BioA11 Lecture Notes: Mendelian Genetics PDF

2023-10-05 MENDELIAN GENETICS Lecture week 5: Text reading: chapters 8 & 9 1 BioA11 Introduction to the Biology of Humans • COURSE OBJECTIVES: INTRO Instructor: Karen Williams, PhD Office: SY210A Office hours: virtual::Thursday 11301200h ; in-person: Friday 1600h-1630h, or by appointment • • •...

2023-10-05 MENDELIAN GENETICS Lecture week 5: Text reading: chapters 8 & 9 1 BioA11 Introduction to the Biology of Humans • COURSE OBJECTIVES: INTRO Instructor: Karen Williams, PhD Office: SY210A Office hours: virtual::Thursday 11301200h ; in-person: Friday 1600h-1630h, or by appointment • • • _______________ _______________ _______________ • See syllabus • Aim for this week: • 5. To understand the figures, plots and charts used in scientific literature for human biology Email: [email protected] 2 1 2023-10-05 BioA11 Introduction to the Biology of Humans Mendelian Genetics: outline • How is the inheritance • Genetics beyond of a single gene analyzed in humans and in peas? • Mendel and the beginning of genetics Mendel and pedigree analysis • Factors that alter phenotypic ratios • ____________________ ____________________ ____________________ 3 BioA11 Introduction to the Biology of Humans OMIM is a database • Krabbe disease • OMIM 245200 Mendel’s garden • Cystic Fibrosis • OMIM 219700 • Sickle cell • OMIM 603903 • Tay Sachs • OMIM 272800 https://flic.kr/p/fsVD7c 4 2 2023-10-05 8.1 The Inheritance of Traits (1 of 13) Newborn Screening • Mandatory tests in U.S. for 4 million babies • Performed 24 hours after birth • Small blood sample from heel • Chemical compounds outside of normal range • New York: screens for 47 disorders • E.g., Krabbe disease and PKU 5 8.1 The Inheritance of Traits (2 of 13) Newborn Screening Test Results • Positive – disease is present • False positive – positive results but no disease is actually present • Many suspicious results are false positives. 6 3 2023-10-05 8.1 The Inheritance of Traits (3 of 13) Adding New Tests for Newborn Screening Federal advisory board recommendations • New test should: • Minimize risk of false positives • Be for well-understood or treatable condition • Inform decisions for future reproduction • Heritable component 7 8.1 The Inheritance of Traits (4 of 13) The human life cycle: growth and reproduction of an individual • Gametes (sperm and egg) fuse during fertilization to form single-celled zygotes. • Continued cell divisions form the embryo. Egg Mother’s egg and father’s sperm each contain half of the information needed to build a human. This single cell contains all the information on how to build a human. Meiosis Tissue differentiation, organ system formation Mitosis and differentiation Fertilization Zygote Sperm Adult Gametes Single-celled embryo Multicellular embryo 8 4 2023-10-05 8.1 The Inheritance of Traits (5 of 13) • The human life cycle (continued): ‒ The embryo grows to become a fetus. ‒ A full-term infant is born and with continued growth, becomes an adult. Birth Mitosis and differentiation Mitosis and differentiation Fetus Baby Mitosis and differentiation Child Adult 9 8.1 The Inheritance of Traits (6 of 13) (a) Stalked adder’s tongue (a fern) Genes and chromosomes • Genes: segments of DNA that code for proteins • Prokaryotes: single, circular chromosomes • Eukaryotes: multiple linear chromosomes • Jumper ant: 2 chromosomes (b) Single fern cell • Stalked adder’s tongue: 1260 chromosomes • Human cells: 46 chromosomes 10 5 2023-10-05 8.1 The Inheritance of Traits (7 of 13) Instruction manual analogy • Genes: analogous to words in an instruction manual for building a human • Chromosomes: analogous to instruction manual pages ‒ Each “page” contains thousands of “words.” ‒ Different types of cells use different words in different orders. build strong heart muscle Genes expressed in muscle cell build grow long dark blood brown strong hair for eyes heart small red muscle build dark brown eyes Genes expressed in eye cell 11 8.1 The Inheritance of Traits (8 of 13) Genetic Diversity