Proteins to Phenotype

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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 Proteins cellular processes 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 purine -Indel: Insertion or deletion of base 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) - Nonconservative: chemically different amino acid (Phe Ser) -Nonsense mutation: stop codon -Frameshift mutation: shift reading frame (Indel) ATG CGA TAT TCA GCC ... ATG CGA TCA TTC AGC... UAC GCU AUA AGU CGG ... UAC GCU AGU AAG UCG... Tyr Ala Ile Ser Arg ... Tyr Ala Ser Lys Ser... Effect on protein Function Colinearity: gene = polypeptide product (Yanofsky) Protein types: active proteins & structural proteins Mutation active site in active proteins Mutation 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.
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