Appendixes



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Appendixes

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A Basic Biological and Genetic Concepts DNA, Genes, and Chromosomes which respond to particular proteins in a tissue-specific man- ner by increasing transcription. At the 3′ end is the termina- The genetic material of living organisms, DNA, is con- tion codon (e.g., TAA, TAG, TGA) and a poly-A tail. tained in chromosomes, which are present in the nuclei of The process by which genetic information in DNA is used cells. Chromosomes contain genes, which are the basic units to produce amino acids and proteins is called transcription. of inheritance. Humans have 23 pairs of chromosomes: one During this process, the entire unit of both introns and exons member of each pair derived from the father and the other is transcribed into precursor messenger RNA (mRNA). The from the mother. Males have 22 pairs of autosomes and an X region of the precursor mRNA transcribed from the introns and a Y chromosome (the latter two are called sex chromo- is then excised and removed and does not form the definitive somes). Females have 22 pairs of autosomes and two X chro- mRNA. Precursor mRNA from the exons is spliced together mosomes. Ordinary body cells (somatic cells) contain the to form the definitive mRNA, which specifies the primary full complement of 23 pairs of chromosomes (referred to as structure of the gene product. The definitive mRNA is then the diploid number), whereas the mature germ cells—sperm transported to the cytoplasm, where protein synthesis oc- and ova—contain only half the diploid number of chromo- curs. somes (referred to as the haploid number) that consists of 3 × 109 base pairs (bp) of DNA. Each of the genes occupies a specific position in a specific chromosome called the locus Mutations and Their Effects on the Phenotype (plural loci). The two genes at each locus, one paternal and Mutations are permanent heritable changes that occur in one maternal, are called alleles. The totality of all the genes the genetic material. They arise spontaneously and can be is the genotype of the individual, and their manifestation is induced by exposure to radiation or chemical mutagens. the phenotype. When mutations arise or are induced in somatic cells, there Most eukaryotic (including human) genes are made up of is a very small probability that they will cause cancer, but sequences (exons) that code for amino acid sequences in pro- somatic mutations are not transmitted to progeny. If muta- teins and noncoding intervening sequences (introns). Genes tions occur or are induced in germ cells, they can be trans- differ not only in the DNA sequences that specify the amino mitted to progeny and they may result in genetic (hereditary) acids of the proteins they encode but also in their structures. diseases. Mutations are classified as dominant or recessive, A few human genes, such as histone genes, interferon genes, depending on their effects on the phenotype (physical ap- and mitochondrial genes, do not contain introns; some con- pearance of the organism). In the case of a dominant muta- tain a considerable number of introns whose lengths vary tion, a single mutant allele inherited from either parent is from a few bases to several kilobases (kb; e.g., the dystrophin sufficient to cause an altered phenotype; the organism has gene, DMD, mutations in which result in Duchenne’s and one mutant and one normal allele of the gene in question and Becker’s muscular dystrophies, is 2400 kb long and contains is called a heterozygote with respect to that gene. In the case 79 introns). of a recessive mutation, two mutant alleles of the same The 5′ end of the gene is marked by the translational start gene—one from each parent—are required to produce a site (the ATG codon). Upstream from this are a number of mutant phenotype; the organism is called a homozygote for noncoding sequences referred to as promoters; further up- the gene. In general, mutations in genes that code for struc- stream are a number of cis-acting regulatory elements of tural proteins are dominant, and those in genes that code for defined sequence (TATAAA and CCAAAT motifs), which enzymatic proteins are recessive. play a role in constitutive gene expression, and enhancers, 327

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328 APPENDIX A Genetic Diseases herited diseases, gain of function usually means that the mutant gene is expressed at the wrong time in development, Genetic diseases are traditionally classified as Mendelian in the wrong tissue, in response to wrong signals, or at an or multifactorial diseases. Mendelian diseases are due to inappropriately high level. The spectrum of gain-of-function mutations in single genes; multifactorial diseases arise as a mutations would therefore be more restricted, and deletion result of the joint action of multiple genetic and environmen- or disruption of the gene would not produce the disease. tal factors. Molecular analyses have revealed that a wide variety of mutational changes underlie Mendelian diseases: “micro- Genetic Effects of Radiation lesions,” such as single base-pair substitutions, deletions, Exposure of cells and organisms to ionizing radiation insertions, or duplications involving one to a few base pairs; causes DNA damage. The cellular processing of radiation- and “gross lesions,” such as whole-gene or multigene dele- induced damage to DNA by enzymes may result in a return tions, complex rearrangements, and large insertions and du- to normal sequence and structure (Lobrich and others 1995), plications. Microlesions dominate the spectrum of Men- or processing may fail or may cause alterations in DNA that delian diseases (Krawczak and Cooper 1997). lead to lethality or heritable changes (mutations and chro- At the functional level, mutations can be classified as mosomal aberrations) in surviving cells. Heritable changes causing either a loss of function or the gain of a new func- induced in reproductive (germ) cells can be transmitted to tion. Normal gene function can be abolished by some types the following generations and cause genetic disease of one of point mutations, partial or total gene deletions, disruption kind or another (a concept that lies at the core of estimation of the gene structure by translocations or inversions of the of the genetic risks posed by radiation). Changes induced in genetic material, and so on. In most cases, loss-of-function nonreproductive (somatic) cells have a small but finite prob- mutations in enzyme-coding genes are recessive, because ability of contributing to the complex process of carcino- 50% of the gene product is usually sufficient for normal func- genesis. tioning. Loss-of-function mutations in genes that code for The types of mutational changes induced by radiation are structural or regulatory proteins, however, result in domi- broadly similar to the types that occur naturally, but the pro- nant phenotypes through haploinsufficiency (a 50% reduc- portions of the different types are not the same. The results tion in the gene product in the heterozygote is insufficient of molecular studies of radiation-induced germ cell muta- for normal functioning but is compatible with viability) or tions in experimental organisms and in mammalian somatic through dominant negative effects (the product of the mu- cells support the view that most radiation-induced mutations tant gene not only loses its own function but also prevents involve changes in large segments of the DNA, such as dele- the product of the normal allele from functioning in a het- tions that often encompass more than one gene. Hence, ra- erozygous organism). Dominant negative effects are seen diation readily induces the kinds of molecular changes that particularly in the case of genes whose products function as can derange a genome and lead to cancer. Conversely, many aggregates (dimers and multimers). of those changes, if they occur in germ cells, are incompat- In contrast, gain of function is likely when only specific ible with embryo development and result in developmental changes cause a given disease phenotype. Gains of truly abnormalities or lethal mutations in the germline, which novel functions are not common except in cancer, but in in- would result in nonviable progeny.