Genetics Review Flashcards
What is pharmacogenetics?
the study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity
What is pharmacogenomics?
the genomic approach to pharmacogenetics and is concerned with the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy
What are pharmacokinetics?
the rate at which the body absorbs, transports, metabolizes, and excretes drugs or their metabolites
What are pharmacodynamics?
the response of the drug binding to its targets and downstream targets
What are the two ways drugs can be modified to increase metabolism (phase I and II)?
Phase I - attach a polar group to make it more soluble
Phase II - attach a sugar/acetyl group to detoxify the drug and make it easier to excrete
What does the cytochrome P450 (CYP450) gene code for and what do they do?
- CYP450 enzymes that are very active in the liver
- they metabolize a wide number of drugs
What enzyme activates codeine?
CYP2D6
What does a frameshift mutation of a CYP450 gene result in?
no activity (poor activity)
What does a splicing mutation of a CYP450 gene result in?
no activity (poor activity)
What does a missense mutation of a CYP450 gene result in?
reduced activity (poor activity)
What does an increase in copy number alleles of a CYP450 gene result in?
increased activity (ultrafast activity)
CYP3A (substrate, inhibitors, inducers)
drug - cyclosporine
inhibitors - ketconazole, grapefruit juice
inducers - rifampin
CYP2C9 and VKORC1
drug - warfarin
What is the indirect method for counting autosomal dominant mutations (where reproductive fitness = 0)?
- all cases represent new mutations
- incidence = 2µ (µ=mutation rate)
What is the direct method for counting autosomal dominant mutations?
- number of new cases with no family history divided by the number who do not have it
- since each has 2 alleles for each gene then multiply denominator by two for the mutation rate
What is the Hardy-Weinberg equation?
p^2 + 2pq + q^2 = 1
p + q = 1
Prader-Willi Syndrome symptoms and cause.
cause - deletion or methylation of chr 15 paternal
- excessive eating
- short stature
- hypogonadism
- some degree of intellectual disability
Angelman Syndrome symptoms and cause.
cause - deletion or methylation of chr 15 maternal
- short stature
- severe intellectual disability
- spasticity
- seizures
Behwith-Wiedemann Syndrome symptoms and causes.
cause - chr 11 - overactive IGF-2 gene (growth factor) and/or CDKN1C (inhibitor of cell proliferation)
- macrosomia
- macroglossia
- midline abdominal defects
- can develop hemihypertrophy and increase risk of cancer
Russell-Silver Syndrome symptoms and causes
cause - hypomethylation H19 and IGF2, maternal uniparental disomy on chr 7
- tiny size and short stature
- mildly abnormal facial features
- can develop hemihypertrophy and increase risk of cancer
IDIC 15 symptoms and causes
cause - inverted duplicated isodicentric 15q
- autism
- NOT dysmorphic
- often hypotonic
- seizures common
15q interstitial duplication
- only has phenotype if inherited from the mother
- autism
- NOT dysmorphic
- seizures common
- hypotonia common during infancy
What causes Downs Syndrome?
usually error of nondysjunction
- increased risk with increasing maternal age
What are common medical issues for Downs Syndrome patients?
- atrioventricular canal
- GI structural anomalies (atresia)
- GERD
- blocked tear ducts, myopia, lazy eye, nystagmus, cataracts
- chronic ear infections, deafness, enlarged tonsils
- thyroid dz, diabetes, reduced fertility
- orthopedic probs
- increased risk of leukemia, iron deficiency anemia
- hypotonia, speech probs
- early Alzheimers and autism
What are alpha-satellite repeats?
- 171 bp repeat unit
- near centromeric region
- may be important to chromosome segregation in mitosis and meiosis
Which chromosomes are hotspots for human-specific evolutionary changes?
chr 1, 9, 16, Y (because of tandem repeats)
What are Alu?
300 bp repetitive element
What are L1?
6 kb repetitive element
What are copy number variations (CNVs)?
