Learning Objectives (not comprehensive) Flashcards
autosomal dominant pedigree
i. One copy of disease allele needed to express phenotype
ii. 50% chance offspring will inherit disease allele
iii. all affected individuals have at least one parent who carries disease allele
iv. males and females equally affected
v. male-to-male transmission observed
vi. ie: muscular dystrophy, Huntington’s
autosomal recessive
i. Two copies of disease allele needed to express phenotype
ii. 25% change offspring inherits disease allele (has phenotype); 50% chance offspring inherits one copy of disease allele (carrier); 25% chