1. GENETICS : Introduction to IEM
Topics:
DNA Structure, Replication & Central Dogma

2. 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

3. How is it known that DNA contains genetic information ???
Q. What is the molecular/biochemical basis of
inheritance?
Parent trait
Offspring trait
How is it known that DNA
contains genetic information
???

4. 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)

5. DNA Structure: Double Helix
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)

6. 4 DNA Nucleotides base phosphate sugar THYMINE (T) ADENINE (A)
CYTOSINE (C)
GUANINE (G)

7. A - T G - C Base pairing Strands have different polarity &
antiparallel

8. equal (randam) base composition AT rich GC rich5’ 3’ or or 3’ 5’
1 bp

9. DNA Replication
parental
strand
as a
template
daughter
strand
has
complement
bases

10. Clones due to replication from 1 cell

11. Alkaptonuria (AKU): accumulation of homogentisic acid
How does DNA relate to proteins?
1908: Garrod
inborn errors
of metabolism
(hereditary disease)
Alkaptonuria (AKU): accumulation of homogentisic acid
1:200,000

12. Phenylalanine/Tyrosine
blocked in
PKU
1:8,000
Phenylalanine/Tyrosine
degradative
metabolic
pathway II
blocked in
Tyrosenemia
III
blocked in
AKU
1:200,000

13. A defective enzyme results from a mutant gene
HOW????

14. Central Dogma of Genetics
Replication
DNA
RNA
Protein
Transcription
Reverse
Transcription
Translation aa aa aa aa aa aa

18. 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).

19. 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
homogentisic
acid
further
metabolites
Phe
Tyr
Accumulation
of homogentisic
acid

20. A novel phenotype may reflects a discrete biochemical difference
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

21. Biochemical Genetics

22. “Real-World Biochemistry”
Aspartame
= a dipeptide: aspartyl-phenylalanine methyl ester
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

23. Biochemical Genetics Archibald Garrod : important contributions
Proposed that inheritance of a defective metabolic enzyme leads to inheritance of a phenotype (disease)
defective
enzyme
Parent trait
Offspring trait

24. 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)

25. George W. Beadle Bread Mold: Neurospora crassa
can grow on minimal media
sucrose
Inorganic salts
biotin
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

26. 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

27. Beadle’s experiment gave rise
to a new field called
Biochemical Genetics
Parent
trait
Offspring
defective
enzyme
defective
gene

28. 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 12

33. Genes and Environment
One gene can affect more than one trait: pleiotropy
Any trait can be affected by more than one gene: epistasis

35. 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

36. 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 

37. 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

38. Autosomal Dominant Genetic Disease

40. 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

41. 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

42. Autosomal Recessive Genetic Disease