Unit 2 Flashcards
In autosomal dominant inheritance, the odds of an offspring inheriting the disease allele is ____
50%
In autosomal dominant inheritance, all affected individuals have ____ parent(s) with the disease allele
at least one
In autosomal recessive inheritance, parents of an affected person must be either _____ or _____
carriers
diseased
Recessive diseases tend to _____ generations
skip
Autosomal dominant diseases tend to _____ generations
be present in all
In X-linked dominant inheritance, _____ can be affected
females and males
In X-linked inheritance, an affected male will pass disease allele to _____ but not to _____
All daughters
any sons
In X-linked recessive inheritance, males with a single copy of disease allele are affected because _____
males are hemizygous for X-linked genes
_____ describes whether a person with disease genotype will have disease phenotype
penetrance
_____ describes the severity (variation) in phenotype when disease genotype is present
expressivity
_____ describes when a single disease genotype results in multiple, unrelated disease phenotypes
Pleiotropy
_____ diseases are associated with reduction of males in pedigree due to lethality
X-linked dominant
In _____ inheritance, females are usually carriers
X-linked recessive
The rate of SNPs between two people is _____
1/1000
human genome sequencing focused on _____ regions of genome
euchromatic
_____ percent of the genome is translated
1.5
_____ percent of genome has genes (introns/exons)
20-25
_____ percent of genome has single copy sequences
50
_____ percent of genome has repeat sequences
40-50
Tandem repeats are found in _____, _____, and _____
genome
heterochromatic regions
centromeric regions
The 2 classes of repetitive DNA are _____
tandem repeats
dispersed repetitive elements
_____ describes genes that have high sequence similarity and that carry out similar but distinct functions
gene families
gene families arise from _____ and facilitate genomic innovation
gene duplication
CNVs increase genomic diversity but lead to many diseases because _____
they are unstable parts of genome
the major limitation of current sequencing/genotyping is ____
highly duplicated/repeated regions of genome are unexamined
_____ describes how in complex diseases, SNPs only account for a small fraction of expected genomic contribution
missing heritability
_____ describes presence of cells with different genotypes in a single organism
mosaicism
The clinical features of Trisomy 21 (down syndrome) are _____
distinct facial features short stature hypotonia (low muscle mass) intellectual impairment cardiac defects leukemia
The clinical features of Trisomy 18 (edward syndrome) are _____
small size
rocker-bottom feet
clenched fingers
The clinical features of Trisomy 13 (patau syndrome) are _____
distinct facial features
intellectual impairment
congenital malformations
What are the 5 possible mechanisms of structural chromosomal rearrangements?
Insertion Deletion Inversion Reciprocal Translocation Duplication
There is no loss of genetic material in _____ chromosomal rearrangements
balanced
In reciprocal translocation, _____ segregation results in balanced progeny, while _____ segregation results in unbalanced progeny
alternate (normal+abnormal)
adjacent (abnormal)
The overall risk of balanced parents having unbalanced progeny is _____
0-30%
_____ describes variations in gene expression not due to DNA sequence changes
epigenetics
DNA and histone _____ mediates gene silencing (usually). These are both examples of _____
methylation
epigenetics
DNA methylation marks are reset in _____ and reestablished during _____
primordial germ cells
gametogenesis
This enzyme mediates propagation of epigenetic marks in somatic cells
Maintenance methyltransferase
When the maternal allele is imprinted, the _____ allele is expressed
paternal
Give 2 examples of disorders associated with genetic imprinting
Prader-Willi
Angelman
PWS and AS are due to deletions in chromosome _____
15q11-13
PWS region of 15q11-13 is expressed only on _____
paternal chromosome
AS region of 15q11-13 is expressed only on _____
maternal chromosome
_____ determines sex-specific expression pattern on 15q11-13
imprinting center
_____ describes inheriting both alleles of a gene from a single parent
uniparental disomy
maternal uniparental disomy can cause _____
PWS
In childhood B-cell ALL, _____ is correlated with a good prognosis, while _____ is correlated with a poor prognosis
hyperdiploidy
hypodiploidy
FISH uses fluorescently tagged _____ to target _____ or _____
single-stranded DNA
specific chromosomes (identify #)
regions/bands of chromosomes (identify translocations)
_____ (FISH probe) is used for _____ in _____
centromere (cen)
enumeration
ALL
_____ (FISH probe) is used for _____ in _____
dual fusion, fusion (DF/F)
translocation
BCR:ABL & PML:RARa
In APML, fusion of _____ (genes) codes for a novel transcription factor that ____ differentiation/transcription
PML:RARa
represses
_____ is a treatment for APML because it recruits _____ that prevents repression of transcription
retinoic acid
coactivators
In CML, fusion of _____ (genes) codes for a novel tyrosine kinase that results in _____
BCR:ABL
cell proliferation
_____ is a treatment for CML because it binds to _____ of BCR:ABL and inhibits cell proliferation
Gleevec
ATP-binding site
Describe how CMA works
Put probes on array, add target single-stranded DNA. detect CNVs. Compare to reference CNVs.
