Genetics Flashcards
locus
unique chromosomal location
allele
alternative forms of the same locus
genotype
allele combination at a locus
haplotype
a combination of alleles on the same chromosome
homozygosity
2 identical alleles at a locus
heterozygosity
2 different alleles at a locus
dominant allele
shows its effect on the phenotype in heterozygosity
recessive allele
does not show its effect on phenotype in heterozygosity
codominant alleles
when both alleles are dominant; alleles have additive effects
germ-line mutation
affects the gametes (sperm or egg); can be passed on to offspring
Somatic mutation
affects somatic (i.e. body) cells only; cannot be passed on (not heritable) Somatic mutations result in mosaicism: the presence of cells with different genotypes
minor allele frequency
the frequency of the least abundant allele in a population
polymorphism
a ‘common’ variant with MAF >1%, does not imply phenotype
mutation
a ‘rare’ variant with MAF <1%
major allele is often referred to as ‘wild-type’ or ‘normal’
does not imply phenotype
main forms of human genetic variation
- Single nucleotide variation- -DNA replication and repair, most abundant
- Structural variation- DNA recombination
- Chromosomal abnormalities- chromosome segregation in mitosis/meiosis
allele frequency equation
frequency of A= # of A alleles in population/ total # of alleles in the population
odds ratio
odds of disease in presence of allele/ odd of disease in absence of the allele
Silent variant
nucleotide substitution in a coding sequence that does not result in amino acid change.
misssense variant
nucleotide substitution that causes one amino acid change
nonsense variant
nucleotide substitution that replaces the codon for an amino acid with a premature termination codon (Ter, Stop, X or *).
frameshifting
a variant that alters the triplet reading frame of mRNA (by inserting or deleting a number of nucleotides that is not a multiple of 3). Usually results in premature termination codon.
regulatory variant
a variant that affects gene expression through effects on a transcriptional regulatory element (e.g. promoter, enhancer).
exon skipping
Altered splicing results in the exclusion of exon sequences from the mature mRNA
intron retention
inclusion of intronic sequences
renaming DNA strands
this3replaced with this
this3 replaced with this fs Ter%
loss of function variants
and example
reduced amount of activity more common,
typically recessive,
example: regulatory mutation reducing
b-globin expression (b-thalassemia)
variants responsible: missense, nonsense, frameshift, splicing, regulatory
2 dominant loss of function variants
Haploinsufficiency: when a single (haplo) functional allele is not sufficient for normal phenotype, nonsense mutations in GATA4 (a transcription factor) lead to congenital heart disease in heterozygous individuals
Dominant negative (DN) effect: when a mutant allele disrupts the function of the normal allele, missense mutations that inactivate the activity of STAT3 homodimers (a signaling molecule) lead to cancer
Haploinsufficiency:
when a single (haplo) functional allele is not sufficient for normal phenotype, nonsense mutations in GATA4 (a transcription factor) lead to congenital heart disease in heterozygous individuals
Dominant negative (DN) effect:
when a mutant allele disrupts the function of the normal allele, missense mutations that inactivate the activity of STAT3 homodimers (a signaling molecule) lead to cancer
gain of function variants
and example
increased amount of activity
regulatory or missense
dominant
example: Missense mutation in FGFR3 causing
receptor signaling without ligand
(Achondroplasia)
monogenetic
single variant, large effect, present in everyone with mutation, rare
polygentic
many variants with smaller allelic effects, more common
susceptibility threshold
Sum of all genetic and environmental factors, pass threshold= you have the disease
genome-wide association studies
why they are used?
Poly- you can’t use family tree because there are multiple factors, gene wide associate are used to determine tendency of allele and disease to occur together across populations
polygenic risk score (PRS)
The polygenic risk score (PRS) is a composite measure of genetic risk conferred by all disease-associated loci in an individual.
Step 1. Identify disease-associated variants in the population by GWAS.
Step 2. In each individual, add up the effects of all alleles (risk minus protective) to obtain the PRS.
Step 3. Correlate PRS with disease risk in the population.
Step 4. Estimate individual’s relative disease risk.
Autosomal dominance
Parent to child transmission (I 1&2)
- Every generation affected (vertical transmission) - Unaffected parents do not transmit to children (II 6&7) - Males & females equally affected - Male to male transmission (differentiates from XLD)
