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J. Sinikar, M.B. B.A.O., M.B.B.Ch., Ph.D.

Associate Professor, Pennsylvania State University College of Medicine

This method, referred to as genetic dissection, is analogous to figuring out how an automobile works by breaking different parts of a car and observing the effects; for example, smash the radiator and the engine overheats, revealing that the radiator cools the engine. Using mutations to disrupt function can likewise be a source of insight into biological processes. For example, geneticists have begun to unravel the molecular details of development by studying mutations, such as tinman, that interrupt various embryonic stages in Drosophila (see Chapter 22). Although this method of breaking "parts" to determine their function might seem like a crude approach to understanding a system, it is actually very powerful and has been used extensively in biochemistry, developmental biology, physiology, and behavioral science (but this method is not recommended for learning how your car works). The Importance of Mutations Mutations are both the sustainer of life and the cause of great suffering. On the one hand, mutation is the source of all genetic variation, the raw material of evolution. The ability of organisms to adapt to environmental change depends critically on the presence of genetic variation in natural populations, and genetic variation is produced-at least partly-by mutation. On the other hand, many mutations have detrimental effects, and mutation is the source of many diseases and disorders. Much of the study of genetics focuses on how variants produced by mutation are inherited; genetic crosses are meaningless if all individual members of a species are identically homozygous for the same alleles. They are essential to the study of genetics and are useful in many other biological fields. Categories of Mutations In multicellular organisms, we can distinguish between two broad categories of mutations: somatic mutations and germ-line mutations. Somatic mutations arise in somatic tissues, which do not produce gametes (Figure 18. Mitosis Population of mutant cells Germ-line tissue Germ-line mutation Sexual reproduction All cells carry mutation No cells carry mutation 3 Germ-line mutations occur in cells that give rise to gametes. The earlier in development that a somatic mutation occurs, the larger the clone of cells within that individual organism that will contain the mutation. Because of the huge number of cells present in a typical eukaryotic organism, somatic mutations are numerous. Typically, a mutation arises once in every million cell divisions, and so hundreds of millions of somatic mutations must arise in each person. Many somatic mutations have no obvious effect on the phenotype of the organism, because the function of the mutant cell (even the cell itself) is replaced by that of normal cells. However, cells with a somatic mutation that stimulates cell division can increase in number and spread; this type of mutation can give rise to cells with a selective advantage and is the basis for cancers (see Chapter 23). A germ-line mutation can be passed to future generations, producing individual organisms that carry the mutation in all their somatic and germ-line cells (see Figure 18. Historically, mutations have been partitioned into those that affect a single gene, called gene mutations, and those that affect the number or structure of chromosomes, called chromosome mutations. This distinction arose because chromosome mutations could be observed directly, by looking at chromosomes with a microscope, whereas gene mutations could be detected only by observing their phenotypic effects. This chapter focuses on gene mutations; chromosome mutations were discussed in Chapter 9. Some classification schemes are based on the nature of the phenotypic effect, others are based on the causative agent of the mutation, and still others focus on the molecular nature of the defect. Here, we will categorize mutations primarily on the basis of their molecular nature, but we will also encounter some terms that relate the causes and the phenotypic effects of mutations. In a transition, a purine is replaced by a different purine or, alternatively, a pyrimidine is replaced by a different pyrimidine (Figure 18. In a transversion, a purine is replaced by a pyrimidine or a pyrimidine is replaced by a purine. Although base substitutions are often assumed to be the most common type of mutation, molecular analysis has revealed that insertions and deletions are often more frequent. Insertions and deletions within sequences that encode proteins may lead to frameshift mutations, changes in the reading frame (see p. Frameshift mutations usually alter all amino acids encoded by nucleotides following the mutation, and so they generally have drastic effects on the phenotype. Not all insertions and deletions lead to frameshifts, however; insertions and deletions consisting of any multiple of three nucleotides will leave the reading frame intact, although the addition or removal of one or more amino acids may still affect the phenotype. Mutations not affecting the reading frame are called in-frame insertions and deletions, respectively. The disorder is so named because, in specially treated cells from persons having the condition, the tip of each long arm of the X chromosome is attached by only a slender thread (Figure 18.

Characteristic arrangements of microtubules (not shown here) are found in centrioles, basal bodies, cilia and flagellae. The tubulin dimers assemble into protofilaments and subsequently into sheets and then cylinders. A microtubule-organizing center, located around a pair of centrioles, nucleates the growth of new microtubules. A third species of tubulin, -tubulin, appears to play an important role in this assembly. Microtubules are in a state of dynamic instability, constantly assembling and disassembling. They exhibit polarity (plus and minus ends); this is important in their growth from centrioles and in their ability to direct intracellular movement. Mutations in genes affecting the synthesis of dynein have been detected in individuals with this syndrome. Certain drugs bind to microtubules and thus interfere with their assembly or disassembly. These include colchicine (used for treatment of acute gouty arthritis), vinblastine (a vinca alkaloid used for treating certain types of cancer), paclitaxel (Taxol) (effective against ovarian cancer), and griseofulvin (an antifungal agent). They are all elongated, fibrous molecules, with a central rod domain, an amino terminal head, and a carboxyl terminal tail. They form a structure like a rope, and the mature filaments are composed of tetramers packed together in a helical manner. They are important structural components of cells, and most are relatively stable components of the cytoskeleton, not undergoing rapid assembly and disassembly and not disappearing during mitosis, as do actin and many microtubular filaments. An important exception to this is provided by the lamins, which, subsequent to phosphorylation, disassemble at mitosis and reappear when it terminates. Lamin A is an important component of the structural scaffolding that maintains the integrity of the nucleus of a cell. It appears that the accumulation of the farnesylated prelamin A makes nuclei unstable, altering their shape, and somehow this predisposes to the development of signs of premature aging. Experiments in mice have indicated that administration of a farnesyltransferase inhibitor may ameliorate the development of misshapen nuclei. Vimentins are widely distributed in mesodermal cells, and desmin, glial fibrillary acidic protein, and peripherin are related to them. Intermediate filaments are very prominent in nerve cells; neurofilaments are classified as low, medium, and high on the basis of their molecular masses. The distribution of intermediate filaments in normal and abnormal (eg, cancer) cells can be studied by the use of immunofluorescent techniques, using antibodies of appropriate specificities. These antibodies to specific intermediate filaments can also be of use to pathologists in helping to decide the origin of certain dedifferentiated malignant tumors. These tumors may still retain the type of intermediate filaments found in their cell of origin. A number of skin diseases, mainly characterized by blistering, have been found to be due to mutations in genes encoding various keratins. The blistering found in these disorders probably reflects a diminished capacity of various layers of the skin to resist mechanical stresses due to abnormalities in keratin structure. The thin filaments contain actin, tropomyosin, and the troponin complex (troponins T, I, and C).

Syndromes

• Do not take cough medicines without first talking to your doctor. Cough medicines may make it harder for your body to cough up the extra sputum.
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• Injury (trauma)
• Enriched, fortified, and whole grain products such as bread, cereals, rice, pasta, and flour
• Splint or sling the injury in the position in which you found it. Do not move the joint. Be sure to immobilize the area above and below the injured joint.
• Social problems
• Culture of amniotic cells
• Blood clots in the legs that may travel to the lungs
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