- where sections of the genome are repeated (one copy to many)
- primary type of structural variation
Why is gene duplication a major mechanism behind evolutionary change?
when a gene duplicates it frees up one copy to vary while the other copy continues to carry out critical function
Describe reciprocal translocation.
- results from the breakage and rejoining of non-homologous chromosomes, with a reciprocal exchange of broken segments
- increased risk of producing unbalanced gametes
For a parent with reciprocal translocation, which segregation produces normal gametes?
Alternate segregation
- adjacent segregation produces unbalanced gametes
What is robertsonian translocation?
- fusion of two acrocentric chromosomes with their centromeric regions
- results in loss of both short arms (rDNA repeats)
- carriers often phenotypically normal
- may lead to unbalanced karyotypes for their offspring
What chromosome is involved in Wolf-Hirschhorn syndrome and what are the symptoms?
- del chr 4
- facial clefting
- prominent ears
- microcephaly, intellectual disability
What chromosome is involved in Cri du chat syndrome and what are the symptoms?
- del chr 5
- microcephaly
- characteristic cry
- seizures, intellectual disability
What chromosome is involved in Bechwith-Wiedemann syndrome and what are the symptoms?
- dup 11 (paternal)
- overgrowth
- omphalocele
- predisposition to Wilms, other tumors
What chromosome is involved in DiGeorge syndrome and what are the symptoms?
- del chr 22
- absent or hypoplastic thymus and parathyroids
- congenital heart disease
What are the gene poor chromosomes?
13, 18, 21
What percent of the genome is AT rich?
54%
What is satellite DNA?
- tandem repeats
- alpha-satellite repeats - found near centromeric region of all human chromosomes - may be important to chromosome segregation in mitosis and meiosis
What is the Alu family?
- dispersed repetitive elements
- e.g. of SINEs (short interspersed repetitive elements)
What is the L1 family?
- dispersed repetitive elements
- e.g. of LINEs (long interspersed repetitive elements)
Why are Alus and L1s clinically relevant?
- retrotransposition may cause insertional inactivation of genes
- repeats may facilitate aberrant recombination events between different copies of dispersed repeats leading to disease
What are minisatellites?
- insertion-deletion polymorphisms (indels)
- tenderly repeated 10-100 bp blocks of DNA
What are macrosatellites?
- insertion-deletion polymorphisms (indels)
- di-, tri-, or tetra-nucleotide repeats
How are single nucleotide polymorphisms detectable?
PCR
What are copy number variations?
- variation in segments of genome from 200 bp - 2Mb
- can be one additional copy to many
What are the limitations of nextgen DNA sequencing?
- no mammalian genome has been completely sequenced
- relies on short read sequences
- complex, highly duplicated regions are typically not examined
What are the limitations of genome-wide association studies?
- “missing heritability” - many studies implicate loci that account for only a small fraction of the expected genetic contribution
- many regions of the genome are unexamined by genome wide screening technologies
What are metacentric chromosomes?
centromere is located in the middle of the chromosome
What are submetacentric chromosomes?
centromere is slightly removed from the center
What are acrocentric chromosomes?
centromere is near one end of the chromosome
What is nondisjunction?
missegregation of chromosomes at metaphase in either mitosis or meiosis
What is monosomy?
cell lacks one copy of a chromosome
What is the two hit theory of maternal age effect?
- diminished recombination (more susceptible to possible nondisjunction)
- the diminishing ability of the oocyte to successfully complete chromosome segregation in the presence of unfavorable recombination events
What is heritability of a trait?
- the proportion of total variance in a trait that is due to variation in genes
- high heritability - differences among individuals can be attributed to differences in genetic makeup
- high heritability does not imply that non-genetic factor are not important and vice versa
What is the disorder in Hb Kempsey?
mutation in beta-globin chain that binds O2 too tight
What is the disorder in Hb Kansas?
mutation in beta-globin chain that binds O2 too weakly
What are thalassemias?
disorders of imbalanced global levels resulting in markedly reduced or no synthesis of one globin type
What is Hereditary Persistence of Fetal Hemoglobin?
group of clinically benign conditions that impair the perinatal switch from gamma to beta globe synthesis, leading to high level production of HbF in adults
What is Hemoglobin C disease?
