Decoding the Language of Genetics

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Index

A Andrews, Brenda J., 135–136 Annotation, genome, 167 ABO locus, 19 Anticodon, 92, 115 Actin, 121–122, 127, 134 Anti-correlation coefficient, 38 Activation, 67 Antimorph, 27 Activator, 157 Antitermination, 149 AraC, 148–149, 151–152 Arabinose (ara) operon in E. coli, 148–150, catabolite activator protein (CAP), 150 151–152 Adams, Alison E.M., 122, 128 AraC, 148–149, 151–152 Adaptors, 92, 104 Arginine biosynthesis, 124–125, 124f Adenosine triphosphate (ATP), 47 Autozygosity, 186 AFLPs (amplified fragment length Auxotrophs, 49–50, 53, 106–112, 131 polymorphisms), 12 Age-related macular degeneration, 203 B Agglutination of red blood cells, 19 Alkaptonuria, 185–186 Backcross, 18 Allele frequencies, 183 Back mutation, 105 Alleles, 12–14 Bacteria, coupling of transcription inferring human gene function from and translation, 139 disease alleles, 195–206 Bacteriophage l, 118–119 mutant, 13, 20–22, 24–27 Bacteriophage T4 null, 14, 26, 28–29 genome, 71–73 pseudoalleles, 28 infection process, 71 wild-type, 13–14 morphogenesis and assembly pathways, 52– Allelism, 12–13, 38 55, 54f Allelomorph, 12 protein biosynthesis regulation, 138 rII Allosteric activation, 64 system, 72 Allosteric inhibition, 63 fine-structure mapping, 78–80 Allosteric interaction, mutations affecting, 200– mutations, 71, 74, 78–81, 95, 107, 201 111–112, 114 Allosteric modulation, 64 polycistronic mRNA, 144 Amber mutations, 110 r phenotypes, 75 Ameliorating interaction, 134 Balanced reciprocal translocations, 97 Amino acids Base-pairing, 88, 92–93 genetic code, 87, 91–92, 92t Bateson, William, 8, 12, 15, 57, 133, 184–185 in metabolic pathways, 61 Benzer, Seymour, 6, 12, 17 number in typical proteins, 94 biography, 84 Amorph, 27 cis–trans test, 81–83, 82f Amplified fragment length polymorphisms function gene definition, 81–83, 84 (AFLPs), 12 phage studies by, 71–74, 78–81, 83, 95, 111 ___ 211 © 2015 Cold Spring Harbor Laboratory Press. All rights reserved. This is a free sample of content from Decoding the Language of Genetics. Click here for more information or to buy the book.

212 INDEX

Bernard, Claude, 69 Chromosomes b-galactosidase, 141, 143–146, 159, 207 gain and loss of entire, 162 b-galactoside permease, 141, 143–145 recombination, 100–103, 102f b-galactoside transacetylase, 141, 143–145 translocations, 97–98, 98f, 161–162 b-globin genes/proteins, 20–22, 172–173 cis-acting elements, regulation and, 156–157, Biochemical reactions, 47. See also Metabolic 162 pathways cis-acting regulatory sites, 177, 202 Biotechnology, 157–160 cis-dominance, 114, 145–146, 157 Blood types, human, 19 cis–trans test, 17, 114 Boone, Charlie M., 135–136 Benzer and, 81–83, 82f BRCA1 alleles, 23–24 cis-dominance, 145–146 Breast cancer, 23–24 Lewis and Pontecorvo, 81, 84 Brenner, Sydney, 114–115 Cistron, 91 Bridges, Calvin, 97, 104 cis–trans test and, 17, 82–83 Brown, Michael, 198, 206 defined, 82–84 Bypass suppressors, 124–125, 124f polycistronic messenger RNA (mRNA), 142 Coding strand, 87, 92–93, 139 CODIS, 11–12 C Codominance, 19, 21, 36 Caenorhabditis elegans, sex determination in, Codons, 87, 91–92, 92f 127 Coinfections, phage, 75–76, 78 CAG repeats, 199, 205–206 Cold-sensitive (Cs) mutations, 119–121 cAMP (cyclic AMP), 150 Combinatorial regulation, 150–151 Cancer Combined DNA Index System (CODIS), amplification of genomic sequences, 101 11–12 applications of genetics and Complementation, 13, 27–29 genomics, 209 Complementation group, 28 causative mutation, 10 Complementation tests. See also cis–trans test loss of heterozygosity and, 201–202 araC cistron, 151 oncogenes, 175, 200 in phage crosses, 75 point mutations and, 175 suppressor mutations and, 120, 125 TP53 gene mutation, 14 T4 conditional-lethal mutants, 53 translocations and, 98, 162 Complement factor H, 203 tumor cell selection assays, 161–163 Complex phenotypes, 131–136 tumor-suppressor genes, 102, 162, 175, 196, disease phenotypes, 203–205 200, 201–202, 206 epistasis, 133 virus integration into genome, 100 gene interactions, 134 Cannon, Walter, 68–69 genetic heterogeneity, 131–132 Catabolite activator protein (CAP), 150, 155 genome-scale genetic interactions in yeast, Catalysis, by enzymes, 47, 48, 49f 134–136, 135f CCR5 gene, 210 polygenic inheritance, 132 Cell cycle, 123 quantitative traits, 132 Centimorgan, 37 synthetic phenotypes, 132–133 Chain-termination mutations, 96 Compound heterozygote, 27–29 Chaperone protein, 118 Conditional-lethal mutations, 52–53, 74–75, 77, Chemokine receptor, 210 107, 119–120, 122–123 Chemostat, 62 Consanguinity, 184 Chlamydomonas reinhardtii, flagella of, Conserved DNA 125–126 conservation of functional sequences, Cholesterol homeostasis, 210 167–169 Chorismic acid, 63, 63f phenotypic effects of mutations in, Chromosomal rearrangements, 161–162, 171 174–179

INDEX 213

Constitutive, 141 haplotype, 42–43 Constitutive mutants, 141 in TP53 gene, 14 Lac system, 141, 143–145 linkage mapping, 11, 196 Copy number variants (CNVs), 98–99, 161–162, linkage phase, 42, 43f 171, 202, 205 segregation of polymorphic loci Corepressors, 148, 155 single locus, 39–40, 39f Correns, Carl Erich, 15 three loci, 41, 41f Crick, Francis, 92, 100, 104, 114 two loci, 40, 40f Cross-feeding, 50–51, 51f, 55, 56 DNA recombination. See Recombination Crossing over, 31, 34, 34f, 36, 101, 102f, DNA repair, 101, 103 187–189 DNA sequence variant, 10, 11 Cyclic AMP (cAMP), 150 DNA variants, 9–14 Cyclins, 123 alleles, 12–14 Cystic fibrosis, 44, 183 mutations, 9–10 Cytological analysis, 97 polymorphisms, 10–12 Cytoskeleton, 121–122, 125–126 Dobzhansky, Theodosius, 1, 14, 132 Domain architecture of proteins and their genes, 163–166, 164f D Dominance, 17–22, 24–27 biological interpretation of, 24–27 Darwin, Charles, 10, 15 cis-dominance, 114, 145–146, 157 Databases codominance, 19, 21 genome sequences, 167 definition, 18 human mutations, 14, 175 gain-of-function, 25 Degeneracy, genetic code, 91–92, 177 genomic rearrangements and, 202 Delbru¨ ck, Max, 84 Deletions (deletion mutations), 13–14, 175 haploinsufficiency, 26 definition, 80 implicit experiment and determination of, gene knockout, 196 17–20 in laboratory selection assays, 162 incomplete (partial) dominance, 19 lac operon genes, 146–147, 147f loss of heterozygosity and, 201–202 nonreverting T4 rII mutants, 79–80 mutant allele relationship to wild-type allele, null alleles, 14, 26 20–22, 24–27 De novo mutations, 205 nonsense suppressors, 112 de Vries, Hugo, 9, 15 overdominance, 21–22 Dihybrid cross, 32, 33f in phage crosses, 75 Diploid, 5–6, 8, 72 Dominant disease phenotypes, 199 Direct repetition, 101 Dominant-negative mutation, 26, 27 Disease, inferring human gene function from Dosage suppression, 122–123 alleles, 195–206 Double crossovers, 37 complex disease phenotypes, Double helix, DNA, 88, 89f 203–205 Double mutant analysis simple Mendelian disease phenotypes, in metabolic pathways, 50–52, 51f, 57 195–202 in regulatory and signal transduction DNA pathways, 55–56, 56f, 57 replication, 88, 157 as test of epistasis, 57 structure, 88, 89f Downstream, 48, 139 transcription, 89–91, 90f Down syndrome, 204 dnaB, 118–119 Drosophila melanogaster, genome of, 169 DNA polymerase, 153 Dulbecco, Renato, 73 DNA polymorphisms, 10, 11, 38–42, 39f–41f, 44, Duplication 187, 190. See also Polymorphisms gene, 27, 171–172, 202 as genetic markers, 13 whole-genome, 173

214 INDEX

E FBI Combined DNA Index System (CODIS), E. coli 11–12 as prototroph, 48 Feedback inhibition, 61, 66 genome size, 169 allosteric interactions, 63–64 human protein production in, 157–159 example, 64–65, 65f induction-repression mechanisms in, 67 in tryptophan biosynthesis, 62–63 Edgar, Robert S., 52–53, 57 speed and reversibility of, 67 Effect size, 191 usage of term, 63 Eisen, Michael, 170, 179 Feldman, Marc, 170, 179 Elongation, 154 Fibrin, 163–165 End-product inhibition, 62–65, 65f, 66, 67 Fibronectin finger domain, t-PA, Energy, 47 164–165, 164f Englesberg, Ellis, 148, 152 Fimbrin, 122, 134 Enhancers, 151, 157 Fine-structure mapping, bacteriophage T4, Enzymes, 47–51 78–80 metabolic regulation at level of enzyme Fisher, Ronald, 43, 46, 133 activity, 62–65 Fitch, Walter, 172, 179 0 0 metabolic regulation at level of enzyme 5 untranslated region (5 UTR), 176, 177 synthesis, 65–67 Flagella, 125–126 Epidermal growth factor domain, t-PA, 164–165, FlyBase, 167 164f Fly room at Columbia University, 32, 46 Epigenetics, 208 Fragile X syndrome, 199 Epistasis, 57, 133 Frameshift mutations, 96–97, 112–115, 175 Eugenic laws, 183 Friedreich’s ataxia, 199 Evolution, 1, 4 Function, 5, 6 as compromise, 163 Functional gene consequences of genome architecture, complementation and definition of, 27–29 160–163 definition, 81–83, 84 conservation of functional sequences, DNA polymorphisms and, 13 167–169 evolutionary conservation of sequences, domain architecture of proteins and their 170–174 genes, 163–166, 164f locus reconciled with, 80–81 duplication and divergence of genes, 171–172 Functional sequences, evolutionary neutral theory of molecular evolution, conservation of, 167–179 170–171 Functional suppression, 117–128 phenotypic effects of mutations in conserved bacteriophage l, 118–119 DNA, 174–179 dosage suppression, 122–123 of replication, transcription and translation Functional suppressors, 109 machinery, 153 bypass, 124–125, 124f tree of life, 168f mutual interaction, 121–122 Exacerbating interaction, 134 protein interaction, 117–119 Exome sequencing, 204 recessive, 125–127 Exons, 91, 165, 176 with novel phenotypes, 119–121 Experimental organisms, 3–4, 14, 182 Expression microarray, 207 Expressivity, 23–24 G Extragenic suppressor, 106 Gain-of-function mutation, 25, 200 Gametes, 8 Gametogenesis, 33 F Garrod, Archibald, 184–185 Familial hypercholesterolemia, 198 Gene amplification, 202 Fanconi anemia, 131–132 Genecards, 14

INDEX 215

Gene conversion, 103 Genotype Gene duplication, 27, 171–172, 202 change (see Mutation) Gene expression, transcriptional regulation of, definition, 7 137–152 penetrance and expressivity, 22–24 Gene interactions, 134 phenotype connection, 22–24 Gene knock-in, 196 Genotype frequencies, 183–184 Gene knockout, 196 Genotyping, 12 Genes, 12 Georgopoulos, Costa, 118, 128 domain architecture of proteins and their GFP (green fluorescent protein), 159–160, 160f genes, 163–166, 164f Gilbert, Walter, 90, 104 Globin genes, 172–173, 173f duplication and divergence of genes, Glutamic semialdehyde, 124–125, 124f 171–172 Goldstein, Joseph, 198, 206 functional definition, 6 Green fluorescent protein (GFP), 159–160, 160f inferring human gene function from disease groE, 118–119 alleles, 195–206 GTPases, 201 meaning of term, 6 Gusella, James F., 199, 205, 206 modular architecture of, 153–166 GWAS. See Genome-wide association study number of, 169, 195 Gene set analysis, 204 Gene therapy, 100 Genetic analysis, 1–6, 8 H actin cytoskeleton, 121–122 lactose utilization in E. coli, 140–141 Haldane, J.B.S., 37, 45 suppression and, 106–109 Haploid, 6, 8, 72–73, 74 Genetic code, 87, 91–92, 92t Haploinsufficiency, 26 Genetic drift, 182 Haplotype, 42–43, 189–191, 196 Genetic heterogeneity, 131–132 Haplotype blocks, 189–191 Genetic markers, DNA polymorphisms as, 13 Hardy, Godfrey Harold, 182, 194 Genetics Hardy-Weinberg law (Hardy-Weinberg equili- applications of, 209–210 brium), 182–185, 194 future of, 207–210 Hawthorne, Donald, 111–112, 115 genomics distinguished from, 207 HBB gene, 20–22, 172 Genetic testing, DNA source for, 38–39 Heat-sensitive mutations, 119–121 Genetic variation, 4–5 Hemizygote, 9 Genome(s) Hemoglobin, 172 dominance relationships in b-globin (HBB) evolutionary consequences of genome gene, 20–22 architecture, 160–163 hemoglobin A, 21 modular architecture of, 153–166 hemoglobin S, 21 non-protein-encoding sequences, 169 Hemophilia A, 10 sequence databases, 167 Hershey, Alfred Day, 72, 74, 84 size of, 169 Herskowitz, Ira, 118, 128 whole-genome duplication, 173 Heterozygote Genome annotation, 167 compound, 27–29 Genome-wide association study (GWAS), 191– dominance and recessiveness, 17–22, 25–26 194, 192f, 193f, 203 Genomic rearrangements, 202 codominance, 19, 21 Genomics haploinsufficiency, 26 applications of, 209–210 human b-globin gene, 20–22 future of, 207–210 incomplete (partial) dominance, 19 genetics distinguished from, 207 simple, 17–18 Genomic sequence diversity, recombination and, dominance via loss of heterozygosity, 100–103, 102f 201–202

