Genetics Flashcards
Autosomal Recesive
Horizontal transmission, males and females equally affected, risk of recurrence in sibling is .25, family history negative
Autosomal Dominant
Vertical Transmission, Males and females are equally affeted, risk of recurrence in sibling is .5, could be due to new mutation
X-linked recessive
trait is usually expressed only in males, both parents are normal, if mother is carrier, .5 of daugthers will be carriers and .5 of sons will be affected; ex. red-green color blindness, G6PD deficiency
X-linked dominant traits
Trait is expressed in males and females, no father to son transmission
Haplotype
a unique combination of genetic markers present on a chromosome
linkage disequilibrium
2 loci are in linkage disequilibrium when their alleles are not randomly associated
Polymorphism
the occurence of 2 or more allelic traits in a population with frequencies of at least 1-2%
Multifactorial/Threshold model
Multiple genes and environmental factors contirbute to individual’s liability to the trait
Heritability
Fraction of the total phenotype variance that is attributable to genes
Mixed model
a major contribution from one gene, polygenic contribution, and environmental component
Conditions for Hardy-Weinberg Equilibrium
Infinitely large population
Random Mating
No selective advantage
No mutation, migration or genetic drift
Autosomal Recessive Disorder
Tay-Sach’s- macular cherry red spot, hyperacusis, progressive weakness and hypotonia. Loss of hexoaminosidase A (loss of hex A allele), GM2 catabolic deficiency
Mucopolysaccharidosis I- depressed nasal bridge, bulgin forehead, protruding skull, vertebral abnormality, short wider bones in hand. Due to buildup of GAG’s
Other’s- urea cycle deficiency, propionyl CoA carboxylase deficiency, loss of biotin recycling (decrease in holocarboxylases), galactosemia(gal-1-P uridyltransferase), I- cell disease (lose mannose-6-phosphate recognition marker)
Allelic/Locus Heterogeneity
Allelic- different alleles at locus that produce different phenotypes (Hurler/Schei)
Locus- mutations at different loci produce identical phenotypes (San fillippos)
Prader Willi
Angelman
Genetic cause: Uniparental disomy for maternal chromosome 15 or deletion of paternal chromosome 15
Clinical Manifestation: obesity, hypotonia, small hands and feet, insatiability
Genetic cause: Deletion of Maternal chromosome 15
Postnatal growth deficiency, severe mental retardation, ataxia, seizures
Autosomal Dominant Disorders
Familial Hypercholestrolemia (defective receptors example of haploinsufficiency) Insulin Chicago (dominant negative) Osteogenesis imperfecta (type one collagen, protein suicide) Achondroplasia (gain of function of FGF receptor which inhibits chondrocyte proliferation) Wolf-Hirschhorn Syndrome (haploinsufficiency of FGFR3 gene) Familial Male Precocious Puberty (gain of function of LH receptor pathway)
Trinucleotide repeat diseases
Friedreichh’s Ataxia- loss of function, autosomal recessive, chromosome 9, associated with GAA repeat in 1st intron, onset typically before 20 years
Myotonic Dystrophy- autosomal dominant, CTG repeat of chromosme 19, progressive weakness andmyotonia
SBMA- CAG repeat in first exon of X chromosome,
toxic to spinal cord and bulbar motor neurons, also leads to partial androgen sensitivity
Huntington’s Disease- autosomal dominant disorder, CAG repeat, dementia, gain of function
Target organs for Mitochondrial disorders
Nervous system, skeletal muscle, cardiac muscle
MELAS
MERRF
NARP
point mutation, childhood onset, seizures, myopathy, recurrent headaches
Myoclonic Epilpsy with Ragged Red Fibers
Neuropathy, Ataxia, Retinitis Pigmentosa
Heteroplasmy
Threshold Effect
mosaicism with a single cell of mtDNA, genetic drift on a cellular level
Dependence on aerobic metabolism is correlated with sensitivity to mtDNA mutation
In vivo
Ex vivo
Direct Delivery, Delivery into differentiated nondividing cells as well as dividing cells, episomal, unstable, treatment may need to be repeated (CFTR)
Genes introduced into patient’s cells in vitro and returned, gene transfer requires cell division, integrates into host genome, stable, gene persists for life (SCID)
Chromosome Abnormalities
Trisomy 21- nondisjunction, mosaicism, or translocation, 1:600, hypotonia, CNS deficit, congential heart disease, duodenal atresia
Trisomy 18- 1:3000, early mortality, severe mental retardation, migrognathia, clenched fist/hand, poor hip abuction
Trisomy 13- 1:5000, early mortality, incomplete forebrain development, retinal dysplasia, severe mental deficiency, cleft lip/palate
Turner’s Syndrome- mosaicism, 1 gamete (X) and 1 gamete (O), 1:2500, short stature, poor social cognition, ovarian detioration, no secondary sex characteristics
Things that contribute to increased frequency of a disorder in a specific population
Founder Effect- when a few individuals migrate and find a new isolated, different population
Genetic Drift- higher or lower frequency transmission of particular gene, particularly impactful with smaller populations
Inbreeding
Heterozygote advantage
Neurofibromatosis I
Autosomal Dominant/haploinsufficiency, 50% cases arise from de novo mutations
Diagnostic Criteria- 6 or more cafe au lait spots, 2 or more neurofibromas (composed of schwann cells, nerve fibers, fibroblasts), first degree relative with nf-1, optic pathway tumor, poor coordination, learning disabilities
NF-1 downregulates Ras oncogene
Target vs Signal Amplication
Examples and Characteristics
Target- PCR, RT-PCR, Gel
Greater analytical sensitivty, lower limit of detection, high risk of contamination and false positives
Signal- Branched, Hybrid Capture, Invader technology