- milder form of hemolytic anemia than sickle cell
- HbC is less soluble than HbA and forms crystals
- autosomal recessive
Hemoglobin SC disease
compound heterozygotes of beta(s), sickle cell, and beta(c), hemoglobin C, have milder anemia than sickle cell disease
alpha-thal-1 allele (- -)
- common in Southeast Asia
- deletion of both copies of alpha-globing genes
- homozygous state results in hydrops fetalis
- heterozygous - mild anemia
alpha-thal-2 (alpha -)
- common in Africa, mediterranean, Asia
- deletion of one of the alpha-globin genes
- no disease phenotype in heterozygotes
- mild anemia in homozygotes
alpha-thal-1/alpha-thal-2 (alpha -/- -)
- only 25% normal alpha-globin level
- severe anemia
Thalassemia major
- severe anemia
- enlarged liver and spleen
- temporarily treat with blood transfusions (cause iron accumulation -> organ failure. can be treated with iron chelation therapy)
Simple beta-thalassemia
- caused by mutations or deletions that impair the production of beta-globing chain alone (other genes unaffected)
Complex thalassemia
- caused by large deletions that remove the beta-globin gene plus other genes in the beta-cluster
beta+-thalassemia
- some beta-globing is made so HbA is present
beta0-thalassemia
zero beta-globing synthesis so no HbA is present
delta-beta0-thalassemia
- no delta or beta synthesis due to deletion in the coding sequence for both
- milder clinical phenotype than beta0-thalassemia because remaining gala genes still active after birth
What is the phenotype of phenylketonuria (PKU)?
- microcephaly
- profound mental retardation
- seizures, tremor, gait disorders
What is the biochemical defect in PKU?
- defect of phenylalanine metabolism
- most due to defects in PAH gene (phenylalanine hydroxyls)
- some cases caused by BH4 defects (coenzyme)
What is the phenotype of alpha1-antitrypsin deficiency?
- 20fold increased risk of developing emphysema (more severe among smokers
- increased risk of liver carcinoma
Which allele results in disease symptoms for alpha1-antitrypsin deficiency?
Z/Z genotype
S/S genotype usually do not express symptoms
What is the biochemical defect in alpha1-antitrypsin deficiency?
mutation in SERPINA1 that normally targets elastase released by neutrophils in the lung
What is the phenotype of Tay Sachs?
- progressively destroys neurons in the brain and spinal cord
- early-onset, fatal disorder apparent in infancy
- eye abnormality called cherry-red spot is characteristic
What is the defect in Tay Sachs?
lysosomal storage disease
- defective in HexA responsible for degrading GM2 ganglioside
What is the defect in Sandhoff disease?
defects in both HexA and HexB
What is the defect in AB-variant of Tay Sachs?
defect in GM2 activator protein
What do you need to know in order to do genotyping?
- must know or suspect a specific genetic diagnosis
- gene must have been identified and the disorder should exhibit little or no allelic heterogeneity
When should you use fragment analysis?
- investigating small-medium deletion/insertions, repeat expansion
- must know or suspect a specific genetic diagnosis
- gene must have been identified
- expected mutation must be of a type expected to result in a larger or smaller amplicon than wild type
When should you use Sanger sequencing?
- mutations in known genes
- clinical sensitivity is below 100%
- must know or suspect a specific genetic diagnosis
- gene must have been identified
- mutation must be detectable by sequencing
- mutation must be located in a region of the gene actually sequenced
When should you use massively parallel sequencing/nextgen sequencing?
- looking at a sequence of known disease genes in highly heterogeneic diseases or clinical cases where diagnosis is uncertain
- do not need to suspect a genetic diagnosis
- gene must have been identified
- mutation must be detectable by analysis algorithm
- mutation must be located in a region of the genome that is captured
What does allelic heterogeneity refer to?
multiple mutations in a particular gene can cause disease
What is genetic heterogeneity?
mutations in multiple genes associated with the same phenotype
