Chapter 4 Extension of Mendelian Genetics PDF

Chapter 4: Extensions of Mendelian Genetics  Extension of Mendelian Genetics Two basic principles of gene transmission from parent to offspring: – Genes on the homolog chromosomes – Their segregation and independent assortment during gamete formation These gene sets d...

Chapter 4: Extensions of Mendelian Genetics  Extension of Mendelian Genetics Two basic principles of gene transmission from parent to offspring: – Genes on the homolog chromosomes – Their segregation and independent assortment during gamete formation These gene sets determine organism’s phenotypes. But, – when gene expression does not adhere to simple dominant/recessive or – more than one gene pairs influence gene expression Classical F2 ratios of 3:1 and 9:3:3:1 are modified  Extension of Mendelian Genetics Gene interaction: a single phenotype is affected by more than set of genes In addition, genes on the X chromosomes, known as X-linkage, – show modified Mendelian ratios Moreover, expression of phenotypic traits not depend on genotypes, But also, depends on the overall environment of gene, cell and organism.  4.1. Alleles Alter Phenotypes in Different Ways Allele: Alternative form of a gene. Wild-type (wt): the most commonly seen allele in the population – Generally dominant – Used as standart to compare mutations at a particular locus Mutant allele: contains modified genetic information and altered gene product. – For example, many known alleles of the genes encoding β chain of human hemoglobine. – The product’s function may be changed or not  4.1. Alleles Alter Phenotypes in Different Ways Mutations are the source of alleles.  New allele must cause the change in the phenotype  A new phenotype results from a change in functional activity of the gene product. Complete loss of enzyme function Change in the relative efficiency of enzyme Complete alteration of enzyme function  Generally mutations causes a decrease, loss and increase of the specific wild type function: Loss of function mutations: change in the activity, and elimination of function of the wild type – For example change in the enzyme activity – Null allele: complete loss of function due to mutation Gain of function mutations: enhance in the wild type function and increase in the quantity of the gene product. – Generally results in dominant allele, a single copy is enough for phenotype – For example the conversion of proto-onkogenes into onkogenes resulting in excessive gene product and cancer Neutral mutations: change in DNA sequence, but no change in gene product and evolutionary fitness of organsims  4.2. Geneticists Use a Variety of Symbols for Alleles Dominant alleles: italicized and uppercased letters (D) or (Wr) – tall (D) and wrinkled wing (Wr) Recessive alleles: italicized, lowercased letters (d) or group of letter with superscripts + (Wr) – dwarf (d) and wild type winged (Wr) Another system is used to distinguish btw mutant and wild type in Drosophila For example body colour – Ebony mutant phenotype (black and recessive): e – Wild type (gray and dominant): e – A diploid flies can have one of the following phenotypes e/e: gray homozygote (wild type) /: gray homozygote (wild type) e/e: gray heterozygote (wild type) or /e: gray heterozygote (wild type) e/e: ebony homozygote (mutant) e/e: ebony homozygote (mutant)  For example, mutant allele is dominant to the normal wild type allele such as wrinkled wing in Drosophila – Wr/Wr (wrinkled wing), Wr/Wr+ (wrinkled wing), Wr+/Wr+ (wild type) When no dominance exits btw alleles, use uppercase letters and superscripts to show alternative alleles – For example: R1, R2, CW, CR To identify genes in various organisms, selected symbol reflects function of the gene or disorder caused by a mutant gene. For example, in bacteria, – leu-, mutation that interrupt the biosynthesis of leucin amino acids – wild type: leu+  Neither Allele is Dominant in Incomplete or Partial Dominance Incomplete/ Partial Dominance: – Cross btw parents with contrasting traits may sometimes generate offspring with intermediate phenotype – Neither of trait is dominant to the other For example, cross of snapdragon plants with white flower and red flower – F1 generation: all pink flower – F2 generation: ¼ red, ½ pink, ¼ white – F2 genotypic ratio: 1:2:1 (identical with Mendel’ monohybrid cross) – Since no dominance, in contrast to Mendel’ s monohybrid phenotypic ratio (3:1), phenotype and genotype ratios are