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Transmission (Classical, Mendelian) Genetics Ch 11 • Gregor Mendel – Experiments in Plant Hybridization, 1865 • Controlled experiments, mathematical analysis Pisum sativum, the garden pea • • • • • What makes this a good model organism? easy to grow hundreds of offspring per cross short generation time can self fertilize or cross – Paint pollen (sperm) from one plant onto the female parts of another (emasculated plant) Mendel’s conclusions 1. Genes are physical units – 2 alleles for each gene – 1 allele inherited from each parent Genes and alleles of Pisum sativum Gene • Pea color • Flower color • Pod shape • Pea surface • Stem height Alleles ? white, purple constricted, inflated ? tall, dwarf 2. Principle of Dominance - One allele dominant, the other recessive - The dominant allele is expressed in the phenotype Gene for flower color P allele = purple p allele = white GENOTYPES Homozygous dominant = Heterozygous = Homozygous recessive = PHENOTYPE 3. Random segregation of alleles into gametes – gamete receives ONE allele per gene – random segregation of alleles 50/50 P generation PP pp What is the phenotype of all offspring in F1 generation? Note that the P generation is true breeding P p Genotype Phenotype p P How did Mendel do it? The Monohybrid cross YY yy Which allele is dominant? What is the genotype of the f1 generation? Cross 2 f1 plants (or let one self-fertilize) What is the ratio of phenotypes? Results of Mendel’s monohybrid crosses Parental Strains F2 progeny Ratio Tall X dwarf 787 tall, 277 dwarf Round seeds X wrinkled 5474 round, 1850 wrinkled Yellow seeds X green 6022 yellow, 2001 green Violet flowers X white 705 violet, 224 white Inflated pods X constricted 882 inflated, 299 constricted Green pods X yellow 428 green, 152 yellow Axial flowers X terminal 651 axial, 207 terminal gene = ? alleles = ? Test cross (one gene) • A mouse has black fur, what are its 2 possible genotypes? Test cross mouse to homozygous recessive mouse If black mouse is BB If black mouse is Bb A mouse was test crossed and 7 offspring black, 2 white. What is mouse’s genotype? Pedigree Analysis Ch 11 Autosomal recessive inheritance (bb) • unaffected parents can have affected offspring • May “skip” a generation • Two affected parents cannot have an unaffected child • Not sex related Autosomal recessive traits • • • • Sickle cell disease Albinism Cystic fibrosis O blood type Phenylketonuria (Ch.4) • PKU (1/12,000) Mutation in gene encoding phenylalanine hydroxylase enzyme needed for phe metabolism Chromosome 12 12q24.1 All US babies tested at birth (Guthrie test) missing phenylalanine hydroxylase enzyme If plasma phe level is too high, phe is converted into a phenylpyruvate toxic to brain tissue Why are these babies normal when born? Pleiotropic effects no tyrosine (little melanin) slow growth retardation blue eyes low adrenaline Ch 4 1902 Archibald Garrod: One gene: one enzyme “Inborn errors of metabolism” PKU Albinism Alkaptonuria Tyrosinemia Black urine arthritis Fill in genotypes. If II,1 and II, 4 mate, what is the chance of offspring having PKU? How do we know this is autosomal recessive? II, 1 X II, 4 •p(aa AND a girl)? p(aa) If III-3 and II-1 mate p (normal child) Product rule: p (affected boy)? All people have harmful recessive alleles, small chance That 2 people with same rare alleles will mate Consanguinous marriage increases the chance Bedoin intermarriage Autosomal dominant disorders Aa and AA =affected aa =unaffected •Tend to show up in every generation •2 affected parents can have unaffected child •2 unaffected parents cannot have an affected child Dominant pedigree Achondroplasia -1/20,000 births • Mutation in FGFR3 gene