LECTURE 9 Extensions of Mendel’s First Law (Chapter 4) INTRODUCTION • Mendel's First Law states that: – Adults are diploid; gametes are haploid – Each trait is controlled by a single gene • For the traits Mendel studied in pea, the following were also true: – – – – – – Each gene has two alternative alleles One allele is completely dominant over the other All gametes are equally viable Mating is random All offspring are equally viable Genotype always determines phenotype • Hence Mendel observed a 3:1 phenotypic ratio when two heterozygotes (dihybrids) are crossed INTRODUCTION • In this lecture we will examine traits that do not result in a 3:1 phenotypic ratio when two dihybrids (heterozygotes) are crossed • Can be due to one of two reasons – Extensions: Mendel's First Law is operating (adults are diploid and gametes are haploid one gene controls the trait) but some of the other assumptions underlying the 3:1 phenotypic ratio are not met – Violations: Mendel's First Law is NOT operating • Adults are not always diploid; gametes are not always haploid • More than one gene controls the trait Mendel Extension OR Violation One allele is completely dominant over the other in all instances EXTENSION: Alleles may be Incompletely Dominant or Codominant; alleles can be dominant in one sex and recessive in the other (Sex Influenced); some alleles are expressed in only one sex (Sex Limited) All offspring from a cross are equally viable EXTENSION: Some genotypes survive better than others; some genotypes may actually be fatal; Overdominance, lethal alleles, semi-lethal alleles Genotype does not always determine phenotype EXTENSION: AA does not always exhibit the dominant phenotype, etc. Incomplete penetrance, variable expressivity Adults are diploid for all genes and gametes are haploid for all genes VIOLATION: Males are haploid for X-linked genes; gametes are nulliploid; Females are nulliploid for Y (Sex linkage); Some adults have more than two sets of genes (polyploidy); Some "adults" are halpoid (haploidy - e.g. yeast); Some organisms are both (Alternation of generations - e.g. moss) More than one gene controls a trait VIOLATION: Often (in fact most of the time) traits are controlled by more than one gene (Gene interactions) Complete Dominance • In a simple dominant/recessive relationship, the recessive allele does not affect the phenotype of the heterozygote • Usually, the mutant allele is recessive to the wild-type because of one of the following: – 1. 50% of the normal protein is enough to accomplish the protein’s cellular function • Refer to Figure 4.2 – 2. The heterozygote may actually produce more than 50% of the functional protein • The normal gene is “up-regulated” to compensate for the lack of function of the defective allele Figure 4.2 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Dominant (functional) allele: P (purple) Recessive (defective) allele: p (white) Genotype PP Pp pp Amount of functional protein P 100% 50% 0% Phenotype Purple Purple White Simple dominant/ recessive relationship • But ... mutations are sometimes dominant – Much less common than recessive – Three explanations for most dominant mutations • Gain-of-function – Protein encoded by the mutant gene is changed so it gains a new or abnormal function • Dominant-negative – Protein encoded by the mutant gene acts antagonistically to the normal protein (also called a "poisonous allele") • Haploinsufficiency – mutant is loss-of-function – heterozygote does not make enough product to give the wild type phenotype Incomplete Dominance • In incomplete dominance the heterozygote exhibits a phenotype that is intermediate between the corresponding homozygotes and different from either one • Example: – Flower color in the four o’clock plant – Two alleles • CR = wild-type allele for red flower color • CW = allele for white flower color – Note how the nomenclature has changed from Cc to superscripts ("C" is still the gene) Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Figure 4.3 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Red White P generation CRCR Gametes CR 1:2:1 phenotypic ratio NOT the 3:1 ratio observed in simple Mendelian inheritance CW CW x CW Pink F1 generation CRCW Gametes CR or CW Self-fertilization Sperm F2 generation CR CW CRCR CRCW CRCW CW CW CR Egg CW In this case, 50% of the CR protein is not sufficient to produce the red phenotype Incomplete Dominance • Whether a trait is dominant or incompletely dominant may depend on how closely the trait is examined • Take, for example, the characteristic of pea shape – Mendel visually concluded that • RR and Rr genotypes produced round peas • rr genotypes produced wrinkled peas – However, a microscopic examination of round peas reveals that not all round peas are “created equal” • Refer to Figure 4.4 Figure 4.4 Copyright © The McGraw-Hill Companies, Inc. 