Genetics: from genes to genomes - Basic principles: how traits are transmitted

*Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or displayPowerPoint to accompanyGenetics: From Genes to GenomesFourth EditionLeland H. Hartwell, Leroy Hood, Michael L. Goldberg, Ann E. Reynolds, and Lee M. SilverPrepared by Mary A. BedellUniversity of GeorgiaCHAPTER OUTLINE*Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3CHAPTERBasic Principles: How Traits Are TransmittedCHAPTERPART IExtensions to Mendel's laws3.1 Extensions to Mendel for Single-Gene Inheritance3.2 Extensions to Mendel for Multifactorial InheritanceSome phenotypic variation poses a challenge to Mendelian analysisExample: Lentils come in an array of colors and patternsCrosses of pure-breeding lines can result in progeny phenotypes that don't appear to follow Mendel's rulesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Fig. 3.1Explanations for some traits:No definitively dominant or recessive alleleMore than two alleles existMultiple genes involvedGene-environment interactionsExtensions to Mendel for single-gene inheritanceDominance is not always completeIncomplete dominance – e.g. snapdragon flower colorCodominance – e.g. lentil coat patterns, AB blood group in humansA gene may have >2 alleles – e.g. lentil coat patterns, ABO blood groups in humans, histocompatibility in humansPleiotropy - one gene may contribute to several characteristicsRecessive lethal alleles – e.g. AY allele in miceDelayed lethalityCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Summary of different dominance relationshipsThe phenotype of the heterozygote defines the dominance relationship of two allelesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Complete dominance: Hybrid resembles one of the two parentsIncomplete dominance: Hybrid resembles neither parentCodominance: Hybrid shows traits from both parentsFigure 3.2Flower color in snapdragons is an example of incomplete dominanceCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Figure 3.3aCrosses of pure-breeding red with pure-breeding white results in all pink F1 progenyPink flowers in snapdragons are the result of incomplete dominanceCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Figure 3.3bF2 progeny ratios: 1 red (AA) 2 pink (Aa) 1 white (aa)Phenotype ratios reflect the genotype ratiosIn codominance, the F1 hybrids display traits of both parents: e.g. lentil coat patternsCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Figure 3.4aSpotted (CSCS) x dotted (CDCD)All F1 progeny are spotted and dotted (CSCD)F2 progeny ratios: 1 spotted (CSCS) 2 spotted and dotted (CSCD) 1 dotted (CDCD)Phenotype ratios reflect the genotype ratiosIn codominance, the F1 hybrids display traits of both parents: e.g. AB blood groupCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Figure 3.4bGene I controls the type of sugar polymer on surface of RBCsTwo alleles, IA and IB, result in different sugars IA IA individuals have A sugarIB IB individuals have B sugarIA IB individuals have both A and B sugars Dominance relations between alleles do not affect transmission of allelesType of dominance (complete, incomplete dominance, codominance) depends on the type of proteins encoded and by the biochemical functions of the proteinsVariation in dominance relations do not negate Mendel's laws of segregationAlleles still segregate randomlyInterpretation of phenotype/genotype relations is more complexCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*A gene can have more than two allelesMultiple alleles of a gene can segregate in populationsEach individual can carry only two allelesDominance relations are always relative to a second allele and are unique to a pair of allelesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*ABO blood types in humans are determined by three alleles of one geneCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Fig. 3.5 aSix genotypes produce four blood typesDominance relations are relative to a second alleleIA and IB are codominantIA and IB are dominant to i IA allele  A type sugarIB allele  B type sugari allele  no sugar Medical and legal implications of ABO blood group genetics Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Figure 3.5 b,cAntibodies are made against type A and type B sugarsSuccessful blood transfusions occur only with matching blood typesType AB are universal recipients, type O are universal donorsSeed coat patterns in lentils are determined by a gene with five allelesFive alleles for C gene: spotted (CS), dotted (CD), clear (CC), marbled-1 (CM1), and marbled-2 (CM2)Reciprocal crosses between pairs of pure-breeding lines is used to determine dominance relations (see Fig 3.6)Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Fig. 3.6Dominance relations are established between pairs of alleles Three examples from Figure 3.6marbled-1 (CM1CM1) x clear (CCCC)  all F1 marbled-1 (CM1CC) F2 progeny: 798 marbled-1 (CM1—) and 296 clear (CCCC) marbled-2 (CM2CM2) x clear (CCCC)  all F1 marbled-2 (CM2CC) F2 progeny: 123 marbled-1 (CM2—) and 46 clear (CCCC) marbled-1 (CM1CM1) x marbled-2 (CM2CM2)  all F1 marbled-1 F2 progeny: 272 marbled-1 (CM1—) and 72 marbled-2 (CM2CM2)3:1 ratio in each cross indicates that different alleles of the same gene are involved Dominance series: CM1 > CM2 > CCCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Human histocompatibility antigens are an extreme example