Concepts of Genetics William S. Klug Michael R. Cummings Charlotte Spencer Michael Palladino Tenth Edition

Transcription

1 Concepts of Genetics William S. Klug Michael R. Cummings Charlotte Spencer Michael Palladino Tenth Edition

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3 their colleagues. They have subsequently postulated that the defect is associated with the formation of a variety of different tumor types. Croce and Huebner first showed that the FHIT gene (standing for f ragile hi stidine t riad), located within the well-defined fragile site designated as FRA3B on the p arm of chromosome 3, is often altered or missing in cells taken from tumors of individuals with lung cancer. More extensive studies have now revealed that the normal protein product of this gene is absent in cells of many other cancers, including those of the esophagus, breast, cervix, liver, kidney, pancreas, colon, and stomach. Genes such as FHIT that are located within fragile regions undoubtedly have an increased susceptibility to mutations and deletions. More recently, Muller Fabbri and Kay Huebner, working with others in Croce s lab, have identified and studied another fragile site, with most interesting results. Found within the FRA16D site on chromosome 16 is the WWOX gene. Like the FHIT gene, it has been implicated in a range of human cancers. In particular, like FHIT, it has been found to be either lost or genetically silenced in the large majority of lung tumors, as well as in cancer tissue of the breast, ovary, prostate, bladder, esophagus, and pancreas. When the gene is present but silent, its DNA is thought to be heavily methylated, rendering it inactive. Furthermore, the active gene is also thought to behave as a tumor suppressor, providing a surveillance function by recognizing cancer cells and inducing apoptosis, effectively eliminating them before malignant tumors can be initiated. EXPLORING GENOMICS Atlas of Genetics and Cytogenetics in Oncology and Haematology Study Area: Exploring Genomics In this chapter, we discussed how variations in chromosome number and alterations in chromosome structure can affect the chromosome content of gametes to create genetic alterations in offspring and abnormal phenotypes. The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer-reviewed, online journal and database of cytogenetics that specializes in cataloging chromosome abnormalities and genes involved in different cancers. Hematology is the study of blood. Much of the information presented in the atlas has been provided from clinical studies of patients with blood cancers, such as different forms of leukemia (cancer of white blood cells), that have revealed variations in chromosome number and chromosome structural defects (duplications, deletions, and translocations). In this exercise we explore the Atlas of Genetics site to learn more about human chromosome abnormalities. Exercise I Exploring Chromosome 9 1. Access the Atlas of Genetics and Cytogenetics in Oncology and Haematology at 2. Notice that the homepage lists database entries in several ways, including an alphabetical listing of cancer genes, a listing by chromosome, and a catalog of case reports. We will explore each of these features here. 3. Under Entities by Chromosome click on chromosome 9. Explore the many links to abnormalities of chromosome 9 involved in different leukemias. Notice that many of these are translocations. For example, t9;12 (q34;p13) symbolizes a translocation between chromosome 9, band 34 of the q- arm, and chromosome 12, band 13 of the p-arm. 4. Find the link to Familial melanoma, review the information on this condition, and then address the following items: a. Describe this disease condition. b. What locus on chromosome 9 is implicated in this disease? What gene is found at this locus? What is the function of this gene? (Use the disease gene links from the familial melanoma page or search the Genes feature of this database to learn about the gene s function.) Exercise II Case Reports: Rare Examples of Chromosome Alterations The Case reports section of the atlas (see the link at the top of the page) provides reports on examples of rare conditions caused by chromosome abnormalities that have been observed in different patients. Many of these case reports contain excellent examples of data generated using the cytogenetic techniques discussed in this chapter. 262