Genetic variation: produced by copying and transmittal of parental genes to next generation • DNA replication: produces duplicate DNA molecule • Analogous to “rewriting” instruction manual page • Mutation: mistakes in copying DNA • Analogous to typographical error in instruction manual 12 6 2023-10-05 8.1 The Inheritance of Traits (9 of 13) Genetic Diversity: Alleles: different versions of genes produced by mutations • Mutation effects may be neutral, beneficial, or dysfunctional Normal allele: grey strong nerve Mutant allele: gray string nzrve (a) The mutant allele has the same meaning (mutant allele function the same as the original allele). (b) The mutant allele has a different meaning (mutant allele functions differently than the original allele). (c) The mutant allele has no meaning (mutant allele is no longer functional). 13 8.1 The Inheritance of Traits (10 of 13) Homologous pairs: equivalent chromosomes; pairs contain one chromosome received from each parent • Body cell has two complete copies of the manual • 23-page copy from mom + 23-page copy from dad = 46 pages Egg Sperm The 23 pages of each instruction manual are roughly equivalent to the 23 chromosomes in each egg and sperm. Zygote The zygote has 46 pages, equivalent to 46 chromosomes. 14 7 2023-10-05 8.1 The Inheritance of Traits (11 of 13) Genetic Diversity • Unique offspring through meiosis events • Segregation: pairs of alleles separate into different gametes • Gamete receives one copy of each manual page • Independent assortment: Homologous pairs separate into gametes, randomly and independently of other chromosomes • Due to random alignment in meiosis I • Uncoordinated “lining up” of chromosomes 15 8.1 The Inheritance of Traits (12 of 13) Due to independent assortment, the instructions in one sperm cell are a unique combination of pages. Parent cells have two copies of each chromosome—that is, two full sets of instruction manual pages, one from each parent. Sperm and egg cells each have only one full set—a random combination of maternal and paternal instruction manual pages. Possible sperm cell 1 Page 3 Blood-group gene from dad Possible sperm cell 2 Page 3 Page 9 Eye-color genes Blood-group gene from mom from mom Page 9 Eye-color genes from dad 16 8 2023-10-05 8.1 The Inheritance of Traits (12 of 13) Due to independent assortment, the instructions in one sperm cell are a unique combination of pages. Parent cells have two copies of each chromosome—that is, two full sets of instruction manual pages, one from each parent. Sperm and egg cells each have only one full set—a random combination of maternal and paternal instruction manual pages. Possible sperm cell 1 Page 3 Blood-group gene from dad Possible sperm cell 2 Page 3 Page 9 Eye-color genes Blood-group gene from mom from mom Page 9 Eye-color genes from dad 17 8.1 The Inheritance of Traits (13 of 13) Genetic Diversity Variety in potential offspring • Independent assortment of 23 pairs of chromosomes ‒ 8 million possible chromosome combinations in gametes • Random fertilization: gametes combine regardless of alleles carried ‒ 8 million × 8 million = 64 trillion possibilities! 18 9 2023-10-05 8.2 Mendelian Genetics: When the Role of Genes Is Clear (1 of 19) Gregor Mendel: (18221884) • Studied botany and math • Considered the first genetic scientist • Accurately described simple rules of inheritance 19 8.2 Mendelian Genetics: When the Role of Genes Is Clear (2 of 19) Mendel’s Experiments: • Controlled mating between pea plants • 30,000 plants over 10 years • Described patterns of inheritance for traits from single genes with a few alleles • Both parents contribute genetic information to offspring • Published results in 1865 • Significance not readily appreciated • Rediscovered in 1900 with applications to genetics 20 10 2023-10-05 8.2 Mendelian Genetics: When the Role of Genes Is Clear (3 of 19) Table 8.1 Pea traits studied by Mendel Character Studied Dominant Trait Recessive Trait Seed shape Round Wrinkled Seed color Yellow Green Flower color Purple White Stem length Tall Dwarf 21 8.2 Mendelian Genetics: When the Role of Genes Is Clear (4 of 19) A pea flower normally self-pollinates. Ovule (contains egg) Stigma Carpel (receives pollen) Pollen-containing structures can be removed to prevent self-fertilization. Tweezers Pollen from another flower is dabbed on to stigma. Paint brush Anthers (produce pollen, which contains sperm) The resulting seeds will contain information on flower color, seed shape and color, and plant height from both parents. 22 11 2023-10-05 8.2 Mendelian Genetics: When the Role of Genes Is Clear (5 of 19) • Phenotype: physical traits of an individual • Genotype: genetic composition of an individual; describes alleles ‒ Homozygous: carries two copies of the same allele ‒ Heterozygous: carries two different alleles • Recessive: the phenotype of an allele is seen only when homozygous • Dominant: the phenotype is seen when homozygous or heterozygous 23 8.2 Mendelian Genetics: When the Role of Genes Is Clear (6 of 19) Genetic Diseases in Humans • Rare, serious diseases • Caused by mutant alleles • Mostly recessive alleles following Mendelian rules • Screened for in newborn testing 24 12 2023-10-05 8.2 Mendelian Genetics: When the Role of Genes Is Clear (7 of 19) Genetic Diseases in Humans • Krabbe disease • Results in loss of myelin sheath around nerve cells • Caused by mutant alleles of GALC gene • Two copies of recessive allele • Mutant alleles cannot produce enzymes to breakdown waste that degrades myelin 25 8.2 Mendelian Genetics: When the Role of Genes Is Clear (8 of 19) Genetic Diseases in Humans • Krabbe disease • Affected children • Normal at birth • Progressive and severe deterioration of mental and motor skills due to myelin loss • Most die by age 3 • Not included in newborn testing for most states 26 13 2023-10-05 8.2 Mendelian Genetics: When the Role of Genes Is Clear (9 of 19) Genetic Diseases in Humans Pleiotropy: a single gene causes multiple effects on an individual’s phenotype • Krabbe disease: loss of myelin causes multiple effects • Galactosemia: inability to digest sugar causes sugar accumulation in various organs Brain damage Cataracts Enlarged liver Kidney damage Jaundice 27 8.2 Mendelian Genetics: When the Role of Genes Is Clear (10 of 19) Genetic Diseases in Humans Carriers: heterozygotes for a recessive disease • Not affected by the disease • Can pass the trait to the next generation • Child receives disease if both parents are carriers 28 14 2023-10-05 8.2 Mendelian Genetics: When the Role of Genes Is Clear (11 of 19) Genetic Diseases in Humans Cystic fibrosis: • Most common recessive disease in Europeans • 1 in 2500 affected in European populations • 1 in 25 is heterozygous carrier ‒ Defect in chloride ion transport in the lungs • Produces thick, sticky mucus that builds up in lungs and digestive system • Average lifespan only 40 years 29 BioA11 Introduction to the Biology of Humans What has been U of T’s role in cystic fibrosis research ? • Krabbe disease • OMIM 245200 • Cystic Fibrosis • OMIM 219700 Mendel’s garden • See bulletin article: • https://www.utoronto.ca/news/willpow er-nutshell-against-odds-elspetharbow-working-towards-u-t-degreedespite-cystic • Sickle cell • OMIM 603903 • Tay Sachs • OMIM 272800 https://flic.kr/p/fsVD7c 30 15 2023-10-05 8.2 Mendelian Genetics: When the Role of Genes Is Clear (14 of 19) Using Punnett Squares to Predict Genotypes • Punnett square: table listing possible gametes and predicting possible outcomes of a cross (mating between two parents) • Developed by Reginald Punnett in 1905 31 8.2 Mendelian Genetics: When the Role of Genes Is Clear (15 of 19) Using Punnett Squares to Predict Genotypes • Punnett square: table listing possible gametes and predicting possible outcomes of a cross (mating between two parents) ‒ Consider a cross between two carriers of the mutant GALC gene for Krabbe disease • “G ” = normal allele; “g ” = recessive disease allele • The cross would be Gg × Gg • What offspring could result? 