216 INDEX

Heterozygote (Continued) Inducible system, 149 hemizygote, 9 Induction, 66 usage of term, 8–9 Informational suppressor, 109 verification of genotype, 18 Information flow, 88–94 HGMD (Human Gene Mutation Database), 14, 175 Informativeness, 40 HIV infection, 210 Inheritance HLA locus, 193 complex modes of, 176 Hodgkin, Jonathan, 127, 129 patterns, 1–2 Homeostasis, regulation and, 66–67, 137 polygenic, 132 Homolog, 173, 173f Inherited disease Homologous chromosomes, 34, 34f genetic lesions causing, 175–176 Homologous (legitimate) recombination, inferring human gene function from disease 100–101, 102f, 165 alleles, 195–206 Homozygosity mapping, 186–187 Inhibition, 67 Homozygote Initiation, 154, 155 autozygosity, 186 Insertion mutations, 99, 103, 175 usage of term, 8 Insulin, human, 157, 159 Host-range mutants, 74 Interallelic complementation, 29 HTT gene, 199 Intragenic complementation, 29 Huang, Bessie, 125–126, 128 Intragenic suppressor, 106 Human b-globin (HBB) gene, 20–22, 172 Intron-exon boundary elements, 176 Human blood types, 19 Introns, 91, 164f, 165, 176 Human Gene Mutation Database (HGMD), 14, Inversions, 100, 101 175 Inverted repetition, 101 Human genome, number of protein-encoding In vitro complementation, 53 genes, 169 Human population genetics, 181–194 Human protein production in E. coli, 157–159 Huntington’s disease, 199, 205–206 J Hybrid organisms, 8 Jacob, Franc¸ois, 66, 68, 84, 139–147, 207 Hypermorph, 27 Jarvik, Jonathan W., 119–120, 128 Hypomorph, 27 Johannsen, Wilhelm, 6, 7, 15 Hypothesis testing, multiple, 203–204 Hypoxia, red blood cell sickling under, 21 K Kimura, Motoo, 170–171, 179 I Knudson, Alfred, 200–202, 206 Identity by descent (IBD), 190 Koshland, Daniel E., Jr., 63, 68 Illegitimate recombination, 102–103 KRAS oncogene, 200–201, 209 Immunoglobulin E (IgE) deficiency, 209 Kringle domains, t-PA, 164–165, 164f Implicit experiment, 3, 17–29, 108 Inactivation, X chromosome, 178 Inborn error of metabolism, 185 Inbreeding, 184–186, 185f L Incomplete (partial) dominance, 19 Laboratory selection studies, 161–163 Indels, 97. See also Deletions (deletion muta- Lac repressor, 143, 144f, 145–148, 151, 155, 202 tions); Insertion mutations Lac system in E. coli (lac operon), 66, 155–157 Independent assortment, 31–33, 41–42 cis-dominance, 145–146 Inducers coordinate expression of structural proteins, in negative-control systems, 148 142 in positive-control systems, 148–149 deletions removing lac operon genes, Inducible, 141 146–147, 147f