4 1. Find the link to the case report by Shambhu Roy, Sonal Bakshi, Shailesh Patel, and colleagues. Explore the information presented in their report and then answer the following questions: a. What chromosome abnormality is reported by this group? b. What techniques were used to diagnose this condition, and what tissue samples were used for the diagnosis? c. What is the disease condition associated with this patient? e. Name another genetic condition associated with extra copies of chromosome Explore more case reports presented in the atlas to learn about other rare examples of chromosome abnormalities that have been observed by scientists and physicians around the world. CASE STUDY Fish tales Aquatic vegetation overgrowth, usually controlled by dredging or herbicides, represents a significant issue in maintaining private and public waterways. In 1963, diploid grass carp were introduced in Arkansas to consume vegetation, but they reproduced prodigiously and spread to eventually become a hazard to aquatic ecosystems in 35 states. In the 1980s, many states adopted triploid grass carp as an alternative because of their high, but not absolute, sterility level and their longevity of seven to ten years. Today, most states require permits for vegetation control by triploid carp, requiring their containment in the body of water to which they are introduced. Genetic modifications of organisms to achieve specific outcomes will certainly become more common in the future and raise several interesting questions. 1. Taking triploid carp as an example, what controversies may emerge as similar modified species become available for widespread use? 2. If you were a state employee in charge of a specific waterway, what questions would you ask before you approved the introduction of a laboratory-produced, polyploid species into your waterway? 3. Why would the creation and use of a tetraploid carp species be less desirable in the above situation? Summary Points For activities, animations, and review quizzes, go to the study area at 1. Alterations of the precise diploid content of chromosomes are referred to as chromosomal aberrations or chromosomal mutations. 2. Studies of monosomic and trisomic disorders are increasing our understanding of the delicate genetic balance that is essential for normal development. 3. When more than two haploid sets of chromosomes are present, these may be derived from the same or different species, the basis of autopolyploidy and allotetraploidy, respectively. 4. Deletions or duplications of segments of a gene or a chromosome may be the source of mutant phenotypes, such as cri du chat syndrome in humans and Bar eyes in Drosophila, while duplications can be particularly important as a source of amplified or new genes. 5. Inversions and translocations may initially cause little or no loss of genetic information or deleterious effects. However, heterozygous combinations of the involved chromosome segments may result in genetically abnormal gametes following meiosis, with lethality or inviability often ensuing. 6. Fragile sites in human mitotic chromosomes have sparked research interest because one such site on the X chromosome is associated with the most common form of inherited mental retardation, while other autosomal sites have been linked to various forms of cancer. 263

5 INSIGHTS AND SOLUTIONS 1. In a cross using maize that involves three genes, a, b, and c, a heterozygote (abc> +++) is testcrossed to abc>abc. Even though the three genes are separated along the chromosome, thus predicting that crossover gametes and the resultant phenotypes should be observed, only two phenotypes are recovered: abc and +++. In addition, the cross produced significantly fewer viable plants than expected. Can you propose why no other phenotypes were recovered and why the viability was reduced? Solution: One of the two chromosomes may contain an inversion that overlaps all three genes, effectively precluding the recovery of any crossover offspring. If this is a paracentric inversion and the genes are clearly separated (assuring that a significant number of crossovers occurs between them), then numerous acentric and dicentric chromosomes will form, resulting in the observed reduction in viability. 2. A male Drosophila from a wild-type stock is discovered to have only seven chromosomes, whereas normally 2n = 8. Close examination reveals that one member of chromosome IV (the smallest chromosome) is attached to (translocated to) the distal end of chromosome II and is missing its centromere, thus accounting for the reduction in chromosome number. (a) Diagram all members of chromosomes II and IV during synapsis in meiosis I. Solution: II IV (b) If this male mates with a female with a normal chromosome composition who is homozygous for the recessive chromosome IV mutation eyeless (ey ), what chromosome compositions will occur in the offspring regarding chromosomes II and IV? Solution: Normal female Translocation male (1) (2) (3) (4) (c) Referring to the diagram in the solution to part (b), what phenotypic ratio will result regarding the presence of eyes, assuming all abnormal chromosome compositions survive? Solution: 1. normal (heterozygous) 2. eyeless (monosomic, contains chromosome IV from mother) 3. normal (heterozygous; trisomic and may die) 4. normal (heterozygous; balanced translocation) The final ratio is 3>4 normal: 1>4 eyeless. Problems and Discussion Questions HOW DO WE KNOW? 1. In this chapter, we have focused on chromosomal mutations resulting from a change in number or arrangement of chromosomes. In our discussions, 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 that the extra chromosome causing Down syndrome is usually maternal in origin? (b) How do we know that human aneuploidy for each of the 22 autosomes occurs at conception, even though most often human aneuploids do not survive embryonic or fetal development and thus are never observed at birth? (c) How do we know that specific mutant phenotypes are due to changes in chromosome number or structure? For instructor-assigned tutorials and problems, go to (d) How do we know that the mutant Bar -eye phenotype in Drosophila is due to a duplicated gene region rather than to a change in the nucleotide sequence of a gene? 2. For a species with a diploid number of 18, indicate how many chromosomes will be present in the somatic nuclei of individuals that are haploid, triploid, tetraploid, trisomic, and monosomic. 3. D efi ne these pairs of terms, and distinguish between them. aneuploidy/euploidy monosomy/trisomy Patau syndrome/edwards syndrome autopolyploidy/allopolyploidy autotetraploid/amphidiploid paracentric inversion/pericentric inversion 4. Contrast the relative survival times of individuals with Down, Patau, and Edwards syndromes. Speculate as to why such differences exist. 264

