Essentials of Genetics Chapter 4 PDF

Essentials of Genetics 9th Edition William Klug, Michael Cummings, Charlotte Spencer, Michael Palladino CHAPTER 4 Modifications of Mendelian Ratios Lectures Adapted by Dr. Amin Majdalawieh American University of...

Essentials of Genetics 9th Edition William Klug, Michael Cummings, Charlotte Spencer, Michael Palladino CHAPTER 4 Modifications of Mendelian Ratios Lectures Adapted by Dr. Amin Majdalawieh American University of Sharjah  Alleles Alter Phenotypes in Different Ways ► There are different modes of inheritance, and this has to do with understanding the potential function of alleles. ► Alternative forms of a gene are called alleles. ► Mutation is the source of alleles. ► The wild-type allele is the one that occurs most frequently in nature and is usually, but not always, dominant (e.g. purple flowers in the case of garden peas). ► Wild-type alleles are responsible for the corresponding wild-type phenotype. ► The wild-type phenotype is usually taken as a “standard” for comparison during genetic analysis.  Alleles Alter Phenotypes in Different Ways ► Since mutations are the source of alleles, a new allele will only be recognized if it causes a change in the phenotype of the organism being studied. ► The change of phenotype reflects a change in the functional activity of the cellular product of the gene in question. ► Often, a mutation causes the reduction or loss of the specific wild- type function. ► Such a case is called a “loss of function mutation”. ► If the loss is complete, the mutation has resulted in what is called a null allele. ► Inversely, other mutations may enhance the function of the wild-type product, representing a “gain of function mutation”. ► Conversion of a proto-oncogene into an oncogene is an example of “gain of function mutation”.  Alleles Alter Phenotypes in Different Ways ► Sometimes, mutations do NOT lead to a change in the function of the gene product (silent mutations). ► Phenotypic traits may be influenced by more than one gene and the allelic forms of each gene involved (e.g. complex enzymatic reactions involve more than one enzyme!). Whether enzyme 1, enzyme 2, OR enzyme 3 is mutated, the end product will NOT be yielded  Geneticists Use a Variety of Symbols for Alleles ► Dominant alleles are usually indicated by an italic uppercase letter (D). ► Recessive alleles are usually indicated by an italic lowercase letter (d). ► The contrasting wild-type trait is denoted by a letter plus the superscript +, whereas the mutant trait is denoted by the same letter only (without the superscript +). ► Example: ebony is a recessive body color mutation in Drosophila gray is the wild-type body color GG (or e+/e+) gray homozygote (wild-type) Gg (or e+/e) gray heterozygote (wild-type) gg (e/e) ebony homozygote (mutant)  Geneticists Use a Variety of Symbols for Alleles ► If NO dominance exists, italic uppercase letters and superscripts are used to denote alternative alleles (R1, R2, CW, CR, LM, LN). ► Usually, the selected symbol reflects the function of the studied gene or even the disorder caused by a mutant gene.  A Note About All Forms of Inheritance ► Patterns of inheritance are the same (meiosis still applies, segregation, independent assortment = no linked genes, yet) ► Can still be expressed using Punnett squares, but……allele interactions are NOT simply dominant/recessive, you must know how the alleles interact. Y y Y y Y Y y y  Neither Allele Is Dominant in Incomplete, or Partial, Dominance ► In incomplete dominance (partial dominance): Neither trait is completely dominant Offspring from a cross between parents with contrasting traits may have an intermediate phenotype Heterozygous individuals produce intermediate phenotypes, Only ½ as much protein product produced (only 1 working homologous chromosome) → intermediate phenotype  Neither Allele Is Dominant in Incomplete, or Partial, Dominance ► The phenotypic ratio is identical to the genotypic ratio in cases of incomplete dominance. R1 R1 R1 R2 R1 R1 R1 R2 R2 R1 R2 R1 R2 R1 R1 R1 R1 R2 R2 R1 R2 R1 R2 R1 R2 R2 R1 R2 R2 R2 R2 R2 Figure 4.1  Neither Allele Is Dominant in Incomplete, or Partial, Dominance ► Note that clear-cut cases of incomplete dominance are rare! ► Usually, there is an intermediate expression of the phenotype. ► So, when it comes to gene expression, a cell can produce the gene product on a scale from 0 to 100 (not just 0%, 50%, or 100%). ► The threshold effect comes about if normal phenotypic expression occurs whenever a certain level (usually 50%) of gene product is attained. ► Unfortunately, in many cases (e.g. enzymes), ~ 50% expression is NOT sufficient to undergo proper cellular activities.  