INDEX 217

functional analysis of lac operon regulatory Malaria, 20–22 elements, 144–146 Manhattan plots, 192–193, 192f, 193f genetic structure of lac operon, 142–144, MAPK protein, 123 144f Mapping. See also Linkage mapping terminology, 140–141 Haldane’s mapping function, 37 Law of mass action, 123 homozygosity, 186–187 Leakiness, of mutations, 79 linkage mapping in human families, 38–43 Lesch–Nyhan syndrome, 45 measuring distance between loci by Lewis, Edward B., 81, 84 recombination, 35–37 Li–Fraumeni syndrome, 14 Maximum likelihood method, 44, 46 Likelihood ratio, 46 McClintock, Barbara, 97, 99, 104 Linkage, 31–33, 35 Meiosis, 32, 34–35, 34f likelihood ratio, 46 crossing over, 34, 34f, 187–189 Linkage disequilibrium, 190–191, 196 homologous recombination, 101 Linkage mapping, 11 Mendel, Gregor disease identification by, 199 biography, 15 in human families, 38–43 central insight of, 5–6 haplotype, 42–43 dominance and recessiveness, 17–18 independent assortment, 41–42 independent assortment, 31–33 informativeness, 40 innovations of, 1–2 linkage phase, 42, 43f word use by, 3, 5 Mendelian segregation, 39–40, 39f Mendelian segregation, 39–40, 39f using DNA polymorphisms, 196 Mendel’s First Law, 39 Linkage phase, 42, 43f, 190–191 Mendel’s Second Law, 40–41 Locus, 12, 78 Messenger RNA (mRNA), 90–91 defining by failure to recombine, 38 instability of, 91, 137–138 definition and usage of term, 6 miRNA binding sites, 178 functional gene reconciled with, 80–81 polycistronic, 142, 148 measuring distance between loci by size, 176 recombination, 35–37 splicing, 90–91, 139, 165 polymorphic, 13 translation, 89, 90f, 91–94 LOD (logarithm of the odds) score, 46, 132 Metabolic pathways Logical operators, 156 analysis, 47–52 Long noncoding RNAs (lncRNAs), 178 cross-feeding assay, 50–51, 51f, 55, Loss-of-function phenotype/mutation, 25, 27, 56 49f, 56f, 105, 197–198, 200 double mutants, use of, 50–52, 51f araC, 148, 152 auxotrophic mutation, 49 terminology, 47–50 lac, 144–145 order of steps in, 50–52 temperature-sensitive mutation, 53 regulation, 59–67 Loss of heterozygosity, 200, 201–202 example, 64–65, 65f Low-density lipoprotein receptor (LDLR) gene/ at level of enzyme activity, 62–65 protein, 194, 198–199 at level of enzyme synthesis, 65–67 Luria, Salvador, 84, 128 posttranslational protein Lysis, 71 modification, 64 schematic, 60f Methionine, 91 Methylation, 64 M Microarrays, 190, 192, 207–208 Maas, Werner K., 142, 152 Micro-RNAs (miRNAs), 177, 178 Macular degeneration, age-related, 203 Microtubules, 125–126 Major histocompatibility group, 193 Missense mutations, 95, 175

218 INDEX

Mitotic recombination, 102 dominant-negative, 26, 27 Model organisms, 195–196. See also Experi- dominant to wild type, 25 mental organisms enhancer and silencer, 151 Modular architecture of genes and genomes, fixation of, 170–171 153–166 frameshift, 96–97, 112–115, 175 biotechnology and, 157–160 gain-of-function, 25, 200 domain architecture of proteins and their haploinsufficiency and, 26 genes, 163–166, 164f human gene, 14 evolutionary consequences of genome indels, 97 architecture, 160–163 insertion, 99, 103, 175 initiation, elongation, and specificity in inversions, 100 macromolecular synthesis, 153–156 loss-of-function, 25, 27, 49, 49f, 56f, 105, separable regulatory sites and coding 197–198 sequences, 156–157 Moir, Donald T., 120, 128 missense, 95, 175 Molecular biology, 87 molecular taxonomy of simple, 94–97 Monod, Jacques, 63, 66, 68, 139–147, 207 multipoint, 94 Morgan, Thomas Hunt, 32, 37, 45, 104 neutral, 170–171, 174, 176 Morphogenesis nonsense, 96, 175 assembly pathways and, 52–55, 54f nonsense suppressors, 109–112 phage experiments, 119–120 nucleotide expansion, 199 Mortimer, Robert K., 111–112, 115 null, 26, 28–29, 49–50, 49f, 96–97, 99 Mouse Genome Informatics, 167 nutritional, 106–112 mRNA. See Messenger RNA passenger, 196 Muller, Hermann, 9, 15, 27, 85 phage mutant phenotypes, 73–74 Multicellular organisms, genomes of, 169 phenotypic effects of mutations in conserved Multiple hypothesis testing, 203–204 DNA, 174–179 Mutant alleles plaque morphology mutants, 73–74, 76–77, dominance relationships, 20–22, 76f 24–27 point, 94–97, 161, 174–175 null alleles, 26 promoter, 139–140, 146 sources of, 13 recessive, 24–25, 27–29, 151 Mutant phenotype, 10, 14 revertant frequency, 79 Mutation(s), 94–100 RNA-splicing defects, 175, 176 auxotrophic, 49–50, 53, 106–112, 131 signal transduction and allosteric interaction, back, 105 200–201 causative, 9–10 silent, 96 chain-termination, 96 somatic, 14 chromosomal rearrangements, strength of phenotype, 79 161–162, 171 substitution, 95 cis-acting, 157 complementation analysis, 27–29 synonymous, 95–96 conditional-lethal, 52–53, 74–75, 77, 107, temperature-sensitive (Ts), 74–75, 119–121, 119–120, 122–123 122, 127, 134 constitutive mutants, 141 translocations, 97–98, 98f, 161–162 copy number variants (CNVs), 98–99, transposons, 99–100, 103, 202 161–162, 171, 202, 205 trinucleotide repeat alleles, 199–200, databases on human, 14 205–206 definition and usage of term, 9–10 Mutation rate, 105, 106, 182 deleterious, 171 Muton, 80 deletions, 13–14, 26, 79–80, 146–147, 147f, Mutual interaction suppressors, 121–122 162, 175, 196 Myopia, 192, 192f de novo, 205 Myotonic dystrophy, 199

