Download Lesson 6.2 Genetics

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)
• cytogeneticists knew that trait inheritance
is associated with the cell nucleus and with
chromosomes
• biochemists knew that chromosomes are
composed of DNA and protein
Q. What is the molecular/biochemical basis of
inheritance?
Parent trait
Offspring trait
How is it known that DNA
contains genetic information
???
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
• 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)
4 DNA Nucleotides
ADENINE (A)
THYMINE (T)
base
phosphate
sugar
GUANINE (G)
CYTOSINE (C)
A - T
G - C
Base pairing
Strands have
different polarity
&
antiparallel
equal (randam)
base
composition
AT rich
GC rich
5’
3’
or
3’
or
5’
1 bp
DNA Replication
parental
strand
as a
template
daughter
strand
has
complement
bases
Clones due to replication from 1 cell
How does DNA relate to proteins?
1908: Garrod
inborn errors
of metabolism
(hereditary disease)
Alkaptonuria (AKU): accumulation of homogentisic acid
1:200,000
Phenylalanine/Tyrosine
degradative
metabolic
pathway
blocked in
PKU
1:8,000
II
III
blocked in
Tyrosenemia
blocked in
AKU
1:200,000
A defective enzyme results from a mutant gene
HOW????
Central Dogma of Genetics
Replication
DNA
Transcription
Reverse
Transcription
RNA
Translation
Protein
aa aa aa aa aa aa
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).
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
Tyr
homogentisic
acid
Accumulation
of homogentisic
acid
further
metabolites
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
Biochemical Genetics
“Real-World Biochemistry”
Aspartame
= a dipeptide:
aspartylphenylalanine
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
Biochemical Genetics
Archibald Garrod : important contributions
Proposed that inheritance of a defective metabolic
enzyme leads to inheritance of a phenotype (disease)
Parent trait
defective
enzyme
Offspring trait
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)
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
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
Beadle’s experiment gave rise
to a new field called
Biochemical Genetics
Parent
trait
defective
gene
defective
enzyme
Offspring
trait
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
• One gene can affect more than one
trait: pleiotropy
• Any trait can be affected by more
than one gene: epistasis
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
• 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
• 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 Dominant Genetic Disease
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
• 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
Autosomal Recessive Genetic Disease