Challenge Questions

19. Mitochondrial DNA sequences have been detected in the nuclear genomes of many organisms, and cpDNA sequences are sometimes found in the mitochondrial genome. Propose a mechanism for how such "promiscuous DNA" might move between nuclear, mitochondrial, and chloroplast genomes.

20. Steven A. Frank and Laurence D. Hurst argued that a cytoplasmically inherited mutation in humans that has severe effects in males but no effect in females will not be eliminated from a population by natural selection, because only females pass on mtDNA. Using this argument, explain why males with Leber hereditary optic neuropathy are more severely affected than females.

21. Several families have been described that exhibit vision problems, muscle weakness, and deafness. This disorder is inherited as an autosomal dominant trait and the disease-causing gene has been mapped to chromosome 10 in the nucleus. Analysis of the mtDNA from affected persons in these families reveals that large numbers of their mitochondrial genomes possess deletions of varying length. Different members of the same family and even different mitochondria from the same person possess deletions of different sizes; so the underlying defect appears to be a tendency for the mtDNA of affected persons to have deletions. Propose an explanation for how a mutation in a nuclear gene might lead to deletions in mtDNA.

SUGGESTED READINGS)_

Anderson, S., A. T. Bankier, B. G. Barrell, M. H. L. de Bruijn, A. R. Coulson, et al. 1981. Sequence and organization of the human mitochondrial genome. Nature 290:457-465. Original report of the complete sequencing of the human mtDNA.

Birky, C. W., Jr. 1978. Transmission genetics of mitochondria and chloroplasts. Annual Review of Genetics 12:471-512. A review of how traits encoded by mtDNA and cpDNA are inherited.

Fox, T. D. 1987. Natural variation in the genetic code. Annual Review of Genetics 21:67-91. A review of nonuniversal codons. Gray, M. W. 1992. The endosymbiotic hypothesis revisited. International Review of Cytology 141:233-357. An excellent review of how data from organelle genomes relate to the endosymbiotic theory.

Gray, M. W. 1998. Rickettsia, typhus and the mitochondrial connection. Nature 396:109-110.

A short commentary on the DNA sequence of Rickettsia prowazekii, the bacterium that causes typhus and is thought to be closely related to the eubacteria that gave rise to mitochondria.

Gray, M. W., G. Burger, and B. Franz Lang. 1999. Mitochondrial evolution. Science 283:1476-1481.

A review of the evolution of mitochondria based on DNA sequence data from a number of different species. Gruissem, W. 1989. Chloroplast RNA: transcription and processing. In A. Marcus, Ed. The Biochemistry of Plants: A Comprehensive Treatise, pp. 151-191. Vol. 15, Molecular Biology. New York: Academic Press.

A review of the transcription and RNA processing that takes place in chloroplasts.

Lehman, N., A. Eisenhawer, K. Hansen, L. D. Mech, R. O. Peterson, P. J. P. Gogan, and R. K. Wayne. 1991. Introgression of coyote mitochondrial DNA into sympatric North American gray wolf population. Evolution 45:104-119.

A report of the introgression of coyote genes into wolf populations as revealed by mtDNA.

Levings, C. S., III, and G. G. Brown. 1989. Molecular biology of plant mitochondria. Cell 56:171-179.

A report of some of the unique characteristics and properties of plant mtDNA. Poulton, J. 1995. Transmission of mtDNA: cracks in the bottleneck. American Journal ofHuman Genetics 57:224-226. A discussion of the transmission of mtDNA.

Sugiura, M. 1989. The chloroplast genome. In A. Marcus, Ed. The Biochemistry of Plants: A Comprehensive Treatise, pp. 133-150. Vol. 15, Molecular Biology. New York: Academic Press. An excellent review of the organization and sequence of cpDNA.

Sugiura, M. 1989. The chloroplast chromosomes in land plants. Annual Review of Cell Biology 5:51-70. A review of the features and evolution of chloroplast DNA among vascular plants. Sugiura, M., T. Hirose, and M. Sugita. 1998. Evolution and mechanism of translation in chloroplasts. Annual Review of Genetics 32:437-459. A review of the translation of cpDNA.

Wallace, D. C. 1992. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256:628-632. A good review of the role of mtDNA in human genetic disease and in aging.

Wallace, D. C. 1999. Mitochondrial diseases in man and mouse. Science 283:1482-1488.

A review of diseases arising from defects in mitochondria, including those due to mutations in mtDNA and nuclear DNA. Yaffe, M. P. 1999. The machinery of mitochondrial inheritance and behavior. Science 283:1493-1497. A discussion of evidence suggesting that movements of mitochondria in cell division may not be random but regulated by the cell.

Advanced Topics in Genetics Developmental Genetics, Immunogenetics, and Cancer Genetics

Flies have been genetically engineered to have extra eyes on their legs, wings, and elsewhere. Through genetic engineering, the eyeless gene can be expressed in cells of body parts where eyes do not normally appear.