32 16 2023-10-05 8.2 Mendelian Genetics: When the Role of Genes Is Clear (16 of 19) Dominant, functioning allele Female carrier Gg g Recessive, nonfunctioning allele g Possible types of sperm Possible types of eggs G Male carrier Gg G GG Gg 25% chance that child carries only functional alleles 50% chance that child will be unaffected carrier of Krabbe disease allele Gg gg 25% chance that child will have Krabbe disease 33 8.2 Mendelian Genetics: When the Role of Genes Is Clear (18 of 19) • Dihybrid cross (two genes): mating crosses that involve two traits ‒ Determine the possible gametes for pea seeds • Round (R) is dominant to wrinkled (r ) • Yellow (Y ) is dominant to green (y) ‒ For a cross: Rr Yy × RrYy ▪ Possible ovule types for parent 1: • RY, Ry, rY, ry ▪ Possible pollen types for parent 2: • RY, Ry, rY, ry 34 17 2023-10-05 8.2 Mendelian Genetics: When the Role of Genes Is Clear (19 of 19) • Dihybrid Cross ‒ The cross results in a 9:3:3:1 phenotypic ratio RrYy × RrYy Possible types of ovules RY Ry rY ry RY RRYY round, yellow RRYy round, yellow RrYY round, yellow RrYy round, yellow Ry RRYy round, yellow RRyy round, green RrYy round, yellow Rryy round, green RrYY round, yellow RrYy round, yellow rrYY wrinkled, yellow rrYy wrinkled, yellow Possible types of pollen rY ry RyYy round, yellow Rryy round, green rrYy wrinkled, yellow rryy wrinkled, green Proportion of each phenotype in offspring and their associated genotypes 9 Phenotype Round, yellow Genotypes RRYY, RrYY, RRYy, RrYy 3 Round, green RRyy, Rryy 3 Wrinkled, yellow rrYY, rrYy 1 Wrinkled, green rryy 35 BioA11 Introduction to the Biology of Humans Mendelian genetics • Pedigree analysis and genetics beyond Mendel • Sickle cell Mendel’s garden • OMIM 603903 • How is sickle cell inherited? • ______________________ ______________________ ______________________ ______________________ https://flic.kr/p/fsVD7c 36 18 2023-10-05 8.3 Extensions of Mendelian Genetics (1 of 9) Incomplete dominance: a heterozygote expresses an intermediate, “blended” phenotype • RR = red flowers • rr = white flowers • Rr = pink flowers Flower color in snapdragons Red = RR Homozygote White = rr Homozygote Pink = Rr Heterozygote 37 8.3 Extensions of Mendelian Genetics (2 of 9) Sickle cell allele shows incomplete dominance • Sickle cell disease – mutates oxygencarrying hemoglobin molecules in red blood cells • Requires two copies of mutant allele • Causes painful sickling attacks and organ damage • Heterozygous carriers produce some mutant hemoglobin (sickle cells). • In low oxygen, sickle cell disease symptoms may occur. 38 19 2023-10-05 8.3 Extensions of Mendelian Genetics (3 of 9) Codominance: the heterozygote’s phenotype is a combination of two fully expressed traits • R1R1 = red coat color in cattle • R2R2 = white coat color in cattle • R1R2 = roan coat color (red and white) Coat color in cattle Red = R1R1 White = R2R2 Roan = R1R2 (patchy red and white coat) 39 8.3 Extensions of Mendelian Genetics (4 of 9) Red blood ABO blood system • Displays multiple allelism: more than two alleles of a gene are possible • Three distinct alleles: IA, IB, and i. • Produce surface sugars on red blood cells • Two alleles are carried by each individual. cell phenotype Red blood cell genotype Type A Sugar A I AI A or I Ai Type B Sugar B I BI B or I Bi Type AB I AI B Sugars A and B Type O ii 40 20 2023-10-05 8.3 Extensions of Mendelian Genetics (5 of 9) Red blood ABO blood system • Three distinct alleles: IA, IB, and i. • i is recessive to both IA and IB. cell phenotype Red blood cell genotype Type A Sugar A I AI A or I Ai Type B Sugar B I BI B or I Bi Type AB I AI • IA and IB are codominant to each other. B Sugars A and B Type O ii 41 8.3 Extensions of Mendelian Genetics (6 of 9) Red blood cell phenotype ABO blood system • Three distinct alleles: I A, I B, Red blood cell genotype Type A Sugar A I AI A or I Ai Type B Sugar B I BI B or I Bi Type AB I AI and i. • IA produces surface sugar A for the Type A blood group (IAIA or IAi). • IB produces surface sugar B for the Type B blood group (IBIB or IBi). • i produces no surface sugars for the Type O blood group (ii). • IA and IB produce surface sugars A and B for theType AB blood group (IAIB). B Sugars A and B Type O ii 42 21 2023-10-05 8.3 Extensions of Mendelian Genetics (7 of 9) Blood transfusions • ABO blood groups must be considered and compatible. • Immune response due to incompatible blood transfusion. • Incompatible blood cells form clumps • Clumps block blood vessels • Recipient may die 43 8.3 Extensions of Mendelian Genetics (8 of 9) Table 8.2 Blood transfusion compatibilities. Recipient Recipient Can Receive Recipient Can Receive Type O Type O Type A Type B Type AB Type A Type B Type AB Type O Type B Type A Type AB Type O Type A Type B Type AB Type O None Type A Type B Type AB 44 22 2023-10-05 8.3 Extensions of Mendelian Genetics (9 of 9) Table 8.3 Sex determination strategies in some nonhuman organisms. Type of Organism Mechanism of Sex Determination Vertebrates (fish, amphibians, reptiles, birds, and mammals) In some vertebrates, the male has two of the same chromosomes and the female has two different chromosomes. In these cases, the female determines the sex of the offspring. Egg-laying reptiles In many egg-laying species, two organisms with the same suite of sex chromosomes could become different sexes. Sex depends on which genes are activated during embryonic development. For example, the sex of some reptiles is determined by the incubation temperature of the egg. Wasps, ants, and bees In bees, sex is determined by the presence or absence of fertilization. Males (drones) develop from unfertilized eggs. Females (workers and queens) develop from fertilized eggs. Bony fishes Some species of bony fishes change their sex after maturation. All individuals will become females unless they are deflected from that pathway by social signals such as displays of dominance. Earthworms Earthworms have both male and female reproductive organs, a condition referred to as hermaphroditism. 45 Male XY 8.4 Sex and Inheritance Female XX (1 of 9) Chromosomal sex determination: • 23 pairs of human chromosomes • 22 pairs of autosomes (nonsex chromosomes) • One pair of sex chromosomes • Women: two X chromosomes • Men: one X and one Y chromosome Meiosis X Y Possible sperm • Sperm cells with an X or a Y determine X X Possible eggs Fertilization the genetic sex of human offspring. • SRY gene on Y chromosome leads to testes development XY This zygote will develop into a male. XX This zygote will develop into a female. 46 23 2023-10-05 8.4 Sex and Inheritance (2 of 9) Sex-linked traits: more common in either males or females • Some traits due to genes on the sex chromosomes • X-linked: located on the X chromosome • Males only have one copy of X-linked genes. • More likely to be affected by recessive alleles on X chromosome • Females are less likely to express X-linkage. • Must carry two defective X chromosomes 47 8.4 Sex and Inheritance (3 of 9) X-linked traits and diseases • Red-green colorblindness: inability to distinguish between red and green • Affects 8% of men and less than 1% of women • Adrenoleukodystrophy (ALD): missing enzyme leads to buildup of waste products that destroy myelin in the brain • Affected boys rarely live longer than 10 years after symptoms develop • Recommended for newborn screening panel 48 24 2023-10-05 8.4 Sex and Inheritance (4 of 9) Carriers of X-linked recessive traits: unaffected females pass X-linked allele to sons (a) Unaffected male Carrier female X AY (b) ALD-affected male X aY X AX a Possible types of eggs Possible types of eggs Xa XA 1 4 XA Y X AX A Unaffected female X AY Unaffected male A = functional allele Unaffected females X AX a Carrier female 1 4 Carrier females 1 4 ALD-affected males 1 4 Unaffected males X aY ALD-affected male Possible types of sperm Possible types of sperm XA Unaffected female X AX A Xa Y 1 2 X AX a Carrier female Carrier females 1 2 Unaffected males X AY Unaffected male a = ALD-causing allele 49 8.4 Sex and Inheritance (5 of 9) Pedigree: a family tree