of multiple allelesThree major genes (HLA-A, HLA-B, and HLA-C) encode histocompatibility antigensCell surface molecules present on all cells except RBCs and spermFacilitates proper immune response to foreign antigens (e.g. virus or bacteria)Each gene has 20-to-100 alleles eachEach allele is codominant to every other alleleEvery genotype produces a distinct phenotypeEnormous phenotypic variationCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Mutations are the source of new allelesChance alterations of genetic material arise spontaneouslyIf mutations occur in gamete-producing cells, they can be transmitted to offspringFrequency of gametes with mutations is 10-4-10-6Mutations that result in phenotypic variants can be used by geneticists to follow gene transmissionMolecular basis of mutations described in Chapter 7Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Nomenclature for alleles in populationsAllele frequency is the percentage of the total number of gene copies for one allele in a populationMost common allele is usually the wild-type (+) alleleRare allele is considered a mutant alleleGene w/ only one common wild-type allele is monomorphicAgouti gene in mice – only one allele in wild populations, many alleles in lab miceGene w/ more than one common allele is polymorphicHigh-frequency alleles of polymorphic genes are common variantsExtreme example – 92 plant incompatibility alleles (Fig. 3.8)Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*The mouse agouti gene controls hair color: One wild-type allele, many mutant allelesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Fig. 3.7cWild-type agouti allele (A) produces yellow and black pigment in hair14 different agouti alleles in lab mice, but only A allele in wild mice e.g. mutant alleles a and at a recessive to Aaa has black onlyat dominant to a but recessive to A atat mouse has black on back and yellow on belly One gene may contribute to several characteristicsPleiotropy is the phenomenon of a single gene determining several distinct and seemingly unrelated characteristicse.g. Many aboriginal Maori men have respiratory problems and are sterileDefects due to mutations in a gene required for functions of cilia (failure to clear lungs) and flagella (immotile sperm)With some pleiotropic genes Heterozygotes can have a visible phenotypeHomozygotes can be inviable (e.g. AY allele of agouti gene in mice, see Fig 3.9)Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*The AY allele produces a dominant coat color phenotype in miceAY allele of agouti gene causes yellow hairs with no blackCross agouti x yellow miceProgeny in 1:1 ratio of agouti to yellowYellow mice must be heterozygous for A and AYAY is dominant to ACopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Fig. 3.9aThe AY allele is a recessive lethal alleleCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Figure 3.9bAY is dominant to A for hair color, but is recessive to A for lethalityCross yellow x yellow miceF1 mice are 2/3 yellow and 1/3 agouti2:1 ratio is indicative of a recessive lethal allelePure-breeding yellow (AYAY) mice cannot be obtained because they are not viableExtensions to Mendel's analysis explain alterations of the 3:1 monohybrid ratioCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Table 3.1A comprehensive example: Sickle-cell diseaseHemoglobin transports oxygen in RBCsTwo subunits – alpha (α) globin and beta (β) globinMutations in β-globin gene cause β-thallasemiaMost common mutation of β-globin (HbβS) causes sickle-cell diseasePleiotropic – affects >1 trait (deformed RBCs, anemia, heart failure, resistance to malaria)Recessive lethality – heart failureDifferent dominance relations for different phenotypic aspects of sickle-cell disease (see Figure 3.10)Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Pleiotropy of sickle-cell anemia: Dominance relations vary with the phenotype under considerationCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Fig. 3.10Extensions to Mendel for multifactorial inheritanceTwo genes can interact to determine one traitNovel phenotypes can result from gene interactions, e.g. seed coat in lentilsComplementary gene action, e.g. flower colorEpistasis, e.g. dog fur, Bombay phenotype in humans, squash color, chicken feather color In all of these cases, F2 phenotypes from dihybrid crosses are in a variation of the 9:3:3:1 ratio expected for independently assorting genesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Novel phenotypes resulting from gene interactions, e.g. seed coat in lentilsCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Dihybrid cross of lentils, tan x gray All F1 seeds are brownF2 progeny:9/16 brown3/16 tan3/16 gray1/16 green9:3:3:1 ratio in F2 suggests two independently assorting genes for seed coat colorFig. 