CHAPTER 18 Molecular Biology and Medicine

Chapter 18: Molecular Biology and Medicine Protein as Phenotype Mutations and Human Diseases Detecting Human Genetic Variations Cancer: A Disease of Genetic Changes Treating Genetic Diseases Sequencing the Human Genome

Protein as Phenotype In many human genetic diseases, a single protein is missing or nonfunctional. Therefore, the one-gene, one-polypeptide relationship applies to human genetic diseases. Review Figure 18.1 3

figure 18-01.jpg 18.1 Figure 18.1

Protein as Phenotype A mutation in a single gene causes alterations in its protein product that may lead to clinical abnormalities or have no effect. Review Figure 18.2 5

figure 18-02.jpg 18.2 Figure 18.2

Protein as Phenotype Some diseases are caused by mutations that affect structural proteins. 7

Protein as Phenotype Genes that code for receptors and membrane transport proteins can also be mutated and cause other diseases. Review Figure 18.3 8

figure 18-03a.jpg 18.3 Figure 18.3 – Part 1

figure 18-03b.jpg 18.3 Figure 18.3 – Part 2

Protein as Phenotype Prion diseases are caused by a protein with an altered shape transmitted from one person to another and altering the same protein in the second person. 11

Protein as Phenotype Few human diseases are caused by a single- gene mutation. Most are caused by interactions of many genes and proteins with the environment. 12

Protein as Phenotype Human genetic diseases show different inheritance patterns. Mutant alleles may be inherited as autosomal recessives, autosomal dominants, X-linked conditions, or chromosomal abnormalities. 13

Mutations and Human Diseases Molecular biology techniques have made possible the isolation of many genes responsible for human diseases. 14

Mutations and Human Diseases One method of identifying the gene responsible for a disease is to isolate the mRNA for the protein in question and use the mRNA to isolate the gene from a gene library. DNA from a patient lacking a piece of a chromosome can be compared to that of a person not showing this deletion to isolate a missing gene. Review Figure 18.6 15

figure 18-06.jpg 18.6 Figure 18.6

Mutations and Human Diseases In positional cloning, DNA markers are used to point the way to a gene. Markers may be restriction fragment length polymorphisms linked to a mutant gene. Review Figure 18.7 17

figure 18-07.jpg 18.7 Figure 18.7

Mutations and Human Diseases Human mutations range from single point mutations to large deletions. Some common mutations occur where the modified base 5-methylcytosine is converted to thymine. Review Figure 18.8, Table 1 19

figure 18-08.jpg 18.8 Figure 18.8

Mutations and Human Diseases Effects of the fragile-X chromosome worsen with each generation. This pattern is caused by a triplet repeat that tends to expand with each generation. Review Figure 18.9 21

figure 18-09 18.9 Figure 18.9

Mutations and Human Diseases Genomic imprinting results in a gene being differentially expressed depending on which parent it comes from. 23

Detecting Human Genetic Variations Genetic screening detects human gene mutations. Some protein abnormalities can be detected by tests for the presence of excess substrate or lack of product. Review Figure 18.10 24

figure 18-10.jpg 18.10 Figure 18.10

Detecting Human Genetic Variations The advantage of testing DNA for mutations directly is that any cell can be tested at any time in the life cycle. 26

Detecting Human Genetic Variations There are two methods of DNA testing: allele-specific cleavage and allele-specific oligonucleotide hybridization. Review Figures 18.11, 18.12 27

figure 18-11.jpg 18.11 Figure 18.11

figure 18-12.jpg 18.12 Figure 18.12

Cancer: A Disease of Genetic Changes Tumors may be benign, growing to a certain extent and stopping, or malignant, spreading through organs and to other parts of the body. 30

Cancer: A Disease of Genetic Changes At least five types of human cancers are caused by viruses, accounting for about 15 percent of all cancers. Review Table 18.2 31

table 18-02.jpg 18.2 Table 18.2

Cancer: A Disease of Genetic Changes Eighty-five percent of human cancers are caused by genetic mutations of somatic cells. These occur most commonly in dividing cells. Review Figure 18.14 33

figure 18-14.jpg 18.14 Figure 18.14

Cancer: A Disease of Genetic Changes Normal cells contain proto-oncogenes, which, when mutated, can become activated and cause cancer by stimulating cell division or preventing cell death. Review Figure 18.15 35

figure 18-15.jpg 18.15 Figure 18.15

Cancer: A Disease of Genetic Changes About 10 percent of all cancer is inherited as a result of mutation of tumor suppressor genes, which normally slow down the cell cycle. For cancer to develop, both alleles of a tumor suppressor gene must be mutated. 37

Cancer: A Disease of Genetic Changes In inherited cancer, an individual inherits one mutant allele and somatic mutation occurs in the second one. In sporadic cancer, two normal alleles are inherited, so two mutational events must occur in the same somatic cell. Review Figures 18.16, 18.17 38

figure 18-16.jpg 18.16 Figure 18.16

figure 18-17.jpg 18.17 Figure 18.17

Cancer: A Disease of Genetic Changes Mutations must activate several oncogenes and inactivate several tumor suppressor genes for a cell to produce a malignant tumor. Review Figure 18.18 41

figure 18-18.jpg 18.18 Figure 18.18

Treating Genetic Diseases Most genetic diseases are treated symptomatically. As more knowledge is accumulated, specific treatments are being devised. 43

Treating Genetic Diseases One treatment approach is to modify the phenotype, for example, by manipulating diet, providing specific metabolic inhibitors to prevent accumulation of a harmful substrate, or supplying a missing protein. Review Figure 18.19 44

figure 18-19.jpg 18.19 Figure 18.19

Treating Genetic Diseases In gene therapy, a mutant gene is replaced with a normal one. Either the affected cells can be removed, the new gene added, and the cells returned to the body, or the new gene can be inserted directly. Review Figure 18.20 46

figure 18-20.jpg 18.20 Figure 18.20

Sequencing the Human Genome Human genome sequencing is determining the entire human DNA sequence, which requires sequencing many 500-base-pair fragments and fitting the sequences back together. 48

Sequencing the Human Genome In hierarchical gene sequencing, marker sequences are identified and mapped, then sought in sequenced fragments and used to align the fragments. In the shotgun approach, the fragments are sequenced, and common markers identified by computer. Review Figure 18.21 49

figure 18-21a.jpg 18.21 Figure 18.21 – Part 1

figure 18-21b.jpg 18.21 Figure 18.21 – Part 2

Sequencing the Human Genome The identification of more than 30,000 human genes may lead to a new molecular medicine. Review Figure 18.22 52

figure 18-22.jpg 18.22 Figure 18.22

Sequencing the Human Genome As more genes relevant to human health are described, concerns about how such information is used are growing. 54