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Dominant (functional) allele: R (round) Recessive (defective) allele: r (wrinkled) Genotype RR Rr rr Amount of functional (starch-producing) protein 100% 50% 0% Phenotype Round Round Wrinkled With unaided eye (simple dominant/ recessive relationship) With microscope (incomplete dominance) Codominance • In Codominance, heterozygotes express the phenotypes of both parents • The ABO blood group provides an example – Phenotype (A, B, AB or O) is determined by the type of antigen present on the surface of red blood cells – Antigens are substances that are recognized by antibodies produced by the immune system • As shown in Figure 4.11, there are three different alleles that determine which antigen(s) are present on the surface of red blood cells – Allele IA, adds antigen A to H antigen – Allele IB, adds antigen B to H antigen – Allele i, doesn't add anything to H antigen • Allele i is recessive to both IA and IB • Alleles IA and IB are codominant – They are both expressed in a heterozygous individual Antigen A Antigen B RBC RBC Antigen A Antigen B H antigen RBC N-acetylgalactosamine Galactose RBC Blood type: O A B AB Genotype: ii IAIA or IAi IBIB or IBi IAIB neither A or B against A and B A against B B against A Surface antigen: Serum antibodies: (a) ABO blood type Figure 4.11a A and B none Figure 4.11c Antigen A Glycosyl transferase encoded by IA allele Active site RBC N-acetylgalactosamine Glycosyl transferase encoded by IB allele RBC Antigen B Active site RBC Galactose (c) Formation of A and B antigen by glycosyl transferase RBC Sex-influenced Traits • Traits where an allele is dominant in one sex but recessive in the opposite sex – Thus, sex influence is a phenomenon of heterozygotes • Sex-influenced does not mean sex-linked!! – Most sex-influenced traits are autosomal Sex-influenced Traits • Example: Pattern baldness in humans – Controlled by an autosomal gene with two alleles • Allele B* is dominant in males, but recessive in females Genotype Phenotype in Males Phenotype in Females B*B* pattern-bald late onset hair loss BB* pattern-bald nonbald BB nonbald nonbald Sex-influenced Traits • Pattern baldness in humans – In males, this trait is characterized by loss of hair on front and top of head but not on the sides © National Parks Service, Adams National Historical Park (a) John Adams (father) Figure 4.15 © National Parks Service, Adams National Historical Park b) John Quincy Adams (son) © National Parks Service, Adams National Historical Park (c) Charles Francis Adams (grandson) © Bettmann/Corbis (d) Henry Adams (great-grandson) Sex-influenced Traits Pattern baldness appears to be related to the production of the male sex hormone testosterone Pattern baldness results from overexpression of a gene that converts testosterone to 5-adihydrotestosterone (DHT) which binds to cellular receptors and alters expression of many genes In females, heterozygotes (Bb) are not bald Women who are homozygous for the baldness allele (BB) will develop the trait, characterized by a significant thinning of the hair relatively late in life The autosomal nature of pattern baldness has been revealed by analysis of human pedigrees Refer to Figure 4.16 Bald fathers can pass the trait to their sons I-1 IV-1 IV-2 I-2 II-1 II-2 II-3 II-4 II-5 II-6 II-7 II-8 III-1 III-2 III-3 III-4 III-5 III-6 III-7 III-8 III-9 III-10 IV-3 IV-4 IV-5 IV-6 IV-7 IV-8 IV-9 IV-10 IV-11 IV-12 (a) A pedigree for human pattern baldness Bb × Bb Sperm B Figure 4.16 b B BB Bald male Bald female Bb Bald male Nonbald female b bb Bb Nonbald male Bald male Nonbald female Nonbald female (b) Example of an inheritance pattern involving