the same Alleles are designated R1 ve R2  The reason of intermediate phenotype in heterozygotes: the quantity of gene expression. The loss of function mutation: the cause of white flower Wild type allele R1: enzyme involving in the synthesis of red pigments Mutant R2 allele: enzyme not catalyze the synthesis of pigment Heterozygotes produces only about half pigment of the red-flowered plant and pink phenotype  Incomplete dominance is rarely seen For example, in human Tay-Sach disease shows incomplete dominance Homozygote recessive: severely affected with fatal lipid storage disorder – Die within first three years – In affected individuals, no activity in enzyme hexoaminidase A, normally in lipid metabolism Heterozygotes: a single copy of mutant genes %50 of enzyme activity Enough for normal biochemical function This situation is normal in enzyme disorder, known as threshold effect Normal phenotypic expression occurs anytime a certain level of gene product is attained Less than %50 in Tay-Sach disorder  In Codominance, the Influence of Both Alleles in a Heterozygote is Clearly Evident If two alleles of a single gene are responsible for producing two distinct, detectable gene product, in heterozygotes, joint expression of both alleles called (codominance) Different from incomplete dominance, or dominance/recessive For example, in human the MN blood groups – Glycoprotein molecule on the surface of red blood cells that act as native antigen, providing biochemical and immunological identity – Individual may have one or both – MN system under control of locus on Chr. 4 with two alleles LM and LN – In human, three combinations are possible  Alelles: LM and LN Genotypes Phenotypes LM LM M LM LN MN LN LN N LM LN X LM LN ¼ LM LM ½ LM LN ¼ LN LN Ratio 1:2:1 Codominance inheritance: Distinct expression of the gene products of both alleles. Incomplete dominance: heterozygote express an intermediate, blended phenotype  Multiple Alleles of A Gene May Exist in a Population In a population, more than two alleles for a gene. Two or more alleles for the same gene, known as multiple alleles Multiple alleles can be studies only in populations, since: – Diploid organism has the most two homologous gene loci that may occuppied by distinct alleles of the same gene – But among member of species, numerous alternative forms of the same gene  The ABO Blood Groups Human AB0 blood group, an example of multiple alleles AB0 system: antigen on the surface of red blood cells A and B antigens are under control of gene on the chr. 9. Three alleles of a single gene are responsible for this phenotypes Like MN system, ABO system with codominance mode of inheritance To understand the phenotype of any individual: – Mix a blood sample with an antiserum containing type A and type B antibodies – If antigen is present, react with antibody and causing clumping, agglutination – 4 phenotype possible: A antigen (A phenotype), B antigen (B phenotype), A and B antigen (AB phenotype) Neither antigen (0 phenotype)  The ABO Blood Groups 3 alleles: – IA allele – IB allele – i allele IA and IB alleles: A ant B antigens (phenotypes) i allele: not produce any antigen, 0 phenotypes IA and IB alleles are dominant againts to i IA and IB alleles are codominant to each other  A and B Antigens Carbohydrates group bounding lipid molecules on the membrane of red blood cells Specifity depending on the terminal sugar of the carbohydrate groups All individuals with H substance to which one or two terminal sugars are added H substance consists of three chemically linked sugar molecules: – galactose, – N-acethylglucoseamine – fucose  A and B Antigens IA allele, responsible for enzyme that can add terminal sugar N- acethylgalactoseamine to the H substance IB allele, H responsible for modified enzyme that can add terminal sugar galactose to the H substance. Heterozygotes IAIB can add either one or the other sugar at the many sites on the red blood cells – Biochemical basis of the codominance 0 blood group, ii can not add any sugar, only have H substance  The Bombay Phenotype In 1952, a woman in Bombay displayed genetic history inconsistent with her blood type. In a need of transfusion, she was found to lack both A and B antigen, thus typed as 0. But in her pedigree, one of her parent was type AB and obvious donor of IB allele to two of her offspring Thus, woman genetically type B, but functionally type 0  The Bombay Phenotype Homozygous recessive for gene FUT1 (encoding fucosyl transferase enzyme) – Normally synthesizing the complete H substance – Mutant does not have fucose on the H substance, added by enzyme Absence of fucose, enzymes specified by IA and IB allelles cannot recognise H substance as proper substrate Even though there are functional enzymes, neither antigen is added to cell surface, – They are functionally type 0 – To distinguish them from the rest of population, Bombay phenotype Frequency of mutant FUT1 is low Mostly synthesize H substance  4.6. Lethal Alleles Represent Essential Genes Many genes’ products are essential of organism survival. Mutation resulting nonfunctional gene product can be tolerated in heterozygotes – Since one wild type allele may be sufficient to produce essential product for survival But homozygote recessive cannot survive: – Since mutation behaves as recessive lethal alleles – Death time depends on when the product is essential – In mammals, during development, early childhood or even adulthood  4.6. Lethal Alleles Represent Essential Genes Lethal alleles: – Potential to cause to death of organism – Appearance as a result of mutations in the essential genes, – Recessive inheritance In some cases, the allele responsible for a lethal effect when homozygous – It may result in distinct mutant phenotype in heterozygotes It behaves as a recessive lethal allele, but dominant in phenotype  For example, in mice mutation causes yellow coat (AY allele) is distinct from normal agouti coat colour (A allele) (normal kırçıllı) Crosses btw two strains various combinations possible: With regard to coat colour, mutant yellow allele (AY allele) is dominant to wild type agouti allele (A allele), so heterozygotes have yellow coat Yellow allele at the same time is homozygous recessive lethal allele, Thus, homozygotes die before birth, no living homozygous recessive individuals  Some mutations lead to dominant lethal allele One copy of it is enough to death For example, huntington disease in human: – Autosomal dominant H allele – In heterozygotes, the onset of disease is delayed until adulthood – Affected people with gradual nervous and motor degenaration until death – Since it is about 40 years, the affected individuals may have family Their children with probability of 50% have lethal allele and inherit into children – Dominant lethal allele is rare: So in order to exist in population, affected individuals must produce before lethal allele is expressed. If not produce, allele will not transmit and disappear from population until it arises as a result of mutation.  The Molecular Basis of Dominance, Recessiveness, and Lethality: The agouti Gene AY allele is gain of function mutation Animals with wild type A allele have yellow pigments deposited as a band on the black hair shaft resulting in the agouti phenotype Heterozygotes with AY allele deposit yellow pigments along entire length of hair shaft as a band, – Due to deletion of the regulatory region before the DNA coding region of the AY allele – Without any mean of regulate expression, one copy of AY allele is turned on in heterozygotes, resulting gain of function leading to dominant effect  The Molecular Basis of Dominance, Recessiveness, and Lethality: The agouti Gene In homozygotes, lethal effect since: – Extensive deletion of genetic material of AY allele extends into the coding region of adjacent gene (Merc), making it nonfunctional – The gene is very critical in embriyonic development.. – The loss of function in AY AY homozygotes is cause of lethality – Heterozygotes can survive since it passes the threshold level  4.7. Combination of Two Gene Pairs with Two Modes of Inheritance Modify the 9:3:3:1 Ratio Example show that modification in Mendel’s 3:1 ratios so expect changes in the classical the 9:3:3:1 ratio Mendel’ principle of independent assortment applies on the situations: – Genes controlling each character are located on the same chromosome : no genetic linkage For example, a mating btw two human who are both heterozygous for autosomal recessive gene and they are both of blood type AB. – What is the probability of a particular phenotypic combinations in their children? Albinism is inherited in the simple Mendelian fashion and blood types are determined by multiple alleles IA, IB and i In contrast to 4 phenotypes in dihybrid cross of 9:3:3:1 ratio, 6 phenotypes occur in 3:6:3:1:2:1 ratio, expected probability of each phenotype.  4.8. Phenotypes Are Often Affected by More Than One Genes Rediscovery of Mendel work showed that – Phenotype is affected by more than one gene and their products (eye colour, hair colour and fruit shape) Gene interaction: Several genes influence a particular characteristic Cellular function of numerous gene products contributes to the development of common phenotype  4.8. Phenotypes Are Often Affected by More Than One Genes For example, development of organs, – Such as eye of insects: – Extremely complex with multiple phenotypes: size, shape, texture and color. Epigenesis: – the development of an organ is a complex cascade of developmental events, resulting in organ formation – Each step of development increases the complexity of the organ and under control of many genes  4.8. Phenotypes Are Often Affected by More Than One Genes Example of epigenesis and multiple gene interaction: formation of inner ear in mammals The structure and function of the inner ear is very complex – Capture, funnel and transmit external sound toward and through middle ear, – Convert sound waves into nerve impulses – So ear forms as result of developmental events by many genes Mutations that interupt many steps of development lead to common phenotype, hereditary deafness – Many genes interact to produce common phenotype. – Mutant phenotype described as heterogeneous trait, many genes involved. A few common alleles are responsible for the vast majority of hereditary deafness (more than 50 genes)  Epistasis Epistasis: the expression of one gene pair masks or modifies the effect of another gene pair. – Sometimes the genes involved influence the same phenotypic characteristic in an antogonistic manner, so leads to masking 1. Presence of recessive allele may prevent the expression of other alleles at a second locus (recessive epistasis) Alleles at the first locus are epistatic, alleles at the second locus are hypostatic 2. A single dominant allele at the first locus may be epistatic to the expression of the alleles at second locus (dominant epistasis)  Epistasis – In other cases, the genes involved exert their influence on one another in a complementary or cooperative fashion 3. Two gene pairs may complement one another (complementary gene interaction) In this case at least one dominant allele in each pair is required to express a particular phenotype  Epistasis example: AB0 blood groups – Bombay phenotype (recessive epistasis): – Homozygote recessive situations – Homozygote mutant form of FUT1 gene masks the expression of IA and IB alelles – Individuals with at least one copy of wild type allele of FUT1 allele can produce A and B antigens – So individuals with IA and IB allelles but mutant FUT1 allele not looking at capacity of production of both antigens show 0 phenotype Outcome of matings btw individuals heterozygous at both loci: Phenotypic ratios: 3A: 6AB: 3B: 40  Important notes when examining cross and predicted phenotypic ratios: 1. In modified dihybrid cross, one characteristic (blood type) or two characteristics (blood type and skin pigmentation) 2. Even though only a single character was followed, the phenotypic ratios come out sixteens. Two gene pairs are interacting in the expression of phenotypes The study of gene interaction reveals distinct inheritance pattern that are modification of classic Mendel dihybrid F2 ratios (9:3:3:1) Epistasis can combine one or more phenotypic categories in variour ways, so modified ratios. Figure 4-7: Generation of various modified dihybrid ratios from the nine unique genotypes produced in a cross btw individuals.  Discussing examples, assumptions: 1. Distinct phenotypic classes and different from each other 2. In each cross genes are independently assorted from each other during gamete formation. Alelles: A, a, B,b 3. When complete dominance exits in gene pairs, AA and Aa, BB and Bb are equivalent to each other. A- or B- for both combinations where – any allele can present, no effect on phenotype 4. All P1 crosses homozygotes individuals: AABB X aabb, AAbb x aaBB yada aaBB x Aabb. F1: AaBb heterozygous 5. In the F2 generation, when two genes involved: 4 categories: 9/16 A-B-, 3/16 A-bb, 3/16 aaB-, 1/16 aabb. Because of dominance, all genotypes in each categories have equivalent effect on the phenotype Recessive Epistasis: example of coat colour in mice wildtype A allele: agouti (grayish pattern) aa genotype: homozygote recessive (black coat colour) B allele: black pigment bb genotype: albino mice, homozygote recessive, eliminate