Chromosome 4 • Affects cartilage growth needed for bone lengthening • Most affected individuals Aa why? • Most cases spontaneous (associated with increasing paternal age) what is the genotype of parents in this case? P(III, 3 and III, 5 have a child of normal height) P ( II, 3 and III, 7 have a boy with achondroplasia) • Mutation in dog FGF4 gene Dihybrid cross – 2 genes Ch. 11 Mendel’s Law of Independent assortment - each allele for a trait is inherited independently of other alleles Seeds: G = yellow allele g = green allele W = round w = wrinkled allele allele gene? gene? Parents = GGWW X phenotype? gametes? F1 genotype ? F1 phenotype ? F1 Gametes? ggww Note that each gene gives the 3:1 ratio of a monohybrid cross Yellow/green ratio = Round/ wrinkled = Forked line method for phenotypes GgWw X GgWw Test cross A pea is round and yellow. What is its genotype? G-W- X ggww Note the cross of the “unknown” to a homozygous recessive If all yellow and round: If all yellow and some wrinkled: If all round and some green: If 1:1:1:1: Probability Product rulethe probability that two outcomes occur simultaneously is product of their individual probabilities assumes independent assortment of genes GgWw X GgWw • What is the probability of a yellow AND wrinkled? p(G-ww) A female lilac tabby X A male black siamese genotype: ww bb CC dd Aa X ww Bb CsCs Dd Aa p( black tabby cat) p (brown solid color cat) W = white B = black C = solid (not siamese) D = not dilute (full color) A = striped (tabby) Trihybrid cross AaBbCc X AaBbCc p(A-B-cc) AabbCcDD X AaBbCcDd p(triply recessive) Modified Mendelian Ratios Ch. 13 1. Multiple alleles (more than 2 alleles for gene in population) Chromosome 9 I gene • Example: Blood Groups Karl Landsteiner 1900’s ABO blood system = polymorphic I gene Blood type A B AB O genotype IAIA or IAi ? IAIB ii What is the mechanism of inheritance of A, B, AB, O? Autosomal or sex chromosome? Which two alleles are codominant? Which allele is recessive? Example • A child has type O blood. The mother of the child has Type B blood. What could the blood types of the father? 2. Incomplete dominance Example: snapdragons Allelic symbols do not specify dominance CR = red color Cw = white color CR CR X Cw Cw 3. Codominance Each allele encodes separate gene product distinct in heterozygote L gene for human blood cell surface protein LM = M antigen LMLN x LMLN LN = N antigen 1M • A man with the M bloodtype has a child with a woman of the MN bloodtype • Expected ratio of offspring? 4. Lethal alleles MM = normal spine MM’ = manx cat (no tail) M’M’ = lethal Cross two manx, what is ratio of phenotypes in offspring? How do breeders obtain manx cats? Lethal alleles in humans • Tay Sach disease tt is fatal • Huntington disease HH is fetal lethal • Hh causes death ~ age 50. Polydactyly, dominant 5. Penetrance • % individuals that exhibit phenotype corresponding to genotype Pp 5,5 pp 6, 5 6, 6 6. Expressivity (ex. Piebald spotting) =the extent to which a trait is exhibited Incomplete penetrance AND expressivity • NF-1 = Neurofibromatosis1 – (1/4000, 17q11.2) – (350 kb gene, 60 exons) • Autosomal dominant trait NN and Nn with 50- 80% penetrance • Variable expressivity Mild form tumors on nerve CT coverings, skin, eyes, organs, face speech, blood pressure, spine curvature, headaches Gene expression also affected by: • • • • Sex (baldness) Temperature (melanin in Siamese cats) Chemicals (PKU) Diet (height, cancer) 7. Epistasis- gene product interactions • A product of one gene influences, or masks, the expression of another gene(s) • Modification of dihybrid cross ratio AaBb X AaBb 9:3:3:1 Epistasis in labrador retrievers • B and E color genes (labs) B black E color b brown e no color (yellow) ee is epistatic Cross two double heterozygotes Phenotypes of parents? Phenotypes of offspring? ratio? Epistasis in Cats • W = white w = not white • B = black b = brown Mate 2 heterozygous cats What is the expected ratio? 