Outline of course Pedigrees (example: cystic fibrosis) Mendel’s experiments with pea plants
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Transcript of Outline of course Pedigrees (example: cystic fibrosis) Mendel’s experiments with pea plants
» Outline of course» Pedigrees (example: cystic fibrosis)» Mendel’s experiments with pea plants» Proteins» Cells
Today… Genome 351, 4 April 2013, Lecture 1
-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.
Cystic fibrosis
Two unaffected individuals have three children, the youngest of whom has cystic fibrosis (CF)
A simple pedigree
= Normal
= cystic fibrosis
A larger familyTwo unaffected individuals have eight children, two of whom have cystic fibrosis
Another generation
Building pedigrees
= Deceased male
= Unaffected male
= Affected male
= Unaffected female
= Affected female
Horizontal line = matingVertical line = offspring
= Identical twins
= Unknown sex
Building pedigrees (cont’d)
=
Building pedigrees (cont’d)
I
II
III
• Blending of traits• Vital spark (paternal or maternal)• Sperm carries preformed individual
(homunculus)
Some early theories on heredity
Gregor Mendel (1822–1884) introduces a more systematic approach
• 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-breeding strains 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
Reasons why Mendel was successful:
Establish true-breeding strains, each of which exhibit clear character differences
Make crosses between different true-breeding strains
Identify and count the progeny traits (phenotypes)
…are the progeny traits (phenotypes) like one parent or the other? How many of each class are there?
??Make crosses between the progeny…
Mendel’s experimentscrosses within the true-breeding population yield progeny that show the same trait as the parent
xx
x
x
Results of Mendel’s experiments:
True-breeding yellow pea pod strain
True-breeding green pea pod strain
Predictions of:Blending
HypothesisVital spark Hypothesis
Homunculus Hypothesis
Generation I:
Generation II:
Actual results:
Hybrid pea plants
x
The yellow trait returns in generation III
True-breeding yellow pea pod strain
True-breeding green pea pod strain
Hybrid pea plants
Generation I:
Generation II:
Cross hybrid plants to one another (or self-cross)
Generation III:
Identical findings seen with other traits…Parental Phenotypes1. Green X yellow pod
Gen IIGreen
Gen III428 Green152 yellow
Ratio (gen III)2.82 : 1
2. Yellow X green seed Yellow 6022 yellow2001 green
3.01 : 1
3. Purple X white petal Purple 705 purple224 white
3.15 : 1
4. Inflated X pinched pod
5. Round X wrinkled seed
6. Axial X terminal flowers
7. Long X short stem
Inflated
Round
Axial
Long
882 inflated299 pinched5474 Round1850 wrinkled651 axial207 terminal787 long277 short
2.95 : 1
2.96 : 1
3.14 : 1
2.84 : 1
Mendel’s interpretations
xTrue-breeding green pea pod strain
True-breeding yellow pea pod strain
Both parents contribute a “determinant” (gene) that influences the seed pod color trait
Mendel’s interpretations
xTrue-breeding green pea pod strain
True-breeding yellow pea pod strain
The g allele (which confers yellow seed pods) is recessive to the dominant G allele (which confers green seed pods).
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)
Cross hybrid plants to one another (or self-cross)
Mendel’s interpretationsGenes are particulate (i.e., do not mix); recessive traits that are not evident in heterozygotes can be unmasked in progeny
Hybrid (heterozygous) pea plants
xTrue-breeding (homozygous) yellow pea pod strain
True-breeding (homozygous) green pea pod strain
Generation I:
Generation II:
Generation III:The recessive trait reappears intact in generation III
How did Mendel explain the 3:1 ratio?
G g
G
g
female gametes
mal
e ga
met
esx
-The Punnett Square
General conclusions of Mendel’s work1. Many traits (phenotypes) are determined by
genes
2. Gene variants (alleles) can confer dominant or recessive traits (phenotypes)
3. There are two copies of each gene
4. Each parent randomly transmits only one of their two alleles of a given gene to their offspring
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 sameHeterozygote: The two copies of the gene are
differentGenotype: the information specifying a traitPhenotype: the manifestation of the trait itself
Genotypes?Phenotypes?
Information passes from one generation to the next!
Applying Mendel’s principles to CF
Two unaffected individuals have eight children, the two of whom have cystic fibrosisC = common allelec = cystic fibrosis allele
The Punnett Square
c
C
cC
Cc
Cc
Heterozygous parents
The cystic fibrosis gene specifies a membrane protein
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
Cystic fibrosis is recessive
CFTR+
CFTR+
CFTR+
CFTR-
CFTR-
CFTR-
Homozygous (wild-type)
Homozygous (mutant)
Heterozygous
Cystic Fibrosis
NO
NO
YES
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)
The 20 amino acids
•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 20100 different 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!)
Proteins adopt a variety of structures
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)
Protein FunctionActin, myosin Muscle contractionAntibodies ImmunityHemoglobin, myoglobin Oxygen transportInsulin, glucagon Blood glucose controlCollagen Tendons,dermisKinases Modulate protein activityDehydrogenases MetabolismThrombin, fibrinogen Blood clottingKeratin Hair and skinTrypsin, proteases DigestionPolymerases DNA, RNA synthesisNaATPases Ion pumps
Collagen
G6PDAlbumin
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Cells -- the basic unit of life
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
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
The plasma membrane
The cystic fibrosis gene specifies a membrane protein
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
Human Cells
• Hundreds of cell types• Several categories– Epithelial (skin, intestinal, lung, but also pancreas, liver, kidney)
– Muscle– Nerve– Connective– Blood
Levels of Organization
• Organism• Organ systems• Organs• Tissues• Cells
Next time…
DNA is the genetic material
Structure of DNA reveals a digital code
Replication of DNA
CFTR regulates Cl- transport across membranes
Gene responsible for Cystic Fibrosis
Cystic Fibrosis
Affected persons can have unaffected parents
Disease can skip generations
Both sexes equally affected
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