baldness I?V-13 IV-14 Sex-limited Traits • Traits that are expressed in only one of the two sexes • Responsible for sexual dimorphism – For example in humans • Breast development is normally limited to females • Beard growth is normally limited to males – In birds • Males have more ornate plumage • Usually due to presence/absence of a hormone Hereditary breast cancer Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. © robert Maier/Animals, Animals © robert Maier/Animals, Animals (b) Rooster Mendel Extension OR Violation One allele is completely dominant over the other in all instances EXTENSION: Alleles may be Incompletely Dominant or Codominant; alleles can be dominant in one sex and recessive in the other (Sex Influenced); some alleles are expressed in only one sex (Sex Limited) All offspring from a cross are equally viable EXTENSION: Some genotypes survive better than others; some genotypes may actually be fatal; Overdominance, lethal alleles, semi-lethal alleles Genotype does not always determine phenotype EXTENSION: AA does not always exhibit the dominant phenotype, etc. Incomplete penetrance, variable expressivity Adults are diploid for all genes and gametes are haploid for all genes VIOLATION: Males are haploid for X-linked genes; gametes are nulliploid; Females are nulliploid for Y (Sex linkage); Some adults have more than two sets of genes (polyploidy); Some "adults" are halpoid (haploidy - e.g. yeast); Some organisms are both (Alternation of generations - e.g. moss) More than one gene controls a trait VIOLATION: Often (in fact most of the time) traits are controlled by more than one gene (Gene interactions) Overdominance • Overdominance is the phenomenon in which a heterozygote is more vigorous than both of the corresponding homozygotes – It is also called heterozygote advantage • Usually due to one of three reasons: – Protection from microorganisms – Homodimer formation – Expansion of range of enzyme function Figure 4.8a • A microorganism will infect a cell if certain cellular proteins function optimally Heterozygotes have one altered copy of the gene Therefore, they have slightly reduced protein function This reduced function is not enough to cause serious side effects But it is enough to prevent infections Examples include Sickle-cell anemia and malaria Tay-Sachs disease Heterozygotes are resistant to tuberculosis Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Pathogen can successfully propagate. A1A1 Normal homozygote (sensitive to infection) Pathogen cannot successfully propagate. A1A2 Heterozygote (resistant to infection) (a) Disease resistance Figure 4.8b • Some proteins function as homodimers Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. – Composed of two different subunits – Encoded by two alleles of the same gene • A1A1 homozygotes – Make only A1A1 homodimers A2A2 homozygotes Make only A2A2 homodimers A1A2 heterozygotes Make A1A1 and A2A2 homodimers AND A1A2 homodimers For some proteins, the A1A2 homodimer may have better functional activity Giving the heterozygote superior characteristics A1 A1 A2 A2 (b) Homodimer formation A1 A2 Figure 4.8c • A gene, E, encodes a metabolic enzyme • Allele E1 encodes an enzyme that functions better at lower temperatures Copyright © The McGraw-Hill Companies, Inc. 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E1 E2 27°–32°C (optimum temperature range) 30°–37°C (optimum temperature range) (c) Variation in functional activity Allele E2 encodes an enzyme that functions better at higher temperatures E1E2 heterozygotes produce both enzymes Therefore they have an advantage in that they function over a wider temperature range than either E1E1 or E2E2 homozygotes Lethal and Semilethal Alleles • Essential genes are those that are absolutely required for survival – The absence of their protein product leads to a lethal phenotype • It is estimated that about 1/3 of all genes are essential for survival • Nonessential genes are those not absolutely required for survival • A lethal allele is one that has the potential to cause the death of an organism – These alleles are typically the result of mutations in essential genes – They are usually inherited in a recessive manner • Many lethal alleles prevent cell division – These will kill an organism at an early age • A lethal allele will produce ratios that deviate from Mendelian ratios • If recessive, the mutant phenotype will never be observed! – Though may lead to more miscarriages in the mother • If dominant and the homozygous dominant offspring do not survive (the usual case), the ratio will be 2 mutant: 1 normal – – – – – An example is the Manx cat Carries a dominant mutation that affects the spine This mutation shortens the tail This allele is lethal as a homozygote for the dominant allele Refer to Figure 4.18b Copyright © The McGraw-Hill Companies, Inc. 