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Outline of course Pedigrees (example: cystic fibrosis) Mendel’s experiments with pea plants

Genome 351 , 4 April 2013, Lecture 1. Today…. Outline of course Pedigrees (example: cystic fibrosis) Mendel’s experiments with pea plants Proteins Cells. Cystic fibrosis. -Inherited disease that affects the lungs and digestive system

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Outline of course Pedigrees (example: cystic fibrosis) Mendel’s experiments with pea plants

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  1. Genome 351,4 April 2013, Lecture 1 Today… • Outline of course • Pedigrees (example: cystic fibrosis) • Mendel’s experiments with pea plants • Proteins • Cells

  2. Cystic fibrosis -Inherited disease that affects the lungs and digestive system -Affects ~30,000 children and adults in the United States (~70,000 worldwide). -A defective gene and its corresponding protein product cause the body to produce unusually thick, sticky mucus that: * clogs the lungs and leads to life-threatening lung infections; and * obstructs the pancreas and stops natural enzymes from helping the body break down and absorb food.

  3. A simple pedigree Two unaffected individuals have three children, the youngest of whom has cystic fibrosis (CF) = cystic fibrosis = Normal

  4. A larger family Two unaffected individuals have eight children, two of whom have cystic fibrosis

  5. Another generation

  6. Building pedigrees Horizontal line = mating Vertical line = offspring = Unaffected male = Affected male = Unaffected female = Identical twins = Affected female = Deceased male = Unknown sex

  7. Building pedigrees (cont’d)

  8. Building pedigrees (cont’d) I II = III

  9. Some early theories on heredity • Blending of traits • Vital spark (paternal or maternal) • Sperm carries preformed individual (homunculus) Gregor Mendel (1822–1884) introduces a more systematic approach

  10. Reasons why Mendel was successful: • Choice of a good model organism—garden pea • relatively short generation time—one per year • lots of progeny per cross • self-pollination and out-crossing possible • - true-breedingstrains readily available from local merchant • Choice of clear character differences to track • Yellow vs. green seed pods, round vs. wrinkled seeds, purple vs. white flowers, etc. • Careful mathematical analysis of the results • allowed him to develop and test specific models

  11. Mendel’s experiments crosses within the true-breeding population yield progeny that show the same trait as the parent Establish true-breedingstrains, each of which exhibit clear character differences x x Make crosses between different true-breeding strains Identify and count the progeny traits (phenotypes) x ?? Make crosses between the progeny… …are the progeny traits (phenotypes) like one parent or the other? How many of each class are there?

  12. Results of Mendel’s experiments: True-breeding green pea pod strain True-breeding yellow pea pod strain x Generation I: Predictions of: Blending Hypothesis Vital spark Hypothesis Homunculus Hypothesis Actual results: Hybrid pea plants Generation II:

  13. The yellow trait returns in generation III True-breeding green pea pod strain True-breeding yellow pea pod strain x Generation I: Hybrid pea plants Generation II: Cross hybrid plants to one another (or self-cross) Generation III:

  14. Yellow 6022 yellow 2. Yellow X green seed 3.01 : 1 2001 green Purple 705 purple 3. Purple X white petal 3.15 : 1 224 white Inflated 882 inflated 4. Inflated X pinched pod 2.95 : 1 299 pinched Round 5474 Round 5. Round X wrinkled seed 2.96 : 1 1850 wrinkled Axial 651 axial 6. Axial X terminal flowers 3.14 : 1 207 terminal Long 787 long 7. Long X short stem 2.84 : 1 277 short Identical findings seen with other traits… Parental Phenotypes Gen II Gen III Ratio (gen III) Green 428 Green 1. Green X yellow pod 2.82 : 1 152 yellow

  15. Mendel’s interpretations Both parents contribute a “determinant” (gene) that influences the seed pod color trait True-breeding green pea pod strain True-breeding yellow pea pod strain x

  16. Mendel’s interpretations There are two forms of a gene (alleles) for the seed pod color trait; the trait conferred by one allele (recessive) can be masked by the trait conferred by the other allele (dominant) True-breeding green pea pod strain True-breeding yellow pea pod strain x The g allele (which confers yellow seed pods) is recessive to the dominant G allele (which confers green seed pods).

