Genetic Variation Flashcards
Isozymes
Distinguishable proteins (sequence based) with the same or similar enzymatic activity (substrate specificity)
Isoforms
Proteins with similar functional and/or structural properties that may be derived from different genes or from alternative splicing/post-translational modification of the same genes.
Polymorphism
Occurrence of two or more allelic traits in a population with frequencies > 1-2% (relatively stable; can’t be accounted for by new, random mutation)
single nucleotide polymorphisms (SNPs)
- Substitution of one base for another
- Synonymous/conservative = no change in AA but can still mess with splice sites, TF factor binding, or other mechanisms that rely on nucleotide sequence
- VERY common: every 100-200 bp
Heterozygosity
- Nucleotide on one allele different from the nucleotide on the other allele (for almost all genes, both alleles are expressed)
How frequent is heterozygosity?
Every 250-500 bp (up to 6-12 million sites in an individual)
Disease predisposition
Polymorphism that leads to susceptibility for disease under certain conditions
How are polymorphisms detected at the protein and genetic levels?
Protein: electrophoretic mobility, Km, thermostability, biophysical properties
Gene: exon sequencing (SNPs and STRs)
Short Tandem Repeats (STRs)
Microsatellite regions consisting of 2-6bp sequences repeating 3-100 times.
Length of STRs associated with the presence of certain polymorphisms
What are the possible consequences of polymorphism?
- No phenotypic effect
- Normal variation
- Disease susceptibility
- Disease (if monogenic)
Principle of Segregation
Sexually reproducing organisms possess genes that occur in pairs but only one member of this pair is transmitted to offspring
Principle of Independent Assortment
Genes at different loci are transmitted independently
Dominance and recessivity
The effects of one allele may mask those of another allele
Genotype frequency
Number of heterozygotes or homozygotes in a population
Allele frequency
Number of times an allele is present (+2 for homozygotes and +1 for heterozygotes) out of the total number of alleles in a population (2n)
Hardy-Weinberg Principle
In an ideal population the relative proportions of different genotypes remain constant from one generation to another
Hardy-Weinberg Equations
p^2 + 2pq + q^2 = 1 and p+q=1
What do p and q represent?
Allele frequencies (dominant and recessive)
What do p^2, 2pq, and q^2 represent?
Genotype frequencies (homozygotes and heterozygotes)
False Assumptions of Hardy-Weinberg
- Random mating (stratification, assortative mating, consanguinity)
- Constant allele frequencies (genetic drift/founder effect, gene flow, mutation and selection -> heterozygote advantage)
Linkage
Two loci are considered linked if they are transmitted together; probability of being transmitted together depends on physical distance between the loci
What are the 3 ways two loci can be related in terms of linkage?
- Unlinked: nonrecombinant = recombinant
- Completely linked: nonrecombinant only
- Partially linked: nonrecombinant > recombinant
Recombination frequency
Percent recombination seen between two loci in a large series of meioses; can infer distance between two loci
Genetic distance
- Unit measure of recombination (centiMorgan)
- 1 crossing over/100 meioses = 1% recombination = 1 cM ~ 1Mb
Determining phase
Figuring out which alleles came from which parents
Haplotype
combination of alleles on each chromosome
Linkage analysis
Can be used to trace the inheritance of one trait (or disease) by presence of a linked trait and to identify unknown disease genes in a family
Logarith of the odds
- Used to determine the likelihood that two loci are linked
- Equation: log of (likelihood of observing pedigree data if the loci are linked at a particular recombination frequency) / (likelihood of observing pedigree data if the loci are unlinked - recombination frequency = 0.5)
- LOD > 3 means 1000x more likely that the loci are linked than that they are associating by chance
Linkage disequilibrium
- Non-random association of alleles at different loci
- Blocks of polymorphism inherited together, though you would expect lots of recombination between them
Genome wide association studies
- Test for altered frequencies of particular alleles or haplotypes in affected individuals compared with controls
- Examines particular alleles or haplotypes for their contribution to the disease
- Looks for polymorphism associated with phenotype, but doesn’t determine cause