In Codominance, the Influence of Both Alleles in a Heterozygote Is Clearly Evident ► Codominance occurs when joint expression of two alleles of a gene in a heterozygote results in phenotypic detection of both gene products. ► Different alleles at a gene locus both produce a detectable gene product (protein). ► In heterozygous individuals, both alleles are expressed in the phenotype without dilution. ► One example is the MN blood group (glycoproteins expressed on RBCs). AB GENOTYPE PHENOTYPE A B LM LM M A AA AB LM LN MN A LN LN N B B AB BB  Multiple Alleles of a Gene May Exist in a Population ► Multiple alleles (>2) can be studied only in populations, because any individual will have at most two alleles of the same gene. ► The ABO blood groups are an example of multiple alleles. ► Each individual is A, B, AB, or O phenotype as a result of dominance of the IA and IB alleles to the IO allele, and codominance of the IA and IB alleles to each other. ► A, B and O are the three alleles that can occupy a locus. ► Since A and B are codominant & both are dominant to the O allele, A produces A blood antigens. B produces B blood antigens. AB produces both A and B antigens (codominant). O produces no antigens (recessive to A and B).  ABO Blood Types AA = A phenotype AO = A phenotype BB = B phenotype BO = B phenotype AB = AB phenotype OO = O phenotype  ABO Blood Types ► Both the IA allele and the IB allele encode enzymes (glycosyltransferases) that can add a “sugar” to the H substance. ► The IA allele is responsible for an enzyme (UDP-GalNAc – FUT1) that can add a terminal sugar N-acetylgalactosamine (AcGalNH) to the H substance. ► The IB allele is responsible for a modified enzyme (UDP-Gal – FUT1) that cannot add N-acetylgalactosamine but instead can add a terminal galactose to the H substance. ► The O phenotype results from an absence of both terminal sugars.  The Bombay Phenotype ► In 1952, a woman in Bombay was first characterized to display the O blood group despite the fact that her parents were A and AB! ► A gene called FUT1 (encoding an enzyme called fucosyl transferase) is defective in individuals with the Bombay phenotype. ► The mutation prevents the transfer of A and B antigens to the surface of RBCs, leading to an “O” blood type. Figure 4.2  Lethal Alleles Represent Essential Genes ► When homozygous, some alleles are lethal. ► Tay-Sachs disease is one example. ► A loss of function mutation can sometimes be tolerated in the heterozygous state, but may behave as a recessive lethal allele in the homozygous state. ► In this case, homozygous recessive individuals will NOT survive. ► “Lethal” may indicate that individuals with this genotype are NOT born (in which case the typical Mendelian phenotype ratios do NOT occur), or death can occur later in life.  Lethal Alleles Represent Essential Genes ► The allele responsible for a lethal effect when it is homozygous can also result in a distinctive mutant phenotype when it is heterozygous. ► Such an allele is behaving as a recessive lethal, but is dominant with respect to the phenotype. A A = agouti “wild type” mouse A AY = yellow mouse AYAY = mouse is not born, as fetus does not develop properly = (dead mouse) Figure 4.3  Lethal Alleles Represent Essential Genes ► In some cases, a mutation can be a dominant lethal allele, in which case the dominant homozygotes & heterozygotes will NOT survive. ► Huntington disease is one example. ► For dominant lethal alleles to exist, the affected individual must reproduce before dying!  Combinations of Two Gene Pairs Involving Two Modes of Inheritance Modify the 9:3:3:1 Ratio ► Mendel’s principle of independent assortment applies to situations in which two modes of inheritance occur simultaneously, provided that the genes controlling each character are NOT linked on the same chromosome. ► The probability of each phenotype arising in a cross can be determined by the forked-line method or by Punnett square, assuming that the genes under consideration undergo independent assortment. »»» Consider mating two humans who are: both heterozygous for the autosomal recessive gene that causes albinism both have AB blood type Combinations of Two Gene Pairs Involving Two Modes of Inheritance Modify the 9:3:3:1 Ratio 3:6:3:1:2:1 Modification of the 9:3:3:1 ratio in Mendelian dihybrid crosses! Figure 4.4  Phenotypes Are Often Affected by More Than One Gene ► What if the phenotypic expression of one gene depends upon another gene? ► It is common for complex structures to depend upon the input of many genes. This is called “gene interaction”. ► Gene interaction is the basis behind the complexity of phenotypes (Drosophila eyes: shape, size, texture, color) ► In many cases, one gene product (A) is modified by other gene products later, but if gene product (A) is not produced, later genes cannot be expressed (i.e. dependence). ► Many traits characterized by a distinct phenotype are affected by more than one gene. ► In gene interaction, the cellular function of numerous gene products contributes to the development of a common phenotype.  Phenotypes Are Often Affected by More Than One Gene ► Epistasis (Greek for “stoppage”) is a phenomenon that results because of complex gene interactions. ► Epistasis occurs when: one gene masks the effect of another gene (i.e. antagonistic interaction) OR two gene pairs complement each other such that one dominant allele is required at each locus to express a certain phenotype (complementary/cooperative interaction) ► For example, the homozygous presence of a recessive/dominant allele prevents or overrides the expression of other alleles on a second locus (or several other loci). Such a recessive/dominant allele is “epistatic” to those suppressed alleles (called hypostatic).  