CMA cannot detect _____
balanced rearrangements
mosaicism (
What are 3 examples of balanced rearrangements?
Inversions
Reciprocal translocations
Robertsonian translocations
_____ inversions include the centromere, while _____ inversions exclude the centromere
Pericentric
Paracentric
_____ translocations result from breakage+rejoining of non-homologous chromosomes
Reciprocal
_____ translocations result in fusion of two acrocentric chromosomes within their centromeric regions (loss of both short arms)
Robertsonian
The chromosomal abnormality in DS is usually _____
Trisomy 21
The risk for errors of _____ increases with rising maternal age
nondysjunction
What are the physical features of DS?
midfacial hypoplasia upslanting palpebral fissures small ears large tongue hypotonia transverse palmar crease short fingers
What medical issues are associated with DS?
Cardiac (AV canal)
GI (atresia, constipation, feeding, GERD)
Ophthalmic (myopia, strabism, nystagmus, blocked tear ducts)
ENT (deafness, apnea, ear inf., nasal congestion)
Endocrine (thyroid disease, infertility, diabetes)
Orthopedic (subluxation)
Hematologic (leukemia, anemia)
What developmental/behavioral issues are associated with DS?
impaired motor development intellectual disability speed problems depression alzheimer's autism
What are the physical features of PWS?
dysmorphic (almond eyes, undescended testicles)
hypotonia
light pigmentation
What medical issues are associated with PWS?
Feeding issues (need tube, become obese)
Opththalmic (strabismus, nystagmus)
Orthpedic (scoliosis)
ENT (apnea)
What developmental/behavioral issues are associated with PWS?
intellectual disability
antagonistic behavior
insatiable desire to eat
List 2 other chromosomal abnormalities associated with 15q11-13
IDIC 15 (supernumerary marker) 15q interstitial duplication (maternally inherited)
_____ is the study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity
pharmacogenetics
_____ is concerned with the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy.
pharmacogenomics
_____ is the rate at which the body absorbs, distributes, metabolizes, or excretes drugs/metabolites.
pharmacokinetics
_____ is the response of the drug binding to its targets and downstream targets. (i.e. what happens)
pharmacodynamics
Phase I metabolism involves attaching a _____ group to compound to make it more _____
polar
soluble
Phase II metabolism involves attaching a _____ group to compound to make it more _____
sugar/acetyl
easily excreted
The CYP450 complex is active mainly in the _____ and to some extent in the _____
liver
intestinal epithelium
Most CYPs function to _____ drugs, but _____ is an exception
inactivate
CYP2D6 (codeine–>morphine)
CYP3A: _____ (substrate), _____ (mechanism), _____ (activators/inhibitors)
cyclosporine
genetically less important
rifampin (activator)
ketoconazole+grapefruit juice (inhibitor)
CYP2D6: _____ (substrates)
codeine
CYP2C9: _____ (substrate)
warfarin
NAT: _____ (drug)
isoniazid for TB
TMPT: _____ (drugs), _____ (notes)
6-mercaptopurine + 6-thioguanine
for ALL
G6PD: _____ (drugs), _____ (mechanism), _____ (notes)
sulfonamide+dapsone
X-linked enzyme
deficiency causes anemia
VKORC1: _____ (drug)
warfarin
What are the assumptions of Hardy-Weinberg?
large population random mating no mutations no selection no population movement
Increased variation through sexual reproduction occurs via _____ and _____
haploid gametes
recombination in meiosis
Gonad determination is _____
chromosomal (presence/absence of Y)
describe embryology of dimorphic reproductive organs
wk4: primordial germ cells form in wall of yolk sac.
wk5: coelomic epithelium becomes genital ridge
wk6: primordial germ cells migrate to dorsal mesentary of hindgut and enter gonad. epithelium of gonadal ridge form primitive sex cords.