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Mm × (Manx) Mm (Manx) Sperm M DEATH M m Mm (Manx) 2 Manx for every one normal kitten Egg m Mm (Manx) mm (non-Manx) (b) Example of a Manx inheritance pattern Figure 4.18b Example of Manx Inheritance patterns Mendel's ratio has now changed to 2:1 • Semilethal alleles – Kill some individuals in a population, not all of them – If the allele is recessive, Mendel's ratio will be >3:1 • Many (but not all) in the "cc" category will die • "CC" and "Cc" categories are enriched relative to "cc" • E.g. 4:1, 15:1, 100:1, etc. depending on what fraction of "cc" offspring die – If the allele is dominant and the homozygous dominant offspring do not survive very well, the ratio will be somewhere between 2:1 (entirely lethal) and 3:1 (Mendelian - no lethality) Mendel Extension OR Violation One allele is completely dominant over the other in all instances EXTENSION: Alleles may be Incompletely Dominant or Codominant; alleles can be dominant in one sex and recessive in the other (Sex Influenced); some alleles are expressed in only one sex (Sex Limited) All offspring from a cross are equally viable EXTENSION: Some genotypes survive better than others; some genotypes may actually be fatal; Overdominance, lethal alleles, semi-lethal alleles Genotype does not always determine phenotype EXTENSION: AA does not always exhibit the dominant phenotype, etc. Incomplete penetrance, variable expressivity Adults are diploid for all genes and gametes are haploid for all genes VIOLATION: Males are haploid for X-linked genes; gametes are nulliploid; Females are nulliploid for Y (Sex linkage); Some adults have more than two sets of genes (polyploidy); Some "adults" are halpoid (haploidy - e.g. yeast); Some organisms are both (Alternation of generations - e.g. moss) More than one gene controls a trait VIOLATION: Often (in fact most of the time) traits are controlled by more than one gene (Gene interactions) Incomplete Penetrance • In some instances, a dominant allele does not influence the outcome of a trait in a heterozygote individual • Example = Polydactyly – Autosomal dominant trait – Affected individuals have additional fingers and/or toes • Refer to Figure 4.5 – A single copy of the polydactyly allele is usually sufficient to cause this condition – In some cases, however, individuals carry the dominant allele but do not exhibit the trait Figure 4.5 Copyright © The McGraw-Hill Companies, Inc. 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I-1 II-1 I-2 II-2 III-1 IV-1 IV-2 II-3 III-2 IV-3 II-4 III-3 II-5 III-4 III-5 Inherited the polydactyly allele from his mother and passed it on to a daughter and son Does not exhibit the trait himself even though he is a heterozygote Incomplete Penetrance • The term indicates that a dominant allele does not always “penetrate” into the phenotype of the individual • The measure of penetrance is described at the population level – If 60% of heterozygotes carrying a dominant allele exhibit the trait allele, the trait is 60% penetrant • Note: – In any particular individual, the trait is either penetrant or not Expressivity • Expressivity is the degree to which a trait is expressed • In the case of polydactyly, the number of digits can vary – A person with several extra digits has high expressivity of this trait – A person with a single extra digit has low expressivity • The molecular explanation of expressivity and incomplete penetrance may not always be understood • In most cases, the range of phenotypes is thought to be due to influences of the – Environment and/or other genes • Please note: A mutant phenotype can be: – BOTH incompletely penetrant and variably expressed – ONLY incompletely penetrant (everybody who exhibits the phenotype does so to the same degree – ONLY variably expressed (everyone expresses the phenotype associated with the genotype but to different degrees Mendel Extension OR Violation One allele is completely dominant over the other in all instances EXTENSION: Alleles may be Incompletely Dominant or Codominant; alleles can be dominant in one sex and recessive in the other (Sex Influenced); some alleles are expressed in only one sex (Sex Limited) All offspring from a cross are equally viable EXTENSION: Some genotypes survive better than others; some genotypes may actually be fatal; Overdominance, lethal alleles, semi-lethal alleles Genotype does not always determine phenotype EXTENSION: AA does not always exhibit the dominant phenotype, etc. Incomplete penetrance, variable expressivity Adults are diploid for all genes and gametes are haploid for all genes VIOLATION: Males are haploid for X-linked genes; gametes are nulliploid; Females are nulliploid for Y (Sex linkage); Some adults have more than two sets of genes (polyploidy); Some "adults" are halpoid (haploidy - e.g. yeast); Some organisms are both (Alternation of generations - e.g. moss) More than one gene controls a trait VIOLATION: Often (in fact most of the time) traits are controlled by more than one gene (Gene interactions) • Humans have 46 chromosomes – 44 autosomes – 2 sex chromosomes • Males contain one X and one Y chromosome – They are termed heterogametic • Females have two X chromosomes – They are termed homogametic • The Y chromosome determines maleness Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 44 + XY (a) X–Y system in mammals 44 + XX • In some insects, – Males are X0 and females are XX • In other insects (fruit fly, for example) – Males are XY and females are XX • The Y chromosome does not determines maleness • Rather, it is the ratio between the X chromosomes and the number of sets of autosomes (X/A) – If X/A = 0.5, the fly becomes a male – If X/A = 1.0, the fly becomes a female Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 22 + X (b) The X–0 system in certain insects 22 + XX • The sex chromosomes are designated Z and W to distinguish them from the X and Y chromosomes of mammals • Males contain two Z chromosomes – Hence, they are homogametic • Females have one Z and one W chromosome – Hence, they are heterogametic Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 76 + ZZ (c) The Z–W system in birds 76 + ZW and some fish • Males are known as the drones – They are haploid – Produced from unfertilized haploid eggs • Females include the worker bees and queen bees – They are diploid – Produced from fertilized eggs Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 16 haploid (d) The haplodiploid system in bees 32 diploid X-inactivation in Female Mammals • Evens out gene dosage between males and females – Both have only one functional X per cell – “All but one” rule – Barr body • In humans, wave of X-inactivation early in embryogenesis – Each cell makes an independent “decision” to turn off the paternal or maternal X – Females are “mosaic” if heterozygous for genes on the X chromosome X-Inactivation Tribble: B_D_S_XOXo Sex Chromosomes and Traits • Sex-linked genes are those found on one of the two types of sex chromosomes, but not both • X-linked – Hemizygous in males • Only one copy • Males are more likely to be affected • Y-linked – Relatively few genes in humans – Referred to as holandric genes – Transmitted from father to son Sex Chromosomes and Traits • Pseudoautosomal inheritance refers to the very few genes found on both X and Y chromosomes – Found in homologous regions needed for chromosome pairing during prophase of MI Mic2 gene X Y Figure 4.14 Mic2 gene Mendel Extension OR Violation One allele is completely dominant over the other in all instances EXTENSION: Alleles may be Incompletely Dominant or Codominant; alleles can be dominant in one sex and recessive in the other (Sex Influenced); some alleles are expressed in only one sex (Sex Limited) All offspring from a cross are equally viable EXTENSION: Some genotypes survive better than others; some genotypes may actually be fatal; Overdominance, lethal alleles, semi-lethal alleles Genotype does not always