6 5. What evidence suggests that Down syndrome is more often the result of nondisjunction during oogenesis rather than during spermatogenesis? 6. What evidence indicates that humans with aneuploid karyotypes occur at conception but are usually inviable? 7. Contrast the fertility of an allotetraploid with an autotriploid and an autotetraploid. 8. Describe the origin of cultivated American cotton. 9. Predict how the synaptic configurations of homologous pairs of chromosomes might appear when one member is normal and the other member has sustained a deletion or duplication. 10. Inversions are said to suppress crossing over. Is this terminology technically correct? If not, restate the description accurately. 11. Contrast the genetic composition of gametes derived from tetrads of inversion heterozygotes where crossing over occurs within a paracentric versus a pericentric inversion. 12. Human adult hemoglobin is a tetramer containing two alpha (a) and two beta (b) polypeptide chains. The a gene cluster on chromosome 16 and the b gene cluster on chromosome 11 share amino acid similarities such that 61 of the amino acids of the a-globin polypeptide (141 amino acids long) are shared in identical sequence with the b-globin polypeptide (146 amino acids long). How might one explain the existence of two polypeptides with partially shared function and structure on two different chromosomes? 13. Discuss Ohno s hypothesis on the role of gene duplication in the process of evolution. What evidence supports this hypothesis? 14. What roles have inversions and translocations played in the evolutionary process? 15. The primrose, Primula kewensis, has 36 chromosomes that are similar in appearance to the chromosomes in two related species, P. floribunda (2 n = 18) and P. verticillata (2 n = 18). How could P. kewensis arise from these species? How would you describe P. kewensis in genetic terms? 16. Certain varieties of chrysanthemums contain 18, 36, 54, 72, and 90 chromosomes; all are multiples of a basic set of nine chromosomes. How would you describe these varieties genetically? What feature do the karyotypes of each variety share? A variety with 27 chromosomes has been discovered, but it is sterile. Why? 17. Drosophila may be monosomic for chromosome 4, yet remain fertile. Contrast the F 1 and F 2 results of the following crosses involving the recessive chromosome 4 trait, bent bristles: (a) monosomic IV, bent bristles * diploid, normal bristles; (b) monosomic IV, normal bristles * diploid, bent bristles. 18. Mendelian ratios are modified in crosses involving autotetraploids. Assume that one plant expresses the dominant trait green seeds and is homozygous ( WWWW ). This plant is crossed to one with white seeds that is also homozygous ( wwww ). If only one dominant allele is sufficient to produce green seeds, predict the F 1 and F 2 results of such a cross. Assume that synapsis between chromosome pairs is random during meiosis. 19. Having correctly established the F 2 ratio in Problem 18, predict the F 2 ratio of a dihybrid cross involving two independently assorting characteristics (e.g., P 1 = WWWWAAAA * wwwwaaaa ). 20. The mutations called bobbed in Drosophila result from variable reductions (deletions) in the number of amplified genes coding for rrna. Researchers trying to maintain bobbed stocks have often documented their tendency to revert to wild type in successive generations. Propose a mechanism based on meiotic recombination which could account for this reversion phenomenon. Why would wild-type flies become more prevalent in Drosophila cultures? 21. The outcome of a single crossover between nonsister chromatids in the inversion loop of an inversion heterozygote varies depending on whether the inversion is of the paracentric or pericentric type. What differences are expected? 22. A couple planning their family are aware that through the past three generations on the husband s side a substantial number of stillbirths have occurred and several malformed babies were born who died early in childhood. The wife has studied genetics and urges her husband to visit a genetic counseling clinic, where a complete karyotype-banding analysis is performed. Although the tests show that he has a normal complement of 46 chromosomes, banding analysis reveals that one member of the chromosome 1 pair (in group A) contains an inversion covering 70 percent of its length. The homolog of chromosome 1 and all other chromosomes show the normal banding sequence. (a) How would you explain the high incidence of past stillbirths? (b) What can you predict about the probability of abnormality/normality of their future children? (c) Would you advise the woman that she will have to bring each pregnancy to term to determine whether the fetus is normal? If not, what else can you suggest? Extra-Spicy Problems For instructor-assigned tutorials and problems, go to In a cross in Drosophila, a female heterozygous for the autosomally linked genes a, b, c, d, and e ( abcde> ) was testcrossed with a male homozygous for all recessive alleles. Even though the distance between each of the loci was at least 3 map units, only four phenotypes were recovered, yielding the following data: Phenotype No. of Flies a b c d e e 48 a b c d + 52 To t a l = 1000 Why are many expected crossover phenotypes missing? Can any of these loci be mapped from the data given here? If so, determine map distances. 24. A woman who sought genetic counseling is found to be heterozygous for a chromosomal rearrangement between the second and third chromosomes. Her chromosomes, compared to those in a normal karyotype, are diagrammed here: A B C E F C D D H H 2 2/3 2/3 3 A B G E F G 265

