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Autosomal recessive de novo mutation
contiguous gene deletion
17p11.2 gene deletion
craniofacial abnormalities, intellectual disability, various organ systems |
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| Chronic myelogenous leukemia |
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Reciprocal translocation between 9 & 22
-Termed 'Philadelphia chromosome'
bcr-abl fusion = unregulated tyrosine kinase |
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| Autosomal dominant pedigree |
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M&F
Doesn't skip generations
50% offspring affected |
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| both alleles expressed (AB blood) |
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| homozygous is more severe than heterozygous |
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| Autosomal recessive pedigree |
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M&F affected
skips generations
25% offspring affected |
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M&F affected
No M-M transmission
Doesn't skip generations |
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males affected, females usually carriers
skips generations
50% males affected
ex: DMD, Hemophilia, fragile X |
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Female --> all offspring
Male --> no offspring
ex: aminoglycoside-induced deafness |
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| Affected individuals vary in disease severity (charcot-marie-tooth IA) or presentation of disease (different organ systems) |
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Frequency that genotype -> phenotype (epigenetics)
Age-related penetrance = Huntington's Dx |
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Condition more severe w successive generations
Seen with trinucleotide repeats
ex: Huntington, myotonic dystrophy, fragile x |
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single nucleotide polymorphisms
must be >1% of population to be SNP
-each person has ~250-300 loss of function mutations (50-100 inherited disorders) |
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-de novo mutation
- CHD7 mutation
Symptoms: Coloboma of eye, Heart defects, Atresia of nasal canal, Retardation, Genital abnormalities, Ear abnormalities |
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| Inactivating point mutations, gene deletions, epigenetic silencing --> inactivates 'car breaks' (BRCA) |
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| Gain of function mutations |
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| Activating point mutations, gene amplifications, gene translocations --> gas pedal always on / proto-oncogenes |
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genotype affects absorption, distribution, metabolism, or elimination of a drug
ex: 7TA repeats = less UGT1A1 enzyme = metabolize drug slower vs 6TA which = more enzyme & drug excreted faster
Genotype helps w correct dosing |
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genotype changes how active drug is inside body
ex: knowing mutation in genotype allows for direct drug targeting (like if tyrosine kinase is always on, you can use Gefitinib which inhibits it) |
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| Defects in epigenetic regulators |
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| ICF, Rett, Kabuki syndrome |
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| Uniparental Disomy defects |
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| Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann syndrome |
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| Nondisjunction - when can this happen? |
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Meisosis I (4 gametes = n+1, n+1, n-1, n-1)
Meiosis II (4 gametes = n+1, n-1, n, n) |
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| Robertsonian translocation |
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2 acrocentric chromosomes becomes fused & lose their short arms - become just one
-increases risk for Down Syndrome |
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| Different mutations at the same locus (eg cystic fibrosis - 1000 mutations). Sometimes can lead to similar or very different phenotypes (lamin mutations) |
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mutations at different loci -> same phenotype
eg BRCA1 & BRCA2 |
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| one mutation -> multiple effects, more than one organ system affected (Marfan's) |
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| Hardy Weinberg Equilibrium |
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| occurs in a small pop where one allele becomes extinct |
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| refers to immigration/migration of population |
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| Hardy Weinberg conditions |
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| random mating, no new mutations, no outside influences, large & stable population (no migration), no heterozygote advantage |
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| microsatellite polymorphisms |
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simple sequence repeats (dinucleotide, trinucleotide, etc)
-used in forensics |
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| mutation will turn gene ON all the time --> unresticted growth -> cancer |
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have a negative effect on cell cycle
Mutation= 'brakes fail' -> cell growth -> cancer |
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genes involved in DNA repair
mutation can cause increases in DNA mutations |
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| Knudsen's 2 Hit Hypothesis |
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Both copies of the gene must be mutated to get cancer
Earlier age of cancer, increased prevalence of bilateral tumors, family history --> inherited genetic mutation, so only need 1 mutation to get dx
Conversely, in non-affected pop, need 2 mutations to occur |
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Long interspersed nuclear segments
-encode retrovirus-like elements so they can replicate & insert in other parts of genome |
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Short Interspersed nuclear segments
100-300 bp |
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account 4-24 MB variation in genome
polymorphic
ex: end of chrom 9 may be different lengths in people |
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Age-related macular degeneration
-GWAS found that 70% was attributable to smoking + SNPs
Diabetes
-genetic variation only accounts for 10% of risk |
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| Missense mutation - CF example |
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missense = alters amino acid sequence
CFTR G551D = proteins gets to membrane but is nonfunctional (drugs trying to increase functionality) |
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| Nonsense suppressor therapy |
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promotes read-thru of nonsense mutations so that they don't get decayed
could be helpful in CF & DMD |
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| Duschenne Muscular Dystrophy |
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frameshift mutation in dystrophin (which normally anchors muscle fiber cytoskeleton to membrane)
x-linked -> progressive loss of muscle function & early death |
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| Duchenne Muscular Dystrophy gene therapy |
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Exon skipping therapy:
antisense oligonucleotide binds & causes exon skip that preserves the reading frame
-> results in shorter DMD, but still functional |
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| Gleevec - inhibits bcr-abl fusion protein activity & decreases cancer growth |
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| Mono-allelic expression when only one of the two homologous alleles of a gene is expressed |
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| Epigentic prediction for cancer treatment |
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chemotherapy used for glioblastoma treatment, but MGMT is a DNA repair mechanism that makes drug inactive.
-> epigenetically silenced MGMT -> functional chemo |
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