determine phenotype EXTENSION: AA does not always exhibit the dominant phenotype, etc. Incomplete penetrance, variable expressivity Adults are diploid for all genes and gametes are haploid for all genes VIOLATION: Males are haploid for X-linked genes; gametes are nulliploid; Females are nulliploid for Y (Sex linkage); Some adults have more than two sets of genes (polyploidy); Some "adults" are halpoid (haploidy - e.g. yeast); Some organisms are both (Alternation of generations - e.g. moss) More than one gene controls a trait VIOLATION: Often (in fact most of the time) traits are controlled by more than one gene (Gene interactions) GENE INTERACTIONS • Gene interactions occur when two or more different genes influence the outcome of a single trait • Indeed, morphological traits such as height weight and pigmentation are affected by many different genes in combination with environmental factors • We will look at three different cases, all involving two genes that exist in two alleles – NOTICE THAT TWO GENES ARE CONTOLLING A SINGLE TRAIT • Mendel would have predicted a 3:1 ratio • But when two genes control the same trait, you are really doing a dihybrid cross, not a monohybrid one! You just don't know it -- until you look at the cross data. A Cross Involving a Two-Gene Interaction Can Produce two distinct phenotypes • Inheritance of flower color in the sweet pea – Lathyrus odoratus normally has purple flowers • Bateson and Punnett obtained several true-breeding varieties with white flowers • They carried out the following cross – P: True-breeding purple X true-breeding white – F1: Purple flowered plants – F2: Purple- and white-flowered in a 3:1 ratio • These results were not surprising CCPP (purple) x ccpp (white) F1 generation Why would Mendel have expected to see a 3:1 ratio? All purple (CcPp) Self-fertilization F2 generation CP F2 generation Cp cP cp CP CCPP Purple CCPp Purple CcPP Purple CcPp Purple Cp CCPp Purple CCpp White CcPp Purple Ccpp White cP CcPP Purple CcPp Purple ccPP White ccPp White cp CcPp Purple Ccpp White ccPp White ccpp White Epistasis: Homozygosity for the recessive allele of either gene results in a white phenotype, thereby masking the purple (wild-type) phenotype. Both gene products encoded by the wild-type alleles (C and P) are needed for a purple phenotype. A Cross Involving a Two-Gene Interaction Can Produce three distinct phenotypes • Inheritance of coat color in laborador retrievers – A true-breeding black lab is crossed to a purebreeding yellow lab • F1 labs are all black – If two F1 animals are crossed, they produce offspring in the following ratios • 9 black • 3 chocolate • 4 albino • 9 B_C_ = black: 3 B_cc = chocolate: 4 bb__ = yellow BC Bc bC bc BC BBCC black BBCc black BbCC black BbCc black Bc BBCc black BBcc chocolate BbCc black Bbcc chocolate bC BbCC black BbCc black bbCC yellow bbCc yellow bc BbCc black Bbcc chocolate bbCc yellow bbcc yellow Gene Redundancy Geneticists have developed techniques to directly generate loss-of-function alleles This is called a gene knockout Allows scientists to understand the affects of the gene on structure or function of the organism Interestingly, many knockouts have no obvious phenotype Gene Redundancy This may be due to gene redundancy where one gene can compensate for the loss of function of another May be due to gene duplication Duplicate genes are called paralogs They are not identical because of accumulated mutations during evolution Gene Redundancy George Shull conducted the first studies on gene redundancy Studied a weed known as shepherd’s purse Trait followed was the shape of the seed capsule which is usually triangular Strains producing small ovate capsules are due to lossof-function alleles in two genes (ttvv) True breeding strains were crossed Triangular x Ovate F1 progeny were crossed to one another Refer to Figure 4.24 for results of the cross Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. x TTVV Triangular ttvv Ovate F1 generation TtVv All triangular F1 (TtVv) x F1 (TtVv) F2 generation TV Tv tV tv TTVV TTVv TtVV TtVv TTVv TTvv TtVv Ttvv TtVV TtVv ttVV ttVv TtVv Ttvv ttVv ttvv TV Tv tV tv Figure 4.24 A 15:1 ratio results from gene redundancy. Either dominant allele, T or V, is sufficient to give a triangular seed