showing trait inheritance through several generations • Scientists analyze matings that have already occurred. • Pedigree symbols include plain or shaded circles and squares connected by lines. Symbols used in pedigrees or Female Male Marriage or mating Offspring in birth order (from left to right) Affected individuals or Known or presumed carriers 50 25 2023-10-05 8.4 Sex and Inheritance (6 of 9) (a) Dominant trait: Polydactyly Modes of inheritance • Pedigrees reveal pp Pp modes of inheritance • Autosomal dominant trait pp Pp pp Pp Pp Pp Two affected parents can have unaffected offspring. pp pp Two unaffected individuals cannot have affected offspring. pp 51 8.4 Sex and Inheritance (7 of 9) Modes of inheritance (b) Recessive trait: Attached earlobes • Pedigree for an autosomal Ff ff recessive trait ff FF Ff Ff The recessive trait can skip a generation completely, producing unaffected individuals. or Affected individuals Ff Ff Ff Ff Ff ff ff Two unaffected parents can produce an affected child. ff or ff ff ff Two affected individuals have affected offspring. Known or presumed carriers 52 26 2023-10-05 8.4 Sex and Inheritance (8 of 9) Modes of inheritance • Pedigree for an X-linked trait 53 BioA11 Introduction to the Biology of Humans Symbols used in pedigree analysis Affected ____ Affected ____ Affected sex unspecified (or Transgender/ Non-binary) Bennett et al. 2008 J. Genet Counsel 17:424-433; Hales 2020 Life Sciences education https://doi.org/10.1187/cbe.19-08-0156 54 27 2023-10-05 Family trees and pedigrees • Charles has come in for genetic counselling he describes his family tree: • Sarah is Charles’s wife • Emily and Helen are Charles’s daughters • Jake is Charles’s son • Jim is Charles’s brother • Carol is Charles’s sister-in-law • Elliot and Thomas are Charles’ nephews • Betty and Lisa are Charles’s nieces • Melissa is Charles’ aunt • Steve is Charles’s uncle • Robert is Charles’s cousin • Jackie is Charles’s mother • Larry is Charles’s father • David is Charles’s grandfather • Ruth is Charles’s grandmother William M. Ciesla, Forest Health Management International, Bugwood.org © 2012 by K.D.Williams -UTSC 55 BioA11 Introduction to the Biology of Humans OMIM ______________________ • https://www.omim.org/ Mendel’s garden • Krabbe disease • OMIM 245200 • Cystic Fibrosis • OMIM 219700 • Sickle cell • OMIM 603903 • Tay Sachs • OMIM 272800 https://flic.kr/p/fsVD7c 56 28 2023-10-05 BioA11 Introduction to the Biology of Humans Tay Sachs • OMIM • https://www.omim .org/ • Go to the OMIM • Describe Tay Sachs • OMIM 272800 • ____________________ ____________________ ____________________ website and enter the OMIM number of Tay Sachs 57 BioA11 Introduction to the Biology of Humans Tay Sachs • Two people (David and Ruth) are planning to have children and they want to know what would be the probability that they would have a child with Tay Sachs if Ruth’s sister had Tay Sachs. • Explain: • By what process do they produce gametes? • Sperm • Eggs • ____________________ ____________________ ____________________ ____________________ ____________________ © 2013 by K.D.Williams -UTSC 58 29 2023-10-05 BioA11 Introduction to the Biology of Humans A Punnett square is _____________ • See Text chapter 8. • If Ruth’s sister had Tay Sach’s then Ruth’s sister would have genotype (tt) because Tay Sach’s is inherited in a homozygous recessive manner • Ruth could be a heterozygote at the T locus (Tt). • If Ruth and David were to have a child with Tay Sachs then Ruth would have been Tt AND David would have been Tt • If both Ruth and David have the Tt genotype what is the probability they could have a child with Tay Sachs (tt)? © 2013 by K.D.Williams -UTSC 59 BioA11 Introduction to the Biology of Humans Genetics • Phenotype ________ • Factors that alter phenotypic ratios • _________________________ _________________________ • Chapter 9: 9.1-9.3: • How can we identify regions of DNA that differ between people in a population? • What key enzyme is involved in DNA synthesis in the body? In PCR? 60 30