What are the clinical features of Turner Syndrome (45, XO)?
short webbed neck cystic hygroma puffy hands/feet infertility low-set ears broad chest cubitus valgus
What are the clinical features of Kleinfelter Syndrome (47, XXY)?
tall small testes infertility gynecomastia reduced hair
What are the clinical features of Jacobs Syndrome (47, XYY)?
tall
autism
learning/developmental issues
behavioral/emotional issues
What are the clinical features of Triple X Syndrome (47, XXX)?
tall
learning/developmental issues
seizures
kidney issues
what are the characteristics of multifactorial inheritance traits?
incomplete penetrance
variable expressivity
heterogeneity (allele+locus)
phenocopies
A higher concordance rate for disease in monozygotic twins than in dizygotic suggests that _____
genetic variation is a more significant risk factor than non-genetic factors
_____ describes the proportion of total variance in a trait that is due to variation in genes
heritability
What are the 3 types of DNA polymorphisms used for finding disease genes?
CNVs
SNPs
microsatellites
describe candidate gene association studies
need prior hypothesis/markers
prone to false-positives
used for common alleles with small/moderate ORs
done in case-control studies
can’t do multiple-testing correction, can’t ethnically match cases/controls, stratification effects
Describe genetic linkage studies
no hypothesis needed
search genome for regions co-inherited with disease in families
used for mendelian traits
Degree of recombination per meiosis event is measured in _____
centiMorgans (cM)
_____ is a statistical measure of genetic linkage
LOD (>3 = proof of linkage)
Describe GWASs
search for SNPs across entire genome
used for common alleles with small/moderate ORs
can do multiple-testing correction and stratification correction
done in case-control studies
requires follow-up study for specific SNPs of interest
In Autosomal Recessive diseases, the majority of mutant alleles are present in _____
carriers
_____ describes multiple, different mutant alleles of a single gene
allelic heterogeneity
A _____ carries two different mutant alleles of a single gene. The phenotype is usually _____
compound heterozygote
moderate
Describe biochemical defects of PKU
mutation in PAH or mutation in BH4 (coactivator) that result in excess Phe buildup and damage to CNS
PKU screening is done via _____
mass spect
Newborns must be screened for PKU _____ so that _____ is no longer present to give false negative result
a few days after birth
maternal PAH
Treatment for PKU is _____
low Phe diet for entire life
describe phenotype and ecogenetics of ATD
emphesyma+liver problems (bc of misfolded protein buildup)
smoking increases severity and causes earlier onset
normally, α1-antitrypsin inhibits _____, thus a mutation causes degradation of too much _____
elastase
elastin
The _____ mutant allele for ATD is the most severe, while the _____ allele is the least severe.
Z
S
describe biochemical defects of T-S
mutation in HexA (α subunit) prevents degredation of GM2 ganglioside in neuronal lysosomes.
In Sandhoff disease, mutation in _____ affects both HexA and HexB
β subunit
In AB variant of T-S, HexA and HexB are _____ but GM2 accumulates due to mutation in _____
GM2 activating protein (GM2-AP) that mediates binding between HexA and GM2
carrier and prenatal screenings for T-S are done for _____ population using _____
Ashkenazi Jew
enzyme assay
_____ controls expression pattern of globin genes
Locus Control Region (LCR)
What is the expression order for α cluster of globin genes?
ζ –> α2 + α1
What is the expression order for β cluster of globin genes?
ε (embryonic)
γG + γA (fetal)
δ + β (adult)
HBA2 is _____ form of hemoglobin in adults and HBA is the _____ form
minor
major
In sickle cell, mutation in _____ creates _____, which is less soluble and forms fibers that cause sickle shape in RBC
β globin (E6V)
HbS
In hemoglobin C, mutation in _____ creates ____, which is less soluble and form crystals that don’t change shape of RBC
β globin (E6K)
Sickle cell is diagnosed using _____
RFLP (loss of restriction site)
α-Thalassemia 1 is most prevalent in _____ and its genotypes are _____ and _____
southeast asia
αα/– (mild. α-thal 1 trait)
–/– (hydrops fetalis)
α-Thalassemia 2 is most prevalent in _____ and its genotypes are _____ and _____
africa, med, asia
α-/α- (mild. α-thal 2 trait)
αα/α- (silent carrier)
The compound heterozygote genotype for α-thalassemia is _____
α-/– (severe. HbH disease)
Thalassemia major vs. thalassemia minor
major: severe disease phenotype
minor: mild disease / carrier
Simple thalassemia vs. complex thalassemia
simple: mutations/deletions affect only β globin gene
complex: mutations/deletions affect multiple genes in β cluster
β+ thalassemia vs. β0 thalassemia
β+: some β globin is made. some HbA present.
