Ron Green

genetic information has a privileged position. Others objected strenuously, saying that one's right to information in complex cases such as this one cannot merely be a matter of who gets to the doctor first.

Still other issues arose in the course of this discussion, most of which fell under the umbrella question of whether the risks of breast cancer for the twins could really be determined with precision. Persons in high-risk families with hereditary breast cancer and cancer-causing mutations face a much greater than average lifetime risk. However, in the absence of a thorough family history, the presence of a certain mutation and breast cancer in the mother alone do not provide the basis for assuming the existence of "hereditary" breast cancer in the family.

A second major area of uncertainty was highlighted when genetic professionals from different institutions disagreed about the statistics regarding risk reduction from prophylactic mastectomy. Some argued that the weighing of benefits and harms must include a comparison of the protection of one twin from the risk of premature death with the risk of psychological distress for the second twin. The research team would be morally justified in choosing the action that is most likely to reduce risk of death by cancer. However, others disagreed on the basis of inconclusive scientific evidence that mastectomy is a valid risk-reduction strategy.

Although there was no agreement on how genetic professionals should respond to this situation, there was a sense that, at this stage of genetic research, individual professionals might ethically and responsibly come to different conclusions about what they would do when faced with competing requests of this sort. __

CONCEPTS SUMMARY]_

• Each multicellular organism begins as a single cell that has the potential to develop into any cell type. As development proceeds, cells become committed to particular fates. The results of early cloning experiments demonstrated that this process arises from differential gene expression.

• In the early Drosophila embryo, determination is effected through a cascade of gene control.

• The dorsal-ventral and anterior-posterior axes of the Drosophila embryo are established by egg-polarity genes. These genes are expressed in the female parent and produce RNA and proteins that are deposited in the egg cytoplasm. Initial differences in the distribution of these molecules regulate gene expression in various parts of the embryo. The dorsal-ventral axis is defined by a concentration gradient of the Dorsal protein, and the anterior-posterior axis is defined by concentration gradients of Bicoid and Nanos proteins.

• After the establishment of the major axes of development, three types of segmentation genes act sequentially to determine the number and organization of the embryonic segments in Drosophila. The gap genes establish large sections of the embryo, the pair-rule genes affect alternate segments, and the segment-polarity genes affect the organization of individual segments.

• Homeotic genes then define the identity of individual Drosophila segments. All these genes contain a consensus sequence called a homeobox that encodes a DNA-binding domain; the products of homeotic genes are DNA-binding proteins that regulate the expression of other genes. Genes with homeoboxes are found in many other organisms.

• Apoptosis, or programmed cell death, plays an important role in the development of many animals. In apoptosis, DNA is degraded, the nucleus and cytoplasm shrink, and the cell undergoes phagocytosis by other cells. Apoptosis is a highly regulated process that depends on caspases—proteins that cleave proteins. Each caspase is originally synthesized as an inactive precursor that must be activated, often through cleavage by another caspase.

• The immune system is the primary defense network in vertebrates. In humoral immunity, B cells produce antibodies that bind foreign antigens; in cellular immunity, T cells attack cells carrying foreign antigens.

• Each B and T cell is capable of binding only one type of foreign antigen. There are vast numbers of different types of B and T cells, and any potential antigen can be bound. When a lymphocyte binds to an antigen, the lymphocyte divides and gives rise to a clone of cells, each specific for that same antigen. This process is a primary immune response. A few memory cells remain in circulation for long periods of time. If the same antigen is encountered again, memory cells can proliferate rapidly and generate a secondary immune response.

• Immunoglobulins (antibodies) consists of two light chains and two heavy chains, each containing variable and constant regions. Light chains are of two basic types: kappa and lambda chains. The genes that encode the immunoglobulin chains consist of several types of gene segments; germ-line DNA contains multiple copies of these gene segments, which differ slightly in sequence. In B-cell maturation, somatic recombination randomly brings together one version of each segment to produce a single complete gene. Many combinations of the different segments are possible. The potential for diversity of antibodies is further increased by the random addition and deletion of nucleotides at the junctions of the segments. A high mutation rate also increases the potential diversity of antibodies.

• T-cell receptors are composed of alpha and beta chains. The germ-line genes for these proteins consist of segments with multiple varying copies. Somatic recombination allows many different types of T-cell receptors in different cells. Junctional diversity also adds to T-cell receptor variability.

• The major histocompatibility complex encodes a number of histocompatibility antigens. Each T cell simultaneously binds a foreign antigen and a host MHC antigen. The MHC antigen allows the immune system to distinguish self from nonself. Each locus for the MHC contains many alleles.

• Cancer is fundamentally a genetic disorder, arising from somatic mutations in multiple genes that affect cell division and proliferation. If one or more mutations is inherited, then fewer additional mutations are required for cancer to develop.

• A mutation that allows a cell to divide rapidly provides the cell with a growth advantage; this cell gives rise to a clone of cells with the same mutation. Within this clone, other mutations occur that provide additional growth advantages, and cells with these additional mutations become dominant in the clone. In this way, the clone evolves. Environmental factors play an important role in the development of many cancers by increasing the rate of somatic mutations.

• Several types of genes contribute to cancer progression. Oncogenes are dominant mutated copies of genes that normally stimulate cell division. Tumor-suppressor genes normally inhibit cell division; recessive mutations in these genes may contribute to cancer. Oncogenes and tumor-suppressor genes often control the cell cycle or regulate apoptosis.

• Defects in DNA repair genes and genes that control chromosome segregation often increase the overall mutation rate of other genes, leading to defects in proto-oncogenes and tumor-suppressor genes that may contribute to cancer progression.

• Mutations in sequences that regulate telomerase, an enzyme that replicates the ends of chromosomes, are often associated with cancer. Telomerase allows cells to divide indefinitely but is not usually expressed in somatic cells. Mutations in tumor cells allow telomerase to be expressed.

• Tumor progression is also affected by mutations in genes that promote vascularization and the spread of tumors.

Colorectal cancer offers a model system for understanding tumor progression in humans. Initial mutations stimulate cell division, leading to a small benign polyp. Additional mutations allow the polyp to enlarge, invade the muscle layer of the gut, and eventually spread to other sites. Mutations in particular genes affect different stages of this progression.

[important terms totipotent (p. 000) determination (p. 000) egg polarity gene (p. 000) morphogen (p. 000) segmentation gene (p. 000) gap gene (p. 000) pair-rule gene (p. 000) segment-polarity gene (p. 000) homeotic gene (p. 000) homeobox (p. 000) Antennapedia complex (p. 000)

bithorax complex (p. 000) homeotic complex (p. 000) Hox gene (p. 000) apoptosis (p. 000) caspase (p. 000) antigen (p. 000) autoimmune disease (p. 000) humoral immunity (p. 000) B cell (p. 000) antibody (p. 000) cellular immunity (p. 000)

T cell (p. 000) T-cell receptor (p. 000) major histocompatibility complex (MHC) antigen (p. 000) theory of clonal selection (p. 000) primary immune response (p. 000) memory cell (p. 000) secondary immune response (p. 000)

somatic recombination (p. 000) junctional diversity (p. 000) somatic hypermutation (p. 000) malignant tumor (p. 000) metastasis (p. 000) clonal evolution (p. 000) oncogene (p. 000) tumor-suppressor gene (p. 000) proto-oncogene (p. 000)

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