3.11aResults of self-crosses of F2 lentils supports the two-gene hypothesisCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Figure 3.11b*This 1: 1: 2: 2: 1: 1: 2: 2: 4 F2 genotypic ratio corresponds to a 9 brown: 3 tan: 3 gray: 1 green F2 phenotypic ratioSorting out the dominance relations by select crosses of lentilsF2 phenotypes from dihybrid crosses will be in 9:3:3:1 ratio only when dominance of alleles at both genes is complete Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Figure 3.11cComplementary gene action in sweet peas*Figure 3.12aCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3Purple F1 progeny are produced by crosses of two pure-breeding white linesComplementary gene action generates purple flower color in sweet peasCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Figure 3.12bDihybrid cross generates 9:7 ratio in F2 progeny9/16 purple (A—B—)7/16 white (A— bb, aa B—, aa bb)Possible biochemical explanation for complementary gene action for flower color in sweet peasOne pathway has two reactions catalyzed by different enzymesAt least one dominant allele of both genes is required for purple pigmentHomozygous recessive for either or both genes results in no pigmentCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Figure 3.13Epistasis results from the effects of an allele at one gene masking the effects of another geneThe gene that does the masking is epistatic to the othergeneThe gene that is masked is hypostatic to the other geneEpistasis can be recessive or dominantRecessive – epistatic gene must be homozygous recessive (e.g. ee)Dominant – epistatic gene must have at least one dominant allele present (e.g. E—)Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Recessive epistasis in Golden Labrador dogs9:3:4 ratio in F2 progeny of dihybrid crosses indicates recessive epistasis9/16 black (B— E—)3/16 brown (bb E—)4/16 yellow (B— ee, bb ee)Genotype ee masks the effect of all B genotypesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Figure 3.14aRecessive epistasis in humans with a rare blood typeGene for substance H is epistatic to the ABO geneWithout the H substance, there is nothing for the A or B sugar to attach toAll type A, type AB, type B, and type O people are H—People with hh genotype will appear to be type OCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Figure 3.14bDominant epistasis I in summer squash12:3:1 ratio in F2 progeny of dihybrid crosses indicates dominant epistasis I12/16 white (A— B—, aa B—)3/16 yellow (A— bb)1/16 green (aa bb) The dominant allele of one gene masks both alleles of another gene Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Figure 3.15aDominant epistasis II in chickens 13:3 ratio in F2 progeny of dihybrid crosses indicates dominant epistasis II13/16 white (A— B—, aa B—,aa bb)3/16 colored (A— bb)The dominant allele of one gene masks the dominant allele of another gene Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Figure 3.15bSummary of gene interactions discussed in this chapterObserving the F2 ratios below is diagnostic of the type of gene interactionThese F2 ratios occur only in dihybrid crosses where there is complete dominance Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3Table 3.2Heterogeneous traits and the complementation testHeterogeneous traits have the same phenotype but are caused by mutations in different genese.g. deafness in humans can be caused by mutations in ~ 50 different genesComplementation testing is used to determine if a particular phenotype arises from mutations in the same or separate genesCan be applied only with recessive, not dominant, phenotypesDiscussed more in Chapter 7Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Genetic heterogeneity in humans: Mutations in many genes can cause deafnessCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Fig. 3.16Interaction of two incompletely dominant genes can produce nine phenotypes Example, two genes A and B:Allele A is incompletely dominant to allele a Allele B is incompletely dominant to allele bFor each gene, two alleles generate three phenotypesF2 progeny have 32 phenotypesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Fig. 3.17F1 (all identical)F2Breeding studies help determine inheritance of a traitHow do we know if a trait is caused by one gene or by two genes that interact?Example: dihybrid cross of pure-breeding parents produces three phenotypes in F2 progenyIf single gene with incomplete dominance, then F2 progeny should be in 1:2:1 ratioIf two independently assorting genes and recessive epistasis, then F2 progeny should be in 9:3:4 ratioFurther breeding studies can reveal which hypothesis is correctCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Two hypotheses to explain phenotypes in F2 progeny of mice with different coat colorsAre these F2 progeny in a ratio of 9:3:4 or 1:2:1?Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Fig. 3.18 (top)Specific breeding tests can help decide between two hypothesesHypothesis 1 – two genes with recessive epistasisHypothesis 2 – one gene with incomplete dominance*Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3Figure 3.18 (bottom)Family pedigrees help unravel the genetic basis of ocular-cutaneous albinism (OCA)Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*OCA is another example of heterogeneityFig. 