INDEX 219

N P Nasmyth, Kim A., 123, 128 Paralogs, 65, 122, 172, 173f, 174 Nearsightedness, 192, 192f Parental gametes, 36 Negative control, 148 Partial diploids, 144–146 Neomorph, 27 Passenger mutations, 196 Neurofibromatosis type 1, 23–24 Pathways, 47–57. See also Metabolic pathways Neurotransmitters, 61 epistasis, 57 Neutral mutation, 170–171, 174, 176 morphogenesis and assembly pathways, Neutral theory of molecular evolution, 170–171 52–55, 54f NF1 gene, 23–24 regulatory and signal transduction, 55–57, Noncoding RNAs, 177–179 56f Nonhomologous end joining, 102 Patterns of inheritance, 1–2 Nonpermissive condition, 53, 75–79 PCR (polymerase chain reaction), 12 Nonsense codons, 154 PCSK9 gene, 210 Nonsense mutations, 96, 175 Penetrance, 23–24 Nonsense suppressors, 109–112 Permissive condition, 52–53, 75–78 Novick, Aaron, 62–63, 68 Phage, 71–84. See also specific bacteriophages Novick, Peter Jay, 127, 129, 134 advantages of phage system for study, 73 Nucleotide expansion mutations, 199 cistrons, 82–84 Null alleles, 14, 26, 28–29, 198 coinfections, 75–76, 78 Null mutation, 26, 28–29, 49–50, 49f, complementation and recombination 96–97, 99 assessments in, 75–78, 76f Null phenotype, 26, 174, 196 gene and locus in T4, 72–73 Nutritional mutation, 106–112 morphogenesis and assembly pathways, 52–55, 54f morphogenesis experiments, O 119–120 Ochre mutations, 110 mutant phenotypes, 73–74 Ohno, Susumu, 171, 179 recombination frequency, 76–77 Omalizumab, 209 selective crosses, 77–78 OMIM (Online Mendelian Inheritance in Man), Phenotypes. See also specific phenotypes 14 causative mutation, 9–10 Oncogenes, 175, 200 complementation analysis, 27–29 KRAS, 200–201, 209 complex, 131–136 proto-oncogenes, 200 complex disease, 203–205 recessive, 102, 162, 200 definition, 7 Online Mendelian Inheritance in Man (OMIM), dominance and recessiveness, 17–22, 14, 195 24–27 Opal mutations, 110 genotype connection, 22–24 Open reading frame (ORF), 94 haploinsufficient, 26 Operator, 155 loss-of-function, 25, 105 cis-acting mutations, 157 null, 26, 174, 196 lac, 143, 144f, 145, 147–148, 156 penetrance and expressivity, 22–24 Operons qualitative differences in, 23 arabinose (ara) operon in E. coli, 148–150, simple Mendelian disease phenotypes, 151–152 195–202 definition, 142 strength of mutant, 79 Lac system in E. coli, 140–147, 144f, 147f synthetic, 132–135 positive control by antitermination, 149 wild type, 10 Ortholog, 172–173, 173f, 195–196, 202 Phenotypic effects of mutations in conserved Ovarian cancer, 23–24 DNA, 174–179 Overdominance, 21–22 cis-acting regulatory sites, 177