7 (a) What kind of chromosomal aberration is shown? (b) Using a drawing, demonstrate how these chromosomes would pair during meiosis. Be sure to label the different segments of the chromosomes. (c) This woman is phenotypically normal. Does this surprise you? Why or why not? Under what circumstances might you expect a phenotypic effect of such a rearrangement? 25. The woman in Problem 24 has had two miscarriages. She has come to you, an established genetic counselor, with these questions: Is there a genetic explanation of her frequent miscarriages? Should she abandon her attempts to have a child of her own? If not, what is the chance that she could have a normal child? Provide an informed response to her concerns. 26. In a recent cytogenetic study on 1021 cases of Down syndrome, 46 were the result of translocations, the most frequent of which was symbolized as t(14;21). What does this symbol represent, and how many chromosomes would you expect to be present in t(14;21) Down syndrome individuals? 27. A boy with Klinefelter syndrome (47,XXY) is born to a mother who is phenotypically normal and a father who has the X- linked skin condition called anhidrotic ectodermal dysplasia. The mother s skin is completely normal with no signs of the skin abnormality. In contrast, her son has patches of normal skin and patches of abnormal skin. (a) Which parent contributed the abnormal gamete? (b) Using the appropriate genetic terminology, describe the meiotic mistake that occurred. Be sure to indicate in which division the mistake occurred. (c) Using the appropriate genetic terminology, explain the son s skin phenotype. 28. To investigate the origin of nondisjunction, 200 human oocytes that had failed to be fertilized during in vitro fertilization procedures were subsequently examined (Angel, R Am. J. Hum. Genet. 61: 23 32). These oocytes had completed meiosis I and were arrested in metaphase II (MII). The majority (67 percent) had a normal MII-metaphase complement, showing 23 chromosomes, each consisting of two sister chromatids joined at a common centromere. The remaining oocytes all had abnormal chromosome compositions. Surprisingly, when trisomy was considered, none of the abnormal oocytes had 24 chromosomes. (a) Interpret these results in regard to the origin of trisomy, as it relates to nondisjunction, and when it occurs. Why are the results surprising? (b) A large number of the abnormal oocytes contained 22 1>2 chromosomes; that is, 22 chromosomes plus a single chromatid representing the 1>2 chromosome. What chromosome compositions will result in the zygote if such oocytes proceed through meiosis and are fertilized by normal sperm? (c) How could the complement of 22 1>2 chromosomes arise? Provide a drawing that includes several pairs of MII chromosomes. (d) Do your answers support or dispute the generally accepted theory regarding nondisjunction and trisomy, as outlined in Figure 1? 29. In a human genetic study, a family with five phenotypically normal children was investigated. Two were homozygous for a Robertsonian translocation between chromosomes 19 and 20 (they contained two identical copies of the fused chromosome). These children have only 44 chromosomes but a complete genetic complement. Three of the children were heterozygous for the translocation and contained 45 chromosomes, with one translocated chromosome plus a normal copy of both chromosomes 19 and 20. Two other pregnancies resulted in stillbirths. It was later discovered that the parents were first cousins. Based on this information, determine the chromosome compositions of the parents. What led to the stillbirths? Why was the discovery that the parents were first cousins a key piece of information in understanding the genetics of this family? 30. A 3-year-old child exhibited some early indication of Turner syndrome, which results from a 45,X chromosome composition. Karyotypic analysis demonstrated two cell types: 46,XX (normal) and 45,X. Propose a mechanism for the origin of this mosaicism. 31. A normal female is discovered with 45 chromosomes, one of which exhibits a Robertsonian translocation containing most of chromosomes 18 and 21. Discuss the possible outcomes in her offspring when her husband contains a normal karyotype. 32. Prader-Willi and Angelman syndromes are human conditions that result in part through the process of genomic imprinting, where a particular gene is marked during gamete formation in the parent of origin. In the case of these two syndromes, a portion of the long arm of chromosome 15 (15q11 to 15q13) is imprinted. Another condition, Beckwith-Wiedemann syndrome (accelerated growth and increased risk of cancer), is associated with abnormalities of imprinted genes on the short arm of chromosome 11. All three of the above syndromes occur when imprinted sequences become abnormally exposed by some genetic or chromosomal event. One such event is uniparental disomy (UPD), in which a person receives two homologs of one chromosome (or part of a chromosome) from one parent and no homolog from the other. In many cases, UPD is without consequence; however, if chromosome 11 or 15 is involved, then, coupled with genomic imprinting, complications can arise. Listed below are possible origins of UPD. Provide a diagram and explanation for each. 1. Trisomic rescue: loss of a chromosome in a trisomic zygote 2. Monosomic rescue: gain of a chromosome in a monosomic zygote 3. Gamete complementation: fertilization of a gamete with two copies of a chromosome by a gamete with no copies of that chromosome 4. Isochromosome formation: a chromosome that contains two copies of an arm (15q-15q, for example) rather than one. 266