β0: no β globin made. no HbA.
describe HPFH
no β or δ globin synthesis. Instead, γ globin synthesis continues bc 1) deletions cause enhancers to be closer to γ-globin gene or 2) mutations in promoter of γ-globin prevent repression of its synthesis
HPFH patients do not have disease because _____
HbF replaces action of HbA and HbA2
Describe Achondroplasia
AD (80% de novo) small stature short limbs GoF mutation in FGFR3. Enhances limitation of bone formation from cartilage. paternal age effect.
Describe Neurofibromatosis Type 1
AD (50% de novo), Var Exp. neurofibromas Lisch nodules cafe-au-lait spots LoF mutation in NF1. lose tumor suppression activity. Need both alleles to be mutant.
Describe Tuberous Sclerosis
AD (66% de novo), Var Exp. angiofibroma cortical dysplasia cardiac rhabodmyoma LAM lung disease Shagreen patch Ungual Fibroma LoF mutation in TSC1 or TSC2. lose cell growth/division regulation (hamartin+tuberin).
Describe Osteogenesis Imperfecta Type 1
AD, Var Exp. multiple bone fractures blue sclera LoF mutation in COL1A1. reduces type 1 collagen by 50%.
What are the 3 characteristics of Trinucleotide Repeat Disorders?
Slipped misparing (in germ cells)
anticipation
parental transmission bias
Describe Huntington Disease
AD, Trinuc Rep Disorder (CAG)
early onset (paternal) or late onset (maternal).
progressive neural degeneration.
expansion of CAG repeat in HTT gene.
X chromosome inactivation occurs during 1st week of _____ and is functionally _____
embryogenesis
mosaic
Describe Fragile X Syndrome.
XD, Trinuc Rep Disorder (CGG) intellectual disability dysmorphic features aggression maternal transmission bias. expansion of CGG repeat in FMR1 gene.
Describe Duchenne Muscular Dystrophy.
XR mutation in DMD gene (loss of Dystrophin). progressive muscle weakness calf hypertrophy dilated cardiomyopathy
Describe Hemphilia A
XR, 10% carrier females affected. bleeding bruising mutation in F8 gene. deficiency of Factor VIII.
mosaicism is analogous to mitochondrial _____
replicative segregation
Describe 4 mitochondrial inheritance disorders.
Kearns-Sayre (eye issues, ataxia, deafness)
MELAS (stroke-like)
MERRF (ragged-red fibers)
LHON (vision failure)
Describe the 4 characteristics of epigenetics
- different gene expression pattern (phenotype) from the same genome
- generational inheritance through cell division
- On/off state. no intermediate.
- eraseable/interconvertable
Describe Waddington’s epigenetic hill thing
Stability of differentiated states of cells is maintained due to being at “lowest energy state” (bottom of valley)
Give 3 examples of epigenetics
X-inactivation
imprinting
heterochromatin domains
Give 3 examples of LoF disorders
Duchene (loss of dystrophin)
HNPP (loss of PMP22 gene)
Osteogenesis Imp I (reduced collagen I)
Give 2 examples of GoF disorders
HbK (tighter O2 binding)
CMT1A (duplication of PMP22 gene)
Give an example of novel property mutation disorder
Hubs’ (sickle shape, but normal function)
What are the 8 steps at which mutations can affect protein function?
Transcription (thalassemia) Translation (thalassemia) Protein folding (Hb disorders) Post-Trans Mod (I-Cell) holomer assembly (Ost Imp I) localization (fam hypercholestrolemia) cofactor binding (homocystinuria) function (HbK)
Trinucleotide Repeat Disorders can occur in _____
5’ UTR (Fragile X)
Intron
Exon (Huntington)
3’ UTR