220 INDEX

Phenotypic effects of mutations in conserved Posttranslational protein modification, 64 DNA (Continued) Precursor (pre-) mRNA, 176 long noncoding RNAs (lncRNAs), 178 Pringle, John, 128 micro-RNAs, 178 Proline biosynthesis, 124–125, 124f noncoding RNAs, 177–179 Promoter fusions, 159–160 protein-coding sequences, 174–176 Promoters, 139–140 transcribed noncoding sequences in genes human protein production in E. coli, 157–159 that encode proteins, 176–177 lac, 143, 144f, 146, 156 Philadelphia chromosome, 98, 98f, 162 mutations, 146 Phosphorylation, 64 cis-acting, 157 Phylogenetic tree, 168f in laboratory selection assays, 162 PKD database, 201–202 transcription initiation and, 154, 155 PKD1/PKD2 genes, 201–202 Protease domain, t-PA, 164–165, 164f Plaque, 74 Protein fusions, 160 Plaque assay, 73–74, 75–77 Protein interaction suppressors, 117–119 Plaque morphology mutants, 73–74, 76–77, 76f Proteins Plasmid, 158 domain architecture of proteins and their Plasmin, 163–164 genes, 163–166, 164f Plasminogen, 163–165 human protein production in E. coli, 157–159 Plasmodium falciparum, 20–21 mRNA translation, 89, 90f, 91–94 Point mutations, 94–97, 161, 174–175 number of amino acids in typical, 94 Polycistronic messenger RNA (mRNA), 142, 148 number of genes encoding, 169 Polycystic kidney disease, 201–202 posttranslational protein modification, 64 Polygenic inheritance, 132 stability of, 138 Polymerase chain reaction (PCR), 12 transcriptional regulation of gene Polymorphisms, 10–12, 38–42, 39f–41f, 44, 187, expression, 137–152 190 Proto-oncogenes, 200 amplified fragment length polymorphisms Prototrophs, 48–49, 107 (AFLPs), 12 Pseudoalleles, 28 definition and usage of term, 10 Pseudo-revertants, 105, 108, 111–112, 120 DNA polymorphisms, 10, 11, 13, 14, 38–42, Punnett, Reginald Crandall, 183, 194 39f–41f, 44, 187, 190 Punnett square, 33f, 183 as genetic markers, 13 Purifying (negative) selection, 171, 176, 177 haplotype, 42–43 Purine auxotrophs, 146–147 linkage mapping, 11, 196 Purine biosynthesis, 149, 155 linkage phase, 42, 43f Purine repressor, 148, 155 restriction fragment length polymorphisms (RFLPs), 11, 13, 39 segregation of polymorphic loci Q single locus, 39–40, 39f Quantitative analysis, 1–3 three loci, 41, 41f Quantitative trait loci (QTLs), 132, 191 two loci, 40, 40f short tandem repeat (STR), 11–12, 13 single-nucleotide polymorphism (SNP), 12, 186–192, 192f, 193f, 203–204 R variable number tandem repeat (VNTR), Random assortment, 31–33 11–12, 13, 39 Random drift, 171 Polypeptide, cistron and, 83–84, 91 Reading frame, 93–94 Pontecorvo, Guido, 81, 84, 85 Recessive, definition of, 18 Population genetics, human, 181–194 Recessive disease phenotypes, 196–199 Positive control, 148–149 Recessive mutations, 24–25 Positive selection, 171 complementation analysis, 27–29

INDEX 221

enhancer and silencer mutations, 151 Replication, DNA, 88, 157 Recessiveness, 17–22, 24–27 Repressible, 141 biological interpretation of, 24–27 Repressible system, 149 implicit experiment and determination of, Repression, 66 17–20 Repressors loss of function, 25 cis-acting mutations, 157 Mendel’s description of, 18 corepressors, 148, 155 non-absolute nature of, 21 definition, 148 Lac repressor, 143, 144f, 145–148, 151, 155, null alleles, 26 202 Recessive oncogenes, 102, 162, 200 purine repressor, 148, 155 Recessive suppressors, 125–127 Restriction fragment length polymorphisms Reciprocal translocation, 162 (RFLPs), 11, 13, 39 Recombinant DNA technology, 157–160 Retinoblastoma, 201–202 Recombinant gametes, 35–36 Revertant frequency, of mutations, 79 Recombination, 31–34, 100–103, 102f Revertants. See also Suppression definition and usage of term, 33, 35 pseudo-revertants, 105, 108, 111–112, 120 frequency of, 35–38, 76–77, 103, 187 true, 105, 108, 113 gene conversion, 103 RFLPs. See Restriction fragment length homologous (legitimate), 100–101, 102f, 165 polymorphisms illegitimate, 102–103 Rheumatoid arthritis, 193, 193f in meiosis, 187–189 Ribosomal ambiguity suppressors, 115 loci defined by failure to recombine, 38 Ribosomal RNAs, 177 measuring distance between loci by, 35–37 Ribosome-binding site, 158 mitotic, 102 Ribosomes, 91, 139, 153 in phage, 76–78, 76f RNA transposition, 103 structure, 88 Recon, 80 transcription, 89–91, 90f Reduction division, 34. See also Meiosis translation, 89, 90f, 91–94 Regulation RNA polymerase, 90f, 118–119, 138 cis-acting elements, 156–157, 162 as multisubunit structure, 83–84 combinatorial, 150–151 catalytic subunits, 153 definition and usage of term, 61–62 cis-dominant phenotypes and, 157 enhancers, 151 promiscuity of, 155 homeostasis and, 66–67, 137 promoter interaction, 139–140 initiation, elongation, and specificity RNA polymerase II holoenzyme, 156 in macromolecular synthesis, transcription factors, 151 153–156 RNA splicing. See Splicing at level of enzyme activity, 62–65 RNA-splicing defects, 175, 176 at level of enzyme synthesis, 65–67 Rotman, Raquel (Sussman), 72, 74, 84 by multiple inputs, 149–151 rpoB, 118–119 negative control, 148 of metabolic pathways, 59–67 operon (see Operons) positive control, 148–149 S posttranscriptional by miRNAs, 178 Saccharomyces cerevisiae separable regulatory sites and coding as prototroph, 48 sequences, 156–157 genome size, 169 silencers, 151 introns, 176 transcriptional regulation of gene Saccharomyces Genome Database (SGD), 167 expression, 137–152, 156 Saliva sample, for genetic testing, Regulatory pathways, 55–57, 56f 38–39 Regulon, 142, 155 Schekman, Randy, 129