  17. Mendel’s interpretations Genes are particulate (i.e., do not mix); recessive traits that are not evident in heterozygotes can be unmasked in progeny True-breeding (homozygous) green pea pod strain True-breeding (homozygous) yellow pea pod strain x Generation I: Hybrid (heterozygous) pea plants Generation II: Cross hybrid plants to one another (or self-cross) The recessive trait reappears intact in generation III Generation III:

  18. G g How did Mendel explain the 3:1 ratio? -The Punnett Square x female gametes G g male gametes

  19. General conclusions of Mendel’s work 1. Many traits (phenotypes) are determined by genes Gene variants (alleles) can confer dominant or recessive traits (phenotypes) There are two copies of each gene Each parent randomly transmits only one of their two alleles of a given gene to their offspring

  20. Some vocabulary Gene: unit of information passed from one generation to the next. Alleles : variants of a gene (e.g., yellow vs. green) Homozygote: both copies of the gene are the same Heterozygote: The two copies of the gene are different Genotype: the information specifying a trait Phenotype: the manifestation of the trait itself Genotypes? Phenotypes?

  21. Information passes from one generation to the next!

  22. Applying Mendel’s principles to CF Two unaffected individuals have eight children, the two of whom have cystic fibrosis C = common allele c = cystic fibrosis allele

  23. C c C c The Punnett Square Cc Heterozygous parents Cc

  24. The cystic fibrosis gene specifies a membrane protein

  25. Proteins are the workhorses of the cell • Many sizes and shapes • Rod-like, globular • Single subunit, multimeric • Many distinct properties • Water soluble, lipid loving • Many functions • Structure, catalysts, motors, signals, pumps • Mutations often alter proteins

  26. CFTR+ CFTR+ CFTR+ CFTR- CFTR- CFTR- Cystic fibrosis is recessive Cystic Fibrosis NO Homozygous (wild-type) Heterozygous NO Homozygous (mutant) YES

  27. But what are proteins (chemically)? Polymers of 20 different amino acids (only 11 can be made by humans, others must be obtained from the diet)

  28. The 20 amino acids

  29. Proteins adopt a variety of structures • Average protein = 300 to 400 aa’s • Variety of linear amino acid sequences is almost infinite... • e.g., a protein of 100 amino acids made with the 20 different known amino acids can have 20100different linear sequences • most often has a globular (spherical) 3-D shape & is negatively charged • E. coli (human intestinal bacteria) makes about 3,000 proteins • humans make about 100,000 different proteins with 25,000 genes (WOW!)

  30. Distinct proteins are different length chains of different amino acids Insulin -- Met-ala-leu-trp-met … glu-gln-tyr-cys-gln (110 aa) Collagen -- Met-his-pro-gly-leu … cys-met-lys-ser-leu (1678 aa) ß-Hemoglobin -- Met-val-his-leu … ala-his-lys-tyr-his (147 aa)

  31. Collagen G6PD Albumin

  32. Cells -- the basic unit of life • Organisms can be single cells (e.g., bacteria, yeast) or collections of many cells • Prokaryotes (bacteria) lack a nucleus • Eukaryotes have a nucleus and other compartments The Basic Unit of Life

  33. An animal cell • Surrounded by the plasma membrane • Contains a nucleus (where >99% of the genes are located) and cytoplasm with specialized organelles • Come in many different shapes

  34. The plasma membrane

  35. The cystic fibrosis gene specifies a membrane protein

  36. Mitochondria • Site of ATP (energy) production • Has its own circular DNA (<1% of the cellular genes located here) • Mitochondrial genes are inherited from the mother

  37. Human Cells • Hundreds of cell types • Several categories • Epithelial (skin, intestinal, lung, but also pancreas, liver, kidney) • Muscle • Nerve • Connective • Blood

  38. Levels of Organization • Organism • Organ systems • Organs • Tissues • Cells

  39. Next time… DNA is the genetic material Structure of DNA reveals a digital code Replication of DNA

  40. CFTR regulates Cl- transport across membranes

  41. Gene responsible for Cystic Fibrosis

  42. Cystic Fibrosis Affected persons can have unaffected parents Disease can skip generations Both sexes equally affected

  43. Genetics of Cystic Fibrosis (CF) • Autosomal recessive trait • ~1/25 Caucasians is a carrier • ~1/65 Africans is a carrier • ~1/90 Asians is a carrier • Gene lies chromosome 7q31.2 • Gene encodes a chloride channel expressed in lung, skin and pancreas • DNA diagnosis in utero

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