Genomics Flashcards
What are monogenic diseases?
Caused by mutations in a single gene; single mutation is both necessary and sufficient
What is genetic linkage?
DNA regions that are located in close proximity are more likely to be co-inherited than DNA regions originating further apart
What is the LOD score?
Detects presence of linkage; LOD = log10 (L(linkage)/L(no linkage)); more than 3 –> linkage; less than -2 no linkage
Which things can act as confounders in single pedigrees?
Non penetrance and phenocopies
What is Hajdu Cheney syndrome?
severe osteoporosis; NOTCH2 heterozygous mutation; autosomal dominant
What is a confounding factor in linkage analysis performed in multiple pedigrees?
Genetic heterogeneity
What is the difference between polymorphism and mutation?
Polymorphism: common DNA variant
Mutation: pathologic DNA variant
What is transition and transversion in single nucleotide substitutions?
Transition: substitution which conserves the base chemistry (G–>A; T–>C), twice as common as transversions
Transversion: substitution which changes the base chemistry (G–>T; A–>C)
What are the consequences of variants in splice sites?
Exon skipping, use of cryptic splice site (in exon or intron), intron retention, combination of these
What are the rarer types of functional variation?
Variants in promoters, untranslated regions (myotonic dystrophy and fukuyama muscular dystrophy), polyadenylation signals
What are the types of functional DNA variation defined by Muller?
Loss of function: amorph (complete loss of function), hypomorph (partial loss of gene function)
Gain of function: hypermorph (increase in normal gene function), antimorph (dominant alleles that act in opposition to normal gene activity), neomorphic (dominant gain in gene function that is different from the normal function)
What is NMD?
non-sense mediated decay
When do ‘loss of function’ alleles exhibit dominant forms of inheritance?
- Haploinsufficiency
- “Dominant negative” effect: homodimeric complex disrupts function of its normal counterpart
- Somatic second hits: cancer gene (recessive at cellular level but dominantly inherited in families)
What is infantile onset epilepsy in Amish?
Autosomal recessive due to nonsense mutation in SIAT9 encoding GM3 synthase –> less production of gangliosides (membrane stability); seizures starting at 6 months of age
What are the differences between phenotypic and genetic heterogeneity?
Phenotypic: one gene, mutations with different clinical outcomes (phenotypes)
Genetic: different genes but same clinical outcomes
What is penetrance?
The proportion of carriers who manifest phenotypic signs of the condition
What is Marfan syndrome?
Tall stature, long limbs, chest abnormalities, scoliosis, arachnodatcyly (long fingers), dislocated lens, risk of aortic aneurism
What is expression?
Gene carriers can be affected to different degrees; extent of clinical manifestation
What are examples of diseases with de novo mutations?
Achondroplasia, marfan syndrome, neurofibromatosis I and II
What is germline mosaicism?
A parent carries a small portion of gametes that harbour the same mutation (achondroplasia, osteogenesis imperfecta, duchenne muscular dystrophy)
How does cosanguinity affect the risk of recessive disorders in the offspring?
increases risk
What are compound heterozygosity and homozygosity?
Heterozygosity: someone who has different allelic mutations at the same locus, i.e. cystic fibrosis
Homozygosity: same allele on both chromosomes, i.e. sickle cell anemia
How can females be affected with X-linked recessive disorders?
- Non-random inactivation leading to chance expression in certain tissues
What is X inactivation?
One X in each cell is switched off before blastocyst implants in female embryos