Phenotypes Are Often Affected by More Than One Gene ► The Bombay phenotype for ABO blood groups is an example of epistasis in which the homozygous recessive condition at one locus masks the expression of a second locus. ► A gene called FUT1 (encoding an enzyme called fucosyl transferase) is defective in individuals with the Bombay phenotype. ► The mutation prevents the transfer of A and B antigens to the surface of RBCs, leading to an O blood type. ► The homozygous presence of the mutant allele of FUT1 masks the expression of the IA and IB alleles. ► So, only individuals with at least one copy of the wild-type (dominant) allele of FUT1 can potentially express A and B antigens. ► Hence, individuals who have IA and/or IB but completely lack the wild-type FUT1 allele will have O blood type.  Phenotypes Are Often Affected by More Than One Gene NOTE: No Type O (1) Although it is a !!! dihybrid cross, only one trait is being analyzed. (2) Although only one trait is being analyzed, the phenotypic ratio is 3:6:3:4 expressed as sixteenths Modification of the (not fourths)! 9:3:3:1 ratio in Mendelian dihybrid crosses! Figure 4.6  Phenotypes Are Often Affected by More Than One Gene ► What if two people heterozygous for making H substance (Hh) and with blood type AB had a child: what are the possible phenotypes, and their phenotypic ratios? HhAB x HhAB (use a Punnett square) HHAB = type AB HhAB = type AB hhAB = type O HHAA = type A HhAA = type A hhAA = type O HHBB = type B HhBB = type B hhBB = type O  Phenotypes Are Often Affected by More Than One Gene 6:4:3:3 phenotypic ratio HhAB HA HB hA hB HA HHAA HHAB HhAA HhAB H HB HHAB HHBB HhAB HhBB h A hA HhAA HhAB hhAA hhAB B hB HhAB HhBB hhAB hhBB Copyright © 2009 Pearson Education, Inc.  A Biological Example of Epistasis ► One gene controls whether hair pigment is produced in mice. ► When the homozygous recessive allele of this gene is present, mice hair will have NO pigment. AA = pigment Aa = pigment aa = no pigment (white) ► A separate gene controls the pattern of the hair pigment: agouti (dominant, Cc or CC = brown) solid (recessive, cc = black)  A Biological Example of Epistasis Use Punnet square for CcAa x CcAa cross (epistasis) C = agouti coat c = black coat C cAa A= pigment a = no pigment C c A a  A Biological Example of Epistasis CcAa 9:4:3 phenotypic ratio CA Ca cA ca (Non-Mendelian ratio in a dihybrid cross) CA CCAA CCAa CcAA CcAa C Ca CCAa CCaa CcAa Ccaa c A cA CcAA CcAa ccAA ccAa a ca CaAa Ccaa ccAa ccaa  Phenotypes Are Often Affected by More Than One Gene ► Eight cases of epistasis are described below. ► These include: recessive epistasis (case 1) dominant epistasis (case 2) complementary gene interaction (case 3) Figure 4.7  Complementation Analysis Can Determine if Two Mutations Causing a Similar Phenotype are Alleles ► Two mutations from different strains result in the same phenotype. Are they alleles of the same gene? Are they mutations of different genes? ► Test this by crossing two individuals with the different mutations, and analyze the phenotype of the resulting F1 offspring. ► Two cases of mutation in Drosophila Case 1: All offspring develop normal wings Case 2: All offspring develop no wings Complementation Analysis Figure 4.9  Complementation Analysis ► Another example of this would be the “Bombay phenotype” and O blood type. O H A h ________ _____ _______ ____ O H A h ► Crossing an OOHH individual (blood type O) with an AAhh individual (blood type O) → a person with type A blood! (AOHh)  Expression of a Single Gene May Have Multiple Effects ► Pleiotropy occurs when expression of a single gene has multiple phenotypic effects, and it is quite common. ► Examples of pleiotropy are Marfan syndrome and porphyria variegata (no unique signs or symptoms).  X-Linkage Describes Genes on the X Chromosome ► Genes present on the X chromosome exhibit unique patterns of inheritance due to the presence of only one X chromosome in males. ► Males cannot be homozygous or heterozygous for X-linked genes, and this condition is called hemizygous. ► One result of X-linkage is the crisscross pattern of inheritance, whereby the phenotypic traits controlled by recessive X-linked genes are passed form homozygous mothers to ALL sons. ► Drosophila eye color was one of the first examples of X-linkage described. X-Linkage in Drosophila Figure 4.10 X-Linkage in Drosophila Figure 4.11  Section 4.11 X-Linkage in Humans ► In humans, many genes are linked to the X chromosome. ► Such X-linked traits can easily be identified in a pedigree because of the crisscross pattern of inheritance. ► Color blindness in humans is one example of X-linkage. Human X-Linked Traits  In Sex-Limited and Sex-Influenced Inheritance, an Individual's Sex Influences the Phenotype ► Sex-limited inheritance occurs in cases where the expression of a specific phenotype is absolutely limited to one sex. ► Sex-influenced inheritance occurs when the sex of an individual influences the expression of a phenotype that is not limited to one sex or the other. ► In sex-limited and sex-influenced inheritance, expression of autosomal genes responsible for a certain phenotype depends on the hormone constitution of the individual. ► Thus, one phenotype may be expressed in males and another in females.  