Lecturem2 revision Flashcards
What are the 5 problems with genetic analysis in humans
- Can’t do controlled matings
- Very few progeny
- Long generation time
- Few useful single gene variants
- Analysis uses pedigrees
Symbols in pedigrees
White square/circle - Unaffected male/female
Black sqaure/circle - Affected male/female
White square/circle with dot - Obligate carriers
Diamond - unknown sex
Circle and square with line - mating
Circle and square with two lines - Consanguineous marrage
Dead- line through square or circle
Vertical line - offspring
Non-identical twins - lines come off at same point
Identical twins - same as non-identical but with line through
Miscarriage - small black dot
Building pedigrees
Often require names and ages/date of birth
Generations can be labelled with normal numerals and individuals labelled with individual number e.g. I1, III5 etc
Consanguineous relationships
Increased likelihood of recessive disease in inbreeding as increased likelihood of two identical loci on each chromosome as inherited same allele from same common ancestor (identity by decent)
Increased risk of miscarriage
Why should you not always assume a single gene disorder
- Could be chromosomal defect (rearrangement or aneuploidy)
- Not inherited (not necessarily genetic)
- Multifactorial (several genes involved)
- Mitochondrial
Mitochondrial inheritance
Maternal inheritance - all children of affected mothers are affected e.g. some forms of Leigh’s disease.
Paternal inheritance extremely rare.
In egg, 1000 copies of mitochondrial DNA inherited.
Penetrance and expressivity
Penetrance - Proportion of people with a genotype that show characteristics
Expressivity - Degree to which an individual with genotype displays characteristics of conditions
Mendelian (single genes) - fully penetrant
Multifactorial - reduced penetrance e.g. MS
Autosomal dominant pedigree with reduced penetrance
Can cause generational skips even though the individual has the correct genotype for the disease due to low expressivity
Give an example of a disease with variable expressivity
Neurofibromatosis (NF1, or von Recklinghausen disease)
Mild - café au lait patches
Moderate - Small neurofibromas
Severe - Large neurofibromas
Modifier alleles in genetic background can explain variable expressivity
How can disease genes be identified by mapping
- Pedigree analysis
- Recombination mapping using molecular marker e.g. VNTRs, STRs
- Haplotype analysis
- Identify small set of candidate genes or mutation by exon sequencing
Give an example of mapping disease gene
Dyschromatosis Symmetrica Hereditaria (DSH)
Explain LOD scores
- They are a measure of linkage probability between disease gene and marker in a pedigree, and are affected by allele frequency
- Log of odds ratios (concordance:non-concordance of phenotype with marker allele)
- z>3 - likely to be linked (1 in 1000 liklihood that data is due to chance)
- z<-2 - unlikely to be linked
- Used in GWAS
Haplotype analysis
Set of alleles on one chromosome of a pair
Yellow, blue, green haplotypes associated with DSH
Recombinant individuals 1-IV3 and 3-IV4 indicate DSH gene lies between D1S2715 and D1S2777, distance of 2Mbp
How can you tell a genetic change is responsible for a disease?
Mutation has strong effect on protein e.g. nonsense mutations, frameshift mutations cause extensive missense, strong missense mutations, splice site mutations, deletions that remove coding sequence
- Unrelated individuals with condition have the same mutation
- Mutation not found in unaffected individuals
ADAR mutations in DSH families
no mutations e.g. R474X, L923P, K952X, F1165S were found in normal Japanese individuals