8. Polygenic traits • Vary continuously – Weight, height, IQ Animal life cycle • 1n haploid gametes have 1 set of chromosomes • 2n diploid zygote has 2 sets of chromosomes Homologous chromosomes 1 pr sex chromosomes 22 prs. autosomes KARYOTYPE 1. Obtain white blood cells from or fetal cells from amniotic fluid 2. Proliferation via growth factor add colchicine at metaphase to arrest spindle formation 3. add water to swell cell -> squash 4. stain ->photograph Detects number of chromosomes, sex, chromosomal abnormalities 57 Arrange in pairs according to: • decreasing size • centromere position METACENT RIC SUBMETACEN TRIC • banding pattern ACROCENT RIC 58 metacentric (1) submetacentric (9) p arm is the upper, shorter arm 59 Normal male 46, XY Which are meta-, submetaacrocentric? 60 Do more chromosomes mean more intelligence? Human Chimpanzee Dog Cat Alligator Goldfish Mosquito Potato Baker’s yeast 46 48 78 72 32 94 6 48 34 Chromosome Theory of Inheritance • 1902 Sutton and Boveri – A chromosome is a linkage group of Mendelian factors (GENES) – How many linkage groups in the human species? • 1920s Morgan et al. – Genes are in a linear sequence on the chromosomes, they can be mapped Sex chromosomes 1 pair sex chromosomes XY heterogametic XX homogametic • Human Male hemizygous for X-linked traits XHY XhY • Human Female = XX – two alleles for each X-linked gene – dominance XHXH XHXh XhXh X-linked genes • Hemophilia (recessive) 1/5000 males – Mutation in gene for clotting factor Xq28 •Mate IV 2 with homozygous normal female p(hemophilia)? •Mate III 13 with III 1 Probability of offspring? Criss cross inheritance of X linked traits Fruit fly nomenclature box 12.1 Red eyes is wildtype phenotype, brown is mutant bw+ = wildtype allele bw = brown allele genotype phenotype red brown • Wingless is recessive mutant (wg allele) • Genotype of wildtype, heterozygote, mutant? w+ = wildtype allele w = white allele X-linked recessive A white-eyed female is crossed with a red- eyed male. An F1 female from this cross is mated with her father and an F1 male is mated with his mother. What will be the eye color of the offspring of these two crosses? The mutant fruit fly discovered by Thomas Hunt Morgan Mammalian sex determination = the Y system A. Embryo is neither male nor female Week 7 How does embryo “know to become male? XY embryo sex chromosomes • The Y determines sex B. SRY gene encodes TDF • SRY (sex determining region Y) • p arm • Gene TDF encode 20 aa transcription factor • Expression stimulates growth of testes -> • testosterone ---> sperm ducts, male brain “sensitization” • Sex of 45, XO? (Turner syndrome) • Sex of 47, XXY? (Klinefelter syndrome) • Non-disjunction during meiosis 74 Clinical application During sperm formation: SRY crossed over to X chromosome X containing sperm fertilized egg Child? Clinical application • 17 year old female presented with streak ovaries, no uterus • Karyotype is XY 3. Experiments with transgenic mice XX males Add SRY DNA to female mouse embryo Pseudoautosomal region of the X and Y •~12 genes on X and Y •regions allow X and Y to pair during meiosis •pseudoautosomal genes are also transcribed from the inactivated X! •both males and females have 2 active copies of these genes Dosage Compensation (mammals) • Females have 2 Xs, males have 1 X. Do females have an extra dose of X-linked genes/alleles? X chromosome inactivation Lyon, 1961 • Dense “Barr body” at edge of nucleus in female cells Male cell female cell cell with 2 Barr bodies Number of X