Download Proteins to Phenotype

From Genes to Phenotype
Genes, mutations and dominance: How genes work
What do we already know?
(last class)
The Process
Genes
translation via ribosome
Proteins
cellular processes
proteins
tissues
individual's phenotype
population variation
HOW???
Mutations
Working backwards:
mutations in cells = mutations in proteins = mutations in genes = change in nucleic acid = change in base composition
So...changes in base composition are responsible for mutations!
Base coding
specific tRNA = specific amino acids
-2,4,6 fold degeneracy
-Wobble
Single base pair mutations:
-Transition: purine
purine / pyrimidine
pyrimidine
-Transversion: Purine
pyrimidine / Pyrimidine
-Indel: Insertion or deletion of base
purine
ATTCGAT ATTCAGC
ATTCGATCATTCAGC
ATTCGATCATTCAGC
ATTCGAT ATTCAGC
Consequences on code:
-Synonymous mutation: code for same amino acid
-Missense mutation: codes for different amino acid
- Conservative: chemically similar amino acid (Lys
Arg)
Ser)
- Nonconservative: chemically different amino acid (Phe
-Nonsense mutation: stop codon
-Frameshift mutation: shift reading frame (Indel)
ATG
UAC
Tyr
CGA
GCU
Ala
TAT
AUA
Ile
TCA
AGU
Ser
GCC ...
CGG ...
Arg ...
ATG
UAC
Tyr
CGA
GCU
Ala
TCA
AGU
Ser
TTC
AAG
Lys
AGC...
UCG...
Ser...
Effect on protein Function
Colinearity: gene = polypeptide product (Yanofsky)
Protein types: active proteins & structural proteins
Mutation
Mutation
active site in active proteins
structural bonds in structural proteins
Enzyme pathways
One enzyme per step
Disease: enzyme deficiency (Enzymopathies)
Developmental consequences
Dominance and recessiveness
Positions of mutations (structure & active site)
Number of copies of mutant gene (functional vs nonfunctional)
Haplo-sufficiency vs haplo-insuffiiciency: albinism (molecular basis)
Glimpse of the bigger picture....Variance
Discontinuous vs Continuous
Environment
Evolution
More on Mutations
Proportionality between number of mutant alleles, gene product and phenotype.
Mutations change:
Protein make up
Enyzme concentrations
Cellular functions
Phenotype!
Mutations create "alleles"
Alleles: Different forms of a gene at same location on chromosome.
Polymorphism: Existence of many common variants (alleles) of a gene in a population.
Morph = allele = variant
Each organism normally has two alleles for each gene!
High number of different alleles leads to genetic variance in populations!
Not all allelic differences lead to major changes!
Mutations to some alleles lead to change or absence of protein.
Mutations that cause loss of function create null alleles.
But some mutations are necessary for evolution!
Phenotypes can be traced to allelic differences!
Most common phenotype in a population is known as the wildtype.
Mutations and Dominance
Dominance & recessiveness relate to severity of mutation.
Dominant traits: Phenotype is expressed if only one allele is abnormal
Recessive traits: Both copies of the gene need to be mutated in order for phenotype to be expressed.
Haplo-sufficiency: One functioning allele provides enough protein for normal function.
Haplo-insufficiency: One normal allele cannot provide enough protein for normal function.
Dominant and recessive describe phenotype only !!!
Can be heterozygous or homozygous dominant/recessive.
Unique types of dominance
Gain of function dominance: Mutant alleles enable new functions wild-type cannot perform.
Dominant negative dominance: Mutations cause loss of function in presence of normal protein levels (multimers).
Incomplete dominance: Heterozygote is intermediate between homozygote phenotypes.
Codominance: Heterozygote expresses both phenotypes to make a new phenotype (i.e AB Blood group).
Genes and labor division
Important to know how many genes contribute to a function.
Unable to answer this question.
Need to know:
1. Genome of an organism.
2. Where all genes are in genome.
3. Function of each gene.
Most known genes code for enzymes.
Most of these are metabolic enzymes.
Proteome: Protein-coding genes in an organism.
Genetics & Disease
Many genetic diseases are a result of mutations in key metabolic, cell cycle, immunological or developmental genes.
Most recessive diseases are known as single gene diseases.
More than 1000 human diseases are known to be single gene disease.
Phenylketonuria is a single gene disease.
Mutations to genes decrease in phenylalanine hydroxylase.
Leads to buildup of phenylalanine.
Phenylalanine converted to phenylpyruvic acid.
Pyruvic acid interferes with nervous system development.
Most single gene diseases are rare.
Other genetic disorders are common in certain populations.
1. Tay-Sachs disease is high in Jewish populations.
2. Sickle-cell anemia reaches 9% in some African countries.
3. Many genetic diseases are high in Newfoundland.
Cancer is genetic in cause, though difficult to trace!
Many diseases thought to be non genetic getting more attention!
Diabetes and mental disorders may have genetic roots!
Genetic diseases can be both hard and easy to treat
Disease affecting early development has severe consequences.
Some diseases may be fixed with gene therapy.
Others require simple diet changes!
Human Genome Project: By mapping out genome, may be able to find genes that cause disease!
Other types of variation
Some variations are hard to classify!
Environment can affect a phenotype.
Some traits are continuous!
Some complex traits very difficult to identify i.e behavior.
On the other hand other traits are quite observable!
Eye color is easy to distinguish in individuals!
Study of Discontinuous traits led to early breakthroughs in genetics!
Mendel did all his work on peas using discontinuous traits!
He did not know the molecular reasons for what he was observing!
Did manage to show in some simple cases it is possible to predict offspring phenotypes given parental phenotype.
Example: smooth vs. wrinkly peas!
Mendialian genetics is a subsection of genetics and does not apply to all genetic modes of inheritance!
Questions? Email Amy or Adrian