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GENETICS : Introduction to IEM. Topics: DNA Structure, Replication & Central Dogma. Studies of Heridity. By geneticists - describe patterns of inheritance traits (phenotypes) heritable (passed from parents to offspring)

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Presentation Transcript
slide1

GENETICS : Introduction to IEM

Topics:

DNA Structure, Replication & Central Dogma

slide2

Studies of Heridity

  • By geneticists
  • - describe patterns of inheritance
  • traits (phenotypes)
  • heritable (passed from parents to offspring)
  • cytogeneticists knew that trait inheritance is associated with the cell nucleus and with chromosomes
  • biochemists knew that chromosomes are composed of DNA and protein
slide3

Parent trait

Offspring trait

Q. What is the molecular/biochemical basis of

inheritance?

How is it known that DNA

contains genetic information

???

slide4

Some Important Definitions

  • Gene:
  • - segment of DNA that contains all the information needed for regulated synthesis of an RNA or protein product.
  • Genome:
  • - the entire DNA sequence content of an organism (nuclear DNA)
dna structure double helix
DNA Structure: Double Helix
  • 1953 - Watson and Crick 3-D structure of DNA
  • DNA is a double helix (ll-stranded)
  • Polymer of nucleotides (phosphate, sugar, base)
  • DNA has 4 base types (adenine, thymine, guanine, cytosine)
slide6

4 DNA Nucleotides

THYMINE (T)

ADENINE (A)

base

phosphate

sugar

CYTOSINE (C)

GUANINE (G)

slide7

A - T

G - C

Base pairing

Strands have

different polarity

&

antiparallel

slide8

equal (randam)

base

composition

AT rich

GC rich

5’

3’

or

or

3’

5’

1 bp

slide9

DNA Replication

parental

strand

as a

template

daughter

strand

has

complement

bases

slide11

How does DNA relate to proteins?

1908: Garrod

inborn errors

of metabolism

(hereditary disease)

Alkaptonuria (AKU): accumulation of homogentisic acid

1:200,000

slide12

blocked in

PKU

1:8,000

Phenylalanine/Tyrosine

degradative

metabolic

pathway

II

blocked in

Tyrosenemia

III

blocked in

AKU

1:200,000

slide14

Central Dogma of Genetics

Replication

DNA

RNA

Protein

Transcription

Reverse

Transcription

Translation

aa

aa

aa

aa

aa

aa

genes and proteins
Genes and Proteins
  • Inborn Errors of Metabolism shown by Garrod to cause hereditary disease.
  • Study of Biochemical Pathways lead to understanding that mutant genes result in defective proteins (enzymes).
slide19

further

metabolites

homogentisic

acid

Tyr

Accumulation

of homogentisic

acid

Biochemical Genetics

Archibald Garrod (1902) - an English doctor

Described “alkaptanurea” disease

Symptom: urine turns black when exposed to air

Found it was due to oxidation of homogentisic acid in urine

homogentisic acid = an intermediate in Phe degradation

Phe

slide20

Biochemical Genetics

Archibald Garrod : important contributions

Described “alkaptanurea” disease

Deduced that it is due to a defective metabolic enzyme

Disease is a hereditary condition (ran in his patients’ families)

Led to concept of “inborn errors of metabolism”

A novel phenotype may reflects a discrete biochemical difference

slide22

Aspartame

= a dipeptide: aspartyl-phenylalanine methyl ester

“Real-World Biochemistry”

Aspartame is metabolized in the body to its components: aspartic acid, phenylalanine, and methanol. Like other amino acids, it provides 4 calories per gram. Since it is about 180 times as sweet as sugar, the amount of aspartame needed to achieve a given level of sweetness is less than 1% of the amount of sugar required. Thus 99.4% of the calories can be replaced.