pigmentation and black colour without looking at presence of A or a alleles bb genotype masks the expression of A allele New F2 ratios: 9:3:4 (some groups together due to gene interaction) Dominant Epistasis: inheritance of fruit color in summer squash Dominant allele at one locus masks the expression of the alleles at the second locus Dominant A allele: white fruit color regardless of genotypes of the second locus Genotypes aa, BB, Bb : yellow color fruit Genotype bb: green color fruit In the F2 ratios: 12:3:1 (due to gene interaction) Complementary Gene Interaction: Flower colour of peas The presence of at least one dominant allele of two gene pair is essential to produce purple colour Only dominant A and dominant B allele are together purple colour Only A or B dominant alelles and other combinations result in white flower In the F2 generation ratio: 9:7 (complementary gene interacion)  YE Ye New Phenotypes As a result of gene interaction, in the F2 not only distinct ratio but also different phenotype Forexample fruit shape of summer squash Disc-shaped fruits (AABB) x long fruits (aabb): F1: all disc-shaped fruits F2: phenotypes of parents and new phenotype (sphere shaped) ratio: 9:6:1 – 9/16 A-B- disc-shaped – 3/16 A-bb sphere shaped , 3/16 aaB- sphere-shaped – 1/16 aabb long fruits  YE Ye New Phenotypes Disc-shaped: one dominant alleles from both locus Sphere-shaped fruits: one dominant allele from either locus Long fruits: absence of both dominant alleles 4.9. Complementation Analysis Can Determine if Two Mutations Causing a Similar Phenotype Are Alleles of the Same Gene Complementation Analysis: prodecure to determine – whether two independently isolated mutations are in the same gene (alleles) or – whether they represent mutations in separate genes. Questions: Are two mutations that yield similar phenotypes present in the same gene or in two different genes? Cross two mutant strains and analyze the F1 generation. There are two possibilities 4.9. Complementation Analysis Can Determine if Two Mutations Causing a Similar Phenotype Are Alleles of the Same Gene Case 1: All offspring develop normal wings Explanation: – Two recessive mutations at distinct genes (not alleles). – In the F1: all heterozgygous for both genes. – Since mutations in the distinct genes, each genes with normal products due to one normal copy of it. – So genes are complementary to each other to make wild type phenotype  4.9. Complementation Analysis Can Determine if Two Mutations Causing a Similar Phenotype Are Alleles of the Same Gene Case 2: All offspring fail to develop wings Explanation: – Both mutations affect the same gene (alleles). – No complementation – F1 flies: homozygous for both mutant alleles. – Gene does not produce normal product and no wings  4.9. Complementation Analysis Can Determine if Two Mutations Causing a Similar Phenotype Are Alleles of the Same Gene Using complementation analysis, possible to screen any number of mutations resulting in the same phenotype So single or many genes involved. All mutations present in a single gene fall into the same complementation groups and they will complement mutations in all other groups Total number of genes involved in the same trait 4.10. Expression of A Single Gene May Have Multiple Effcets Pleiotropy: expression of a single gene has multiple phenotypic effects For example: Marfan sendrome: – Autosomal dominant mutation in the gene coding connective tissue protein fibrillin. – Since protein widespread in many tissues, multiple phenotypic defect. – Lens of the eyes, aort, vessels, bones and other tissues 4.10. Expression of A Single Gene May Have Multiple Effcets Pleiotropy: expression of a single gene has multiple phenotypic effects çok sayıda fenotipe sebep olmasıdır. For example: Porphyria variegata: – Not metabolize porphyrin component of hemoglobine when this pigment is broken down as red blood cells are replaced. – Accumulation of porphyrin lead to toxicity especially in brain – Abdominal pain, fever, insomnia, headache and vision problems 4.11. X-Linkage Describes The Genes on the X Chromosomes In many plant and animals, one of the sex with a pair of chromosomes – involve in sex determination Drosophila and human: – Males: XY – Females: XX Homologous region on the X and Y chromosome – Pairing and synapsis and segregation during meiosis In human and many other species, Y chromosome – A few male specific genes – Not have copy of man genes on the X chromosomes Thus, genes on the X chromosome show X-linkage inheritance, distinct from autosomal genes  X-Linkage in Drosophila In 1910, Thomas Morgan : X-linkage using white eye mutation in Drosophila Wild type red eye dominant to white eyed Inheritance pattern of white eyed depend on sexes of parent. Results of reciprocal crosses btw white eyed and red eyed – Not identical (change sex) White locus on the X chromosme – X-linked inheritance – Corresponding locus absent on the Y chromosome Thus, females have two available gene loci on each X chromosome, But males have only one locus.  X-Linkage in Drosophila Since Y chromosome lacks homology of the genes on the X chr. Genes on the X chr. of male will be directly on the phenotype. Males referred as hemizygous – Neither homozygous or heterozygous for X-linked genes X-linked genes show crisscross pattern of inheritance – Traits controlled by recessive X-linked genes passed from homozygous mothers to all sons – Since males receive one copy of mothers and hemizygous for all X linked alleles, they will express all X-linked recessive alleles in their phenotypes. © 2017 Pearson Education, Ltd. Figure 4-12 © 2017 Pearson Education, Ltd. Figure 4-13  X-Linkage in Human X-linked traits easily seen in the pedigree due to crisscross pattern of inheritance. For example, color blindness in human – Red/green color blindness – In the first generation mother passes the trait to all sons, But not to her daugthers – In the second generation, individuals marry with normal, Color-blind sons will produce all normal male and female offspring (III-1, 2, 3). Normal visioned daugthers will produce normal-visioned female offspring (III-4, 6, 7), as well as color-blind (III-8) and normal- visioned (III-5) male offspring © 2017 Pearson Education, Ltd. Figure 4-14  Lethal Recessive X-linked Disorders Only in male Lethal, – the affected individuals prior to reproductive maturation. Source, – heterozygous females that are carrier and not express the disease Females to sons, – Hemizygous – Develop disorder, rarely reproduce Heterozygous females to half of their daughters – Carrier not develop disorders  Lethal Recessive X-linked Disorders For example: Duchenne muscular dystrophy: – Onset prior to age 6 – Lethal around age 20 – Normally only in males  In Sex-Limited and Sex-Influenced Inheritance, an Individual’s Sex Influences the Phenotype The patterns of gene expression by sex of an individuals – Even genes not on the X chromosomes In many organisms, sex is very important to determine expression of specific phenotype i) Sex-limited inheritance: – the expression of specific phenotype is absolutely limited to one sex ii) Sex-influenced inheritance: – The sex of an individual influences the expression of phenotype that is limited to one sex or the other.  In Sex-Limited and Sex-Influenced Inheritance, an Individual’s Sex Influences the Phenotype In both autosomal genes are responsible for the existence of contrasting phenotypes, – but expression of genes depend on the hormon concentration of an individuals So heterozygous may exhibit one phenotype in males and contrasting one in females  In Sex-Limited and Sex-Influenced Inheritance, an Individual’s Sex Influences the Phenotype For example, sex-limited inheritance in domestic fowl – Distinct tail and neck plumage in male and female – Cock feathering with longer, more curved and pointed Hen feathering is shorter and less curved Single autosomal alleles whose expression is modified by individual’s sex hormones Hen feathering due to is dominant H allele regardless of h recessive allele Cock feathering only in male with hh genotype In female homoygous recessive hh genotype shows hen feathering Real expression can be changed by individual sex hormones  In Sex-Limited and Sex-Influenced Inheritance, an Individual’s Sex Influences the Phenotype For example, sex-influenced inheritance in human: – baldness Autosomal genes responsible for contrasting phenotypes The trait in both female and males The expression of genes depends on hormon concentration of individuals – Heterozygous genotype exhibit one phenotype in one sex and the contrasting one in the other. – B allele behaves as dominant in females and recessive in males – In females with BB genotypes, phenotype is less pronounced than males In Sex-Limited and Sex-Influenced Inheritance, an Individual’s Sex Influences the Phneotype  4.13. Genetic Background and Environment May Alter Phenotypic Expression Actually, genotype of an organism not directly expressed in its phenotype. – Complex event – Product of gene function within cells and cells interact with each other in many ways – Organisms live under distinct environmental conditions. Phenotype as a result of gene expression changed by interaction btw organisms’ genotype and environment  Penetrance and Expressivity Some mutant genotypes are always expressed as a distinct phenotype In others, phenotype of proportion of individuals cannot differentiate from wild type The degree of expression of a trait can be studied quantitatively by determining – Penetrance – Expressivity  Penetrance The percentage of individuals that show at least some degree of expression of mutant phenotype in population. The rest cannot be distinguished from wild type. For example, in Drosophila expression of many mutant alleles overlap with with wild type – If 15% of mutant flies are in wild type appearance, the penetrance of mutant gene is %85 – From 100 mutant flies, only 85 flies show mutation in their phenotypes.  Expressivity The range of expression mutant genotype – For example, flies with homozygous recessive mutant gene of eyeless Phenotypes from normal eyes to partial reduction in eyes, and complete absence of one or both eyes Expressivity range from complete loss of eyes to complete both eyes. Other genes, genetic background, environmental factors (temperature, humidity and nutrition)  Penetrance and Expressivity Penetrance; – quantitative method to determine whether disease or phenotype is seen. – It explains how often gene that causes this phenotype is expressed. Expressivity explains; Disease and phenotype how often appear and, Genes that causing those how often express qualitatively  Genetic Background: Position Effects Position effect: the physical location of a gene in relation to other genetic material may influence its expression – For example, if a region of chromosome is relocated or rearranged (translocation or inversion effect) normal expression of genes in that chromosomal region are modified. – Especially genes near to the areas of chromosome that are condensed and genetically inert, known as heterochromatin  Genetic Background: Position Effects For example of position effect, female Drosophila heterozygous for X-linked recessive eye color mutant white (w) A. Wild type female: w+/w red eyed normally B. Due to translocation of the region of X chromosome containing w+ allele close to heterochromatin region, – w+ modified, no dominant effect – instead of red color, variegated with red and white pathces Heterochromatic regions inhibit expression of other regions.  Temperature Effects: Conditional Mutations Chemical activity depends on the kinetic energy of the reacting substances, so surrounding temperature. So effect of temperature on phenotype. For example, even in primrose that produce red flower at 23 C, but white flower at 18 C Or Siamese cats and Himalayan rabbits – Exhibit dark fur in certain regions where their body temperature is slightly cooler – Especially nose, ears, paws – Enzyme normally functional in these extreme body regions, – But loses the catalytic activity at the slightly higher temperature in the rest of the body Temperature Effects: Conditional Mutations  Temperature Effects: Conditional Mutations Temperature sensitive mutations: expression of mutations affected by temperature. These are examples of conditional mutations whereby phenotypic expression is determined by environmental conditions – Viruses, bacteria, fungi, and Drosophila – Organism with mutant allele express a mutant phenotype at one temperature, – But express the wild type phenotype in another temperature. – Useful to study mutations that interrupt essential processes during development, and thus normally detrimental and lethal  Nutritional Effects Nutritional mutations: phenotypes are not always a direct reflection of organismal genotypes. In microorganisms, mutations prevent the synthesis of common nutrient molecules – Such as enzyme becomes inactive involving in essential biosynthetic pathway. Microorganisms bearing such mutations, called auxotrophs If the end product of the biochemical pathways can no longer be synthesized, If that molecule is essential to normal growth and development, – Mutation prevents growth and be lethal – For example, ıf the bread mold Neurospora can no longer synthesize the amino acid leucine, proteins cannot be synthesized – If there is leucine in the growth medium, lethal effect can overcome  Nutritional Effects In human, certain dietary substances can be consumed by normal individuals, but with different genetic structure can be harmful. Mutation can prevent an individual from metabolizing some substances commonly found in normal diets. For examples, – people with disorder phenylketonuria cannot metabolize the amino acid phenylalanine. – Galactosemia cannot metabolize galactose – Lactose intolerance cannot metabolize lactose Dietary intake of these molecules cannot reduce or eliminate the effect of associated phenotype  Onset of Genetic Expression Not all genetic traits at the same time during organism’life. In human, the prenatal, infant, preadult and adult – Require distinct genetic information Thus, many severe disorders cannot seen until after birth For example: Tay-sach disease Autosomal recessive Lethal lipid metabolism disease (anormal hexoaminidase A) normal newborn at the first three months But slow development, paralysis, blindness, die about at age 3  Lesch-Nyhan syndrome – X-linked recessive – Abnormal nucleic acid metabolism – Mutation in the HPRT gene – Accumulation of uric acid in blood and tissue, – Mental retardation, palsy – Normal newborns until fisrt 6 months Duchene muscular dystrophy (DMD) – X-linked recessive disorder – Muscular wasting – Diagnosis only early 3-5 years old, – Disease is fatal at age 20  Huntington Disease: – Onset of disesae is variable – Autosomal dominant disease – Effect on the frontal lobes of the cerebral cortex – Progressive cell death and brain deterioration – Onset of disease at age 30-50 with death  Genetic Ancipitation Genetic anticipation: Progressively earlier age of onset and increased severity of the disorder in each successive generations Forexample: Myotonic dystrophy (DM1) – Most common type of adult – Autosomal dominant – Increased severity and earlier onset with successive generations than mother and father – Mutation in DMPK gene (3 nucleotide sequence repeat variable times and unstable) – In normal individuals: 5-35 copies of number, and in affected individuals 150-2000 copies of number – Greater number of repeats more severely affected – In the successive generations, in copy number of DM1 repeats increases and mutant RNA transcript causes of disease  Genomic (Parental) Imprinting The process of selective gene silencing occurs during early development, impacting on subsequent phenotypic expression (genomic imprinting). – Genes or region of chromosome is imprinted in one homolog, but not the other. – The impact of silencing depends on the parental origin of genes or chromosomal regions – This silencing leads to direct phenotypic expression of an allele on the homolog that is not silenced. – During gamete formation or earlier – So homologos in sperm and eggs are differentially imprinted  Genomic Imprinting Examples of genomic imprintings in human: – Prader-Willi sendrome (PWS) – Angelman sendrome (AS) Differential imprinting of the same region of the chr. 15 In both disorders, identical deletion of this region in one member of the chr. 15 Phenotypically different  Genomic Imprinting – Prader-Willi sendrome: paternal segment deletion, and undeleted maternal chromosome remains, but imprinted/silenced Mental retardation, uncontrollable appetite, obesity, diabetes – Angelman sendrome: maternal segment deletion, and undeleted paternal segment remains, but imprinted/silenced not fillfull the function Mental retardation, involuntary muscle contraction, seizure Since region of chr. 15 is differently imprinted in male and female gametes, – for normal development, both undeleted maternal and paternal segments are required.  Genomic Imprinting The region of chromosome rather than genes is imprinted, an example of general topic epigenetics: – Genetic expression is not direct result of the information stored in nucleotide sequence – Instead, alteration of DNA in a wat affecting its expression. – Stable changes, transmitted to progeny during cell division and through gametes future generations  Genomic Imprinting Imprinting and epigenetic are related to DNA methylation events: – Methyl groups can be added to the carbon atom at position 5 in cytosine as a result of activity of DNA metyhl tranferase enzyme – Methyl group are added when the dinucleotide CpG or CpG islands are present along a DNA chain – Highly methylated genes remain inactive – So active genes often are unmethylated.