• Flies with Extra Eyes

• Developmental Genetics

Cloning Experiments

The Genetics of Pattern Formation in

Drosophila

Homeobox Genes in Other Organisms

Programmed Cell Death in Development

Evo-Devo: The Study of Evolution and Development

• Immunogenetics

The Organization of the Immune System

Immunoglobulin Structure

The Generation of Antibody Diversity

T-Cell-Receptor Diversity

Major Histocompatibility Complex Genes

Genes and Organ Transplants

• Cancer Genetics

The Nature of Cancer

Cancer As a Genetic Disease

Genes That Contribute to Cancer

The Molecular Genetics of Colorectal Cancer

Flies with Extra Eyes

We can all imagine situations where an extra set of eyes might come in handy: eyeing members of the opposite sex while still paying attention to the professor during lecture, looking both ways at the same time before crossing the street; or watching your backside in a barroom brawl. However useful extra eyes might be, creating them at selected locations is no simple matter. An eye is, after all, an exceedingly complex structure, consisting of photoreceptors, lens, nerves, and other tissues. It would be very unlikely for all of these structures to develop at a site where eyes don't normally exist. Nevertheless, in 1995, a group of geneticists succeeded in genetically engineering fruit flies with extra eyes on their wings, legs, and antennae. How was this amazing feat accomplished?

The story of creating flies with extra eyes began in 1915, when Mildred Hoge discovered a mutant fruit fly with small eyes due to a recessive mutation in a gene called eyeless. The product of the normal allele of the eyeless locus is required for proper development of the fruit-fly eye.

In 1993, Walter Gehring and his collaborators were investigating Drosophila genes that encode transcription factors (see Chapter 13). One of these genes mapped to the same location as that of the eyeless gene and, in fact, turned out to be the eyeless gene. To see what effect eyeless might have on development, Gehring's group genetically engineered cells that expressed the eyeless gene in parts of the fly where the gene is not normally expressed. When these flies hatched, they had huge eyes on their wings, antennae, and legs. These structures were not just tissue that resembled eyes; they were complete eyes with a cornea, cone cells, and photoreceptors that responded to light, although the flies could not use them to see, because they were not connected to the nervous system. The eyeless gene appears to be one of the long-sought master control switches of development: its protein activates a set of other genes that are responsible for making a complete eye.

The eyeless gene has counterparts in mice and humans that affect the development of mammalian eyes. There is a striking similarity between the eyeless gene of Drosophila and the Small eye gene that exists in mice. In mice, a mutation in one copy of Small eye causes small eyes; a mouse that is homozygous for the Small eye mutation has no eyes. There is also a similarity between the eyeless gene in Drosophila and the Aniridia gene in humans; a mutation in Aniridia produces a severely malformed human eye. Similarities in the sequences of eyeless, Small eye, and Aniridia suggest that all three genes evolved from a common ancestral sequence. This possibility is surprising, because the eyes of insects and mammals were thought to have evolved independently. Similarities among eyeless, Small eye, and Aniridia suggest that a common pathway underlies eye development in flies, mice, and humans.

This chapter focuses on three specialized topics in genetics: developmental genetics, immunogenetics, and cancer genetics. We begin with a discussion of the genetic control of the early development of Drosophila embryos, one of the best-understood developmental systems. We then turn to the genetics of the immune system in vertebrates. This system is capable of generating proteins that recognize virtually any foreign substance in the body. The generation of this huge diversity of proteins relies on a special type of genetic recombination unique to the immune system. Last, we consider the genetic basis of cancer and how mutations in particular types of genes contribute to the growth of tumors in humans.

Developmental Genetics

Every multicellular organism begins life as a unicellular, fertilized egg. This single-celled zygote undergoes repeated cell divisions, eventually producing millions or trillions of cells that constitute a complete adult organism. Initially, each cell in the embryo is totipotent—it has the potential to develop into any cell type. Many cells in plants and fungi remain totipotent, but animal cells usually become committed to developing into specific types of cells after just a few early embryonic divisions. This commitment often comes well before a cell begins to exhibit any characteristics of a particular cell type; once the cell becomes committed, it cannot reverse its fate and develop into a different cell type. A cell becomes committed by a process called determination, the mechanism of which is still unknown.

For many years, the work of developmental biologists was limited to describing the changes that take place in the course of development, because techniques for probing the intracellular processes behind these changes were unavailable. But, in recent years, powerful genetic and molecular techniques have had a tremendous influence on the study of development. In a few model systems such as Drosophila, the molecular mechanisms underlying developmental change are now beginning to be understood.

Cloning Experiments

If all cells in a multicellular organism are derived from the same original cell, how do different cells types arise? One possibility is that, throughout development, genes might be selectively lost or altered, causing different cell types to have different genomes. Alternatively, each cell might contain the same genetic information, but different genes might be expressed in each cell type. Early cloning experiments helped to answer this question.

In the 1950s, Frederick Steward developed methods for cloning plants. He disrupted phloem tissue from the root of a carrot, separating and isolating individual cells. He then placed individual cells in a sterile medium that contained nutrients. Steward was successful in getting the cells to grow and divide, and eventually he obtained whole edible carrots from single cells (IFigure 21.1). Because all parts of the plant were regenerated from a specialized phloem cell, i

Phloem tissue from the carrot is disrupted.

^ .and single cells are isolated.

■ 3 A single cell is placed in a nutritive medium that contains growth hormones.

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