In Sex-Limited and Sex-Influenced Inheritance, an Individual's Sex Influences the Phenotype ► Pattern baldness is an example of sex-influenced trait. ► Females can be bald, but only if homozygous BB. ► Males are bald if homozygous BB or heterozygous Bb. ► Female baldness is less pronounced than male baldness. Genotype Phenotype FEMALES MALES BB Bald Bald Bb Not bald Bald bb Not bald Not bald Figure 4.14  Genotypic Background and the Environment May Alter Phenotypic Expression ► Phenotypic expression of a trait may be influenced by the environment as well as by the genotype. ► The degree of expression depends on the penetrance and expressivity of the mutant genotype. ►“Penetrance” of a mutant gene refers to the percentage of genotypically recessive individuals that exhibit the recessive phenotype (regardless of degree/range). It is a “yes or no” answer. If fruit flies are homozygous recessive for the “eyeless” allele, some may still develop eyes! If 90% of homozygous recessive flies do not develop eyes, then the penetrance is 90%. ►“Expressivity” reflects the degree/range of expression of the mutant phenotype.  Variable Expressivity The effects of penetrance and expressivity through a hypothetical character “pigment intensity.” In each row, all individuals have the same allele giving them the same “potential to produce pigment.” However, effects deriving from the rest of the genome and from the environment may suppress or modify pigment production in some individual. Figure 4.15  Genetic Background: Suppression & Position Effects ► Although it is difficult to assess the specific effect of the genetic background and the expression of a gene responsible for determining a potential phenotype, two effects of genetic background have been well characterized. ► First, genetic suppression occurs when other genes affect the phenotype produced by the gene in question. ► Second, the physical location of a gene may influence its expression due to a position effect. If a region of a chromosome is relocated or rearranged (translocation or inversion event), normal expression of genes in that chromosomal region may be modified (especially if translocation happens in a genetically inert, condensed area of the chromosome (heterochromatin).  Genetic Background: Temperature & Nutrition Effects ► Chemical activity depends on the kinetic energy of the reacting substances, which depends on the surrounding temperature. ► Mutations affected by temperature are called “conditional or temperature-sensitive” mutations. ► They are useful in studying mutations that affect essential processes. ► Nutritional mutations may prevent the phenotype from reflecting the genotype. ► Examples include mutations in a biosynthetic pathway. Figure 4.16  Genetic Background: Genetic Anticipation ► Genetic anticipation as an idea was put forward in 1992. ► As a result of genetic anticipation, some heritable disorders exhibit a progressively earlier age of onset with an increased severity in each generation. ► For some human disorders, there is extreme variation in the severity of symptoms (normal, mild, medium, severe). ► In myotonic dystrophy (MD), normal individual (~5 copies of mutated regions) mildly affected (~50 copies of mutated regions) severely affected (>1000 copies of mutated regions) ► Remarkably, the size of the repeated segments increases with successive generations (i.e. earlier onset of severity).  Genetic Background: Genomic Imprinting ► Genomic imprinting was first discovered in 1991. ► In cases of genomic (parental) imprinting, phenotypic expression may depend on the parental origin of the chromosome. ► Imprinting is thought to occur before or during gamete formation and may involve DNA methylation (added methyl groups interfere with gene expression/transcription). ► Alleles may be inactivated when present in the gametes of one sex, but this does not occur in the gametes of the other sex (i.e. a gene may be inactivated within cells leading to production of an egg in the mother, but not inactivated in cells that become sperm in the father ). Genomic Imprinting Figure 4.17  Extranuclear Inheritance Modifies Mendelian Patterns ► Patterns of inheritance sometimes vary from that expected during the biparental transmission of nuclear genes. ► Phenotypes most often appear to result from extranuclear genetic information transmitted through the egg (maternal effect). ► Organelle heredity is based on the genotypes of chloroplast and mitochondrial DNA. ► Chloroplast mutations affect the photosynthetic capabilities of plants, whereas mitochondrial mutations affect energy homeostasis. IGNORE the details on pages 81-85