recessive? c. How frequently would you expect to see antimorphic mutations in the average gene? d. How would you diagram the effect of an antimorphic mutation as in problem 1g? e. What would be the effect of adding another copy of the wild-type gene? f. Given your answer in parts d and e, could you come up with a situation in which the opposite answer to the one you gave in part b is correct? 8. Summarize the characteristic of a standard or average gene? 9. For the Herskowitz paper a. What is a dominant negative mutation? What would Muller call it? b. What makes it dominant? c. What makes it negative? d. How can these mutations be generated?

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Ans1
a) Polytene chromosomes arise in Drosophila due to a failure of separation after repeated replication of the parent chromosome, banding pattern of which is clearly visible under a microscope. During division, if there is a heterozygous deletion of a portion of a chromosome its pair with its homolog would result in a ring-like structure. (deletion loops) The position of the deleted portion indicated by the bands that are present in the ring, while missing from the homolog is clearly detected in cytogenetic analysis.
This can be seen in the following picture. Here the portion of the chromosome corresponding to the loci D, E and F are deleted from its homolog and hence there is no sequence available to pair, so it forms a loop.
The lethality of the homozygous deletion of a particular gene suggests that it is an essential gene for the viability of the organism and there is no other gene exists with a redundant function.
b) It means that most of these deletions are viable in the heterozygous state. So, if the gene is dominant, the organism can still survive due to the presence of a normal counterpart. Alternatively, if the gene is recessive, then the deletion will “expose” the function of that recessive allele because the fly still survives due to the expression of that recessive allele. In Drosophila many genes have been identified in that manner.
c) Deletions of some of the regions have not been found because, in the heterozygous conditions, these deletions might be lethal. Hence, we are not been able to find the genotype to phenotype in that case. Say, if the gene has a homozygous deletion that is a lethal but heterozygous deletion that is not lethal but shows a particular phenotype, then it can be mapped. If the heterozygous condition is also lethal then it cannot be found.
d) The above phenomenon is called “haplo-insufficiency” because in haploid organism there is only one allele. So, this one copy of the gene is unable to make the fly survive. Haploid status of this gene is lethal; hence it is called as haplo-insufficient. In other words, the deletion mutation is dominant....
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