222 INDEX

Schizophrenia, 205 definition, 105–106 Segregation dosage, 122–123 Mendelian, 39–40 functional, 117–128 of polymorphic loci genetics, 105–115 single locus, 39–40, 39f genetic test for, 109 Suppressors three loci, 41, 41f bypass, 124–125, 124f two loci, 40, 40f extragenic, 106 Selection, 174 functional, 109 extreme, 183 genetic properties of, 106–112 laboratory selection assays, 161–163 informational, 109 positive, 171 intragenic, 106 purifying (negative), 171, 176, 177 mutual interaction, 121–122 Selective crosses, 77–78 nonsense, 109–112 Sequence databases, 167 with novel phenotypes, 119–121 Sequence homology, 100 protein interaction, 117–119 Sex chromosomes, 8–9 recessive, 125–127 Sex determination in Caenorhabditis elegans, ribosomal ambiguity, 115 127 tRNA-based frameshift, 115 SGD (Saccharomyces Genome Database), 167 Swiss Prot Diseases and Variants (database), 14 Short tandem repeat (STR) polymorphism, 11– Synergistic interaction, 134 12, 13 Synonymous mutations, 95–96 Sickle cell anemia, 20–22, 172, 198 Synthetic lethality, 132, 134, 135 Sickle cell trait, 20–21 Synthetic phenotype, 132–135 Signal sequence, 164–165, 164f Szilard, Leo, 62–63, 68 Signal transduction mutations affecting, 200–201 pathways, 55–57, 56f, 127 recessive functional suppression and, 127 T Silencers, 151 T4. See Bacteriophage T4 Silent mutations, 96 Temperature-sensitive (Ts) mutations, 74–75, Single-nucleotide polymorphism (SNP), 12, 39, 119–121, 122, 134 42, 186–192, 192f, 193f, 203–204 Template strand, 93, 138 Snapdragons, flower color in, 19 Termination codons, 154, 158 SNPs, 39, 42 Termination factors, 154 Somatic mutation, 14 Test cross, 18 Spinocerebellar ataxia, 199 Thought experiment, 17 Spliceosome, 176 30 untranslated region (30 UTR), 176, 177, 178 Splicing, 90–91, 139, 154, 165 Tissue-type plasminogen activator (t-PA), defects, 175, 176 163–165, 164f, 173 Statistical significance, 3 TMG, 207 Statistics, 43–45 TP53 gene mutation, 14, 196–197, 197f likelihood ratio, 46 Transcription, 89–91, 90f LOD score, 46 basics of, 138–140 Stop codons, 91, 92t, 94, 154, 158 Transcriptional regulation of gene expression, nonsense suppressors, 109–112 137–152 STR (short tandem repeat) polymorphism, Transcription factors, 151 11–12, 13 Transfer RNA (tRNA), 92, 177 Structure, 5, 6 Translation, 89, 90f, 91–94, 139, 154 Sturtevant, Alfred, 32, 45, 97, 104 Translocations, 97–98, 98f, 161–162 Substitution mutations, 95 Transmission coefficient, 79 Suppression Transporters, 162, 172 by frameshift mutations, 112–115 Transposition, 103

INDEX 223

Transposons, 99–100, 103, 202 W Tree of life, evolutionary, 168f Watson, James, 100, 104 Trinucleotide repeat alleles, 199–200, 205–206 Weinberg, Wilhelm, 182, 194 Trios, 205 Wexler, Nancy, 199, 205 tRNA-based frameshift suppressors, 115 Wild type, 10, 13–14 tRNAs, 92, 177 Wood, William B., 52–53, 57 True breeding, 2 WormBase, 167 Tryptophan auxotrophs, 62, 65, 107–109, 111–112, 131 biosynthesis regulation, 62–63, 65–66 X chemical structure, 63f X chromosome, 8–9 Tryptophanase, 207–208 fragile X syndrome, 199 Tschermak von Seysenegg, Erich, 15 inactivation, 178 Tubulin, 125 Tumor cells, in laboratory selection assays, 161– 163 Tumor-suppressor genes, 102, 162, 175, 196, 200, Y 201–202, 206 Y chromosome, 8 Two-factor cross, 35–37 Yeast actin mutations, 121–122, 127, 134 auxotrophs, 107–112 conditional-lethal mutations, 122–123 U dosage suppression, 123 Umber mutations, 110 genome-scale genetic interactions, studying, Upstream, 48, 139 134–136, 135f genome size, 169 laboratory selection assays, 161–163 MAPK protein, 123 V network of functional relationships among Variable number tandem repeat (VNTR) poly- genes, 135f morphism, 11–12, 13, 39 suppressor mutations and, 120–121 Vector, 158 synthetic lethality, 134 Virus integration into genome, 100 transporters, 162, 172