3.19The same genotype does not always produce the same phenotypeIn all of the traits discussed so far, the relationship between a specific genotype and its corresponding phenotype has been absolutePhenotypic variation for some traits can occur because of:Differences in penetrance and/or expressivityEffects of modifier genesEffects of environment Pure chance Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Phenotype often depends on penetrance and/or expressivityPenetrance is the percentage of a population with a particular genotype that shows the expected phenotypeCan be complete (100%) or incomplete (e.g. penetrance of retinoblastoma is 75%)Expressivity is the degree or intensity with which a particular genotype is expressed in a phenotypeCan be variable or unvaryingCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Some traits result from different genes that do not contribute equally to the phenotypeModifier genes alter the phenotypes produced by alleles of other genesCan have major effect or more subtle effectsExample: T locus of miceMutant T allele causes abnormally short tailIn some inbred strains, mice with T allele have tails that are 75% the length of normal tailsIn other inbred strains, mice with the same T mutation have tails that are 10% the length of normal tailsDifferent inbred strains must carry alternative alleles of a modifier gene for the T mutant phenotype Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Environmental effects on phenotypeTemperature is a common element of the environment that can affect phenotypeExample 1: Coat color in Siamese catsExtremities are darker than body because of a temperature sensitive alleleExample 2: Survivability of a Drosophila mutantShibire mutants develop normally at 29oCConditional lethal mutations are lethal only under some conditionsPermissive conditions - mutant allele has wild-type functionsRestrictive conditions - mutant allele has defective functions Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*A temperature sensitive mutation affects coat color in Siamese catsCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Fig. 3.20Other effects of environment on phenotypePhenocopy - phenotype arising from an environmental agent that mimics the effect of a mutant geneNot heritableCan be deleterious or beneficialExamples in humansThalidomide produced a phenocopy of phocomelia, a rare dominant trait Children with heritable PKU can receive a protective dietGenetic predisposition to cardiovascular disease can be influenced by diet and exerciseGenetic predisposition to lung cancer is strongly affected by cigarette smokingCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Mendelian principles can also explain continuous variationDiscontinuous traits give clear-cut, "either-or" phenotypic differences between alternative allelesExample: All of the traits Mendel studied in peas were discontinuousContinuous traits are determined by segregating alleles of many genes that interact together and with the environmentExamples in humans: height, weight, skin colorOften appear to blend and "unblend"Also called quantitative traits because the traits vary over a range that can be measuredUsually polygenic – controlled by multiple genesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*Two continuous traits in humanHeight is a continuous traitSkin color is a continuous trait*Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3Fig. 3.21Mendelian explanation of continuous variationThe more genes or alleles, the more possible phenotypic classes and the greater the similarity to continuous variation*Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3In these examples, all of the alleles are incompletely dominant and have additive effectsFig. 3.22 (partial)*Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3Mendelian explanation of continuous variation(continued)The more genes or alleles, the more possible phenotypic classes and the greater the similarity to continuous variationIn these examples, all of the alleles are incompletely dominant and have additive effectsFig. 3.22 (partial)Gene 1: Agouti or other color patternsWild-type (A) allele specifies bands of yellow and black on each hairAY allele specifies solid yellow (no black)a allele specifies solid black (no yellow)at allele specifies black on the back and yellow on the bellyDominance series for coat color: AY > A > at > aDominance series for survivability: A = at = a > AYCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*A comprehensive example: Mouse coat color is determined by multiple alleles of several genesA comprehensive example: Mouse coat color is determined by multiple alleles of several genesGene 2: Black or brown with yellow bandsGene that specifies dark color in hair has two alleles: B specifies black and b specifies brownAY acts in dominant epistatic manner to B geneA— B— genotype gives wild-type agouti color (black and yellow bands)A— bb genotype gives cinnamon color (brown and yellow bands)aa bb gives solid brown (no yellow bands)atat bb has brown on back and yellow on bellyCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*A comprehensive example: Mouse coat color is determined by multiple alleles of several genesGene 2: Black or brown with yellow bands (continued)Progeny of dihybrid cross of AYa Bb (yellow) x AYa Bb (yellow) is an example of dominant epistasis and recessive lethality8/12 yellow (AYa BB, AYa Bb, and AYa bb)3/12 black (aa B—)1/12 brown (aa bb)4/16 of total progeny will be inviable (AYAY ——)Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*A comprehensive example: Mouse coat color is determined by multiple alleles of several genesGene 3: Albino or pigmentedC gene controls function of enzyme required for pigment synthesisC gene acts in a recessive epistatic manner to all other genes that control coat colorHomozygous recessive (cc) are pure white, regardless of A or B genes (or other colors)C— mice are agouti, black, brown, yellow, or black and yellow depending on alleles at A and B genesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th ed., Chapter 3*