What is a phenotype?
A physical, social, behavioral, or emotional quality (characteristic) that varies from one individual to another
For sample, eye, skin or hair colour, blood pressure or IQ
What is a genotype?
The genetic makeup of an organism - the gene (or allele) combination an individual organism has
What is an SNP?
Single Nucleotide Polymorphism- DNA sequence variation occurring commonly within a population (e.g., 1%) in which a single nucleotide A, T, C, or G in the genome differs between members of a biological species or paired chromosomes
What are CNVs?
Copy number variations
5-10% of human genome contributes to repeated sequences of size ranging from 50bp to 3Mb
What is the difference between Monogenic and polygenic traits/ diseases?
Monogenic trait/disease:
- Controlled by a SINGLE gene mutation
- Also called Mendelian inheritance
- Disease caused by preexisting mutant alleles passed down from one generation to next
- Polygenic trait/disease:
- Controlled by MORE THAN TWO GENES
- Also called multifactorial inheritance
- Multiple genes interact with environment
What are polymorphisms and give 2 examples?
Individual variation within a species - anything that differs between individuals, species, etc.
Examples:
- DNA molecule versions (SNPs creating different genotypes)
- Flower color variations (4 versions shown with different SNPs)
Give 6 key factors affecting genetic variation
- Population Bottleneck - sharp reduction in population size due to environmental events (famines, earthquakes)
- Selection - change in DNA caused by environment adaptation causing variation in fitness; heritable
- Mutation - change in DNA of genes
- Admixture - mix of two previously isolated (genetics isolate populations)
- Migration and Environment - movement of genes across populations (vectors: pollen, spores, physical movements)
- Recombination, Non-random Mating, Random Genetic Drift
What is the VCF and its key features?
Variant cell format- tankard for genetic variants
SNP: Reference and alternate sequences are of length 1 and base nucleotide is different
MNP: Reference and alternate sequences are of the same length AND have to be greater than 1, and all nucleotides differ
INDEL: Reference and alternate sequences are NOT of the same length
CLUMPED: A clumping of nearby SNPs, MNPs or Indels Structural Variant: Large-scale variants
What is allele frequency and how is it calculated?
The proportion in the population of all alleles of a gene that are of the specified type
Formula for gene with genotypes AA, Aa, aa:
pA = (2×NAA + NAa)/(2N)
Where:
- NAA = number of AA individuals
- NAa = number of Aa individuals
- Naa = number of aa individuals
- N = total sample size
Then: pa = 1 - pA, pa is frequency of ‘a’ allele
Calculate allele frequency from 1000 individuals with 298MM, 498MN and 213NN genotypes
Calculation:
pM = (2×298 + 489)/(2×1000)
pM = (596 + 489)/2000
pM = 1085/2000
pM = 0.54 95%
Confidence Interval:
- Valid for non-small (>0.1) and non-high (<0.9) frequencies
- Formula: [fM - 2×√(p×√(1-p))/√n, fM + 2×√(p×√(1-p))/√n]
- Result: [0.52 ; 0.56]
What does the Hardy-Weinberg Equillibrium assume?
- Organism is diploid
- Reproduction is sexual
- Generations non-overlapping (complete generation turnover before next matures)
- Allele frequencies identical in males and females 5. Population is large
- Mating is random
- Migration and mutation is negligible
- Natural selection does not affect allele
How do you test for Hardy-Weinberg equilibrium?
- Pearson chi-square test of goodness of fit:
- Compare observed to expected genotype counts
- 3 genotypes and 1 parameter estimated (p)
- Test with 1 degree of freedom (df) - Fisher Exact Test (FET):
- Inappropriate for rare variants (low genotype counts)
- Use for rare variants
What is FST and what does it measure?
The FST between two populations is the value such that the allele frequency difference has mean 0 and variance 2FST×p(1-p), where p is allele frequency in ancestral population
What is Linkage Disequillibirum and what are its types?
Correlations between genotypes of nearby markers Three types:
1. Mixture LD: - Due to population admixture - Between unlinked genetic markers
2. Admixture LD: - Occurs when considerable chromosomal segments transmitted from particular ancestral population
3. Background LD: - Exists within ancestral populations - Correlation among polymorphisms over very short distances
Define Population Structure
- Genetic differences due to geographic ancestry
- Use genome-wide data to classify genome-wide ancestry (Global Ancestry proportion)
Define population admixture
- Mixed ancestry from multiple continental populations
- Examples: African Americans, Latino Americans, South African Coloured individuals
- Classify local ancestry at each location in genome (Local ancestry)
- Shows admixture over several generations
- Can have 0, 1, or 2 copies from different populations
What are the 3 main approaches to associate genotype with phenotype?
- Segregation Analysis:
- Does the trait have a genetic component? - Linkage Analysis: - Uses families
- Takes unbiased look at whole genome - Association Analysis:
- Where are the disease genes? (More precise location)
- Identifies specific genetic variants associated with traits/diseases
What are GWAS and their key features?
Genome-wide association studies
Evaluate association between a particular genetic variant and trait (disease) in a population
Focuses on unrelated individuals - usually case-control study
What is the difference between direct and indirect association testing?
Direct Association:
- Functional SNP is genotyped
- Association is found directly with the causal variant
- Shows single SNP with diamond marker
Indirect Association:
- Functional SNP (blue) is NOT genotyped
- But a number of other SNPs (red), in LD with the functional SNP, ARE genotyped
- Association is found for these proxy SNPs
- Shows multiple SNPs in linkage with functional variant
What are 3 key disease examples showing different genetic patterns?
Autosomal Recessive:
- Sickle-cell anemia: Abnormal hemoglobin, deformed red blood cells, capillary blockage, malaria resistance (1/625 sub-Saharan African)
Autosomal Dominant:
- Huntington’s disease: Defective neural protein (huntingtin), assembles into aggregates causing neural tissue damage (1/10,000 European)
X-linked Recessive:
- Duchenne muscular dystrophy (DMD): Defective cytoskeletal protein dystrophin, impaired muscle function (1/3500 males)