Look on your diet soda cans and read the warning

slide23

defective

enzyme

Parent trait

Offspring trait

Biochemical Genetics

Archibald Garrod : important contributions

Proposed that inheritance of a defective metabolic enzyme leads to inheritance of a phenotype (disease)

slide24

George W. Beadle

  • born in Wahoo, Ne
  • undergraduate degree at UNL
  • did graduate work at Cornell
  • got a faculty position at CalTech
  • ended up as the president of the Univ of Chicago
  • did work in the 1930’s & 40’s on Drosophila eyes
  • and on Neurospora (bread mold)
  • “one gene - one enzyme” hypothesis (1941)
  • awarded Nobel prize in 1958 (with research colleagues J. Lederberg and E. Tatum)
slide25

sucrose

Inorganic salts

biotin

George W. Beadle

  • Bread Mold: Neurospora crassa
  • can grow on minimal media
  • Beadle selected for nutritional mutants (auxotrophs)
  • irradiated fungal spores, grew these up on complete
  • media, and transferred part of the stock to minimal media
  • He looked for mutants that can grow on complete media but NOT on minimal media
  • These mutants are lacking an enzyme for the synthesis of an essential nutrient
slide26

Beadle’s Experiment Summary

  • Beadle could identify mutants in specific steps of a pathway
  • Assuming each mutant was defective in a single gene, Beadle postulated that the different mutant classes each lacked a different enzyme for Arg biosynthesis
  • Therefore, he could show a one-to-one correspondance between mutation and absence of an enzyme.
  • one gene specifies/encodes one enzyme
slide27

Parent

trait

defective

gene

defective

enzyme

Offspring

trait

Beadle’s experiment gave rise

to a new field called

Biochemical Genetics

mutations
Mutations
  • Mutation = change in the base sequence of DNA
  • Any mutation that causes the insertion of an incorrect amino acid in a protein can impair its function
  • Base substitutions alter the genetic code which specifies amino acid placement in proteins
genes and environment
Genes and Environment
  • One gene can affect more than one trait: pleiotropy
  • Any trait can be affected by more than one gene: epistasis
pedigree analysis
Pedigree Analysis
  • The analysis of an unknown trait from a family history (pedigree) 
    • Is the trait dominant
      • does every affected offspring have an affected parent
    • Is the trait determined by a single gene
      • affected progeny born to heterozygous parents (carriers) should occur with a frequency of 3:1 (unaffected to affected)
    • Is the trait sex-linked
      • is it expressed more frequently in males
      • not, if expressed at equal frequency in male and female progeny
autosomal dominants
Autosomal Dominants
  • At least one parent of the index case (proband) is affected, both male and female progeny are affected equally and can transmit the condition, when an affected person has offspring, they have a one chance in two of inheriting the trait
  •  For dominantly inherited traits:
    • generations not skipped
    • some patients do not have affected parents, the result of a new mutation
    • clinical features:
      • reduced penetrance - reduced fraction of individuals show the phenotype
      • variable expressivity – trait is expressed to different extents among affected individuals
    • for many dominant traits the age of onset is delayed beyond reproductive age 
mechanisms of dominant disorders
Mechanisms of dominant disorders
  • Usually a loss of function mutation
    • Loss of a component of an enzymatic, regulatory or signaling pathway
    • Loss of a structural protein such as collagen
  • These can produce a dominantly active phenotype by:
    • reducing function below a level necessary to maintain a normal phenotype (familial hypercholesterolemia, LDL receptor)
    • acting as a “dominant negative” (Marfan Syndrome, fibrillin-1 or some forms of Ehlers-Danlos Syndrome, collagen) which prevents the function of the normal allele in the heterozygous state
  • Gain of Function Mutation
    • Huntington disease results from a mutation in the Huntington gene which gives rise to an over-expression of an altered protein that is toxic to neural cells
autosomal recessive
Autosomal Recessive
  • The trait does not usually affect the parents, but siblings may show the disease
  • Siblings have a 1-in-4 chance of inheriting the disease
  • The majority of the mutant genes in the gene pool are in heterozygous “carriers”
  • If the mutant gene occurs with a low frequency in the population, there is a likelihood the proband is the product of a consanguineous marriage
mechanisms of recessive disorders
Mechanisms of Recessive Disorders
  • Features of autosomal recessive disorders
    • Complete penetrance
    • Early age of onset
    • Molecular change usually results in a loss of function
  • In the heterozygous carrier the presence of 50% of the protein is sufficient to provide a normal phenotype
    • Essentially all inborn errors of metabolism are inherited as autosomal recessive traits