chromosomes? Random X-inactivation Epigenetic silencing of 1 X chromosome Random 1000 cell embryo (16 day old in humans) Female mosaics • Females heterozygous for X-linked traits are mosaics for those traits. red/green colorblindness phenotype = ? XCXc Anhydrotic ectodermal dysplasia XAXa female What happens to XaY? Other sex determination systems A. Drosophila Ratio of X to sets of autosomes The Y is not related to sex X/A = 1 or >1 ------> female X/A = 0.5 or <0.5 --------> male X/A between 0.5 and 1 ---> intersex Male Sex of an XY fly with 2 sets of autosomes? Sex of a fly with with 2 sets of autosomes, 1 X chromosome Sex of a triploid fly with 2 X chromosomes? Female ZW system - birds • Females ZW (heterogametic) • Males ZZ (homogametic) Barred feathers is Z-linked and a dominant allele A male with non-barred feathers is crossed to a female with barred feathers. Allele key: All female offspring? Temperature sex determination (TSD) • In some reptiles sex is not determined genetically Parthenogenesis – eggs develop without sperm (asexual) Haplodiplod sex determination Wasps Haploid male Diagnosis of disease Ch4 Fetal Chromosomal Analysis Amniocentesis > week 14 needle into amniotic sac Fluid contains fetal cells Karyotype, DNA test Risk of miscarriage = 1/300 90 Chorionic villus sample (CVS) ~week 8 Biopsy of chorion More risky 91 Ch. 16 Variations in chromosomes • Chromosomal aberration – Spontaneous – Induced Visible aberration in 6/1000 live births Deletions (del) • • • • Part of chromosome missing observe large ones by karyotype If centromere lost chromosome lost Cause – Chemicals, radiation – Unequal crossing over during meiosis • If deletion homozygous lethal 93 46,XX,del(7)(q21.12,q21.2) Heterozygous del pseudodominance 94 Cri du Chat • 46, XY, 5p- Microcephaly, myotonia, “cry of cat”, brain impairment if individuals make it past childhood, symptoms lessen Duplications • segment of a chromosome doubles • May be tandem or reverse • problems during meiosis 96 dup(5)(qter->q33.1::p15.3->qter) • Sample of cord blood from stillborn male with anencephaly 97 • Inversions (inv) – 180o turnaround of segment • no loss of genetic material • may change length ratio of p/q arms – Position effect • change in gene position with respect to centromere may influence expression 98 Translocations • segment moves to other chromosome interstitial or reciprocal exchange • Individual has all genetic material, but what about gametes? 99 t(11;13) (q21;q14.3) • parent who has translocation is phenotypically normal • The gametes are not multiple miscarriages 100 Translocation (cont.) • Robertsonian fusion – ends of 2 acro- or telocentric break/fuse – 45 chromosomes but no, or little, loss of genetic material 101 Aneuploidy: chromosome # changes • Nullisomy – Loss of homologous pair of chromosomes – Not viable in animals Monosomy (only 1 viable in humans!) • 45 XO – Turner Syndrome (1/2000 live births) • Partial monosomy 46, 5p- 103 • Trisomy • 47, 21+ (1/800 live births) 21 may be small, but contains 33,546,361 bp of DNA! 104 Trisomy 13 (Patau) • Fatal< 1 year (usually) • Deaf, blind, clyclopia, polydactly, cleft palate • 1/5000 live births 47, XY, 13+ 105 47, XY, 18+ (Edward’s) • < few months 1/5000 live births 106 • Tetrasomy – Extra chromosome pair 108 Polyploidy = extra SETS of chromosomes 109 • Many plants are polyploid • Some bees and wasps are monoploid 110 Somatic mosaics More than one genetically distinct population of cells in individual Ex: 46XX embryo, one cell loses an X --- 46,XX/45X mosaic – Symptoms less severe than the standard Turners syndrome 111 • Somatic mosaics – chimeras in people and animals Note: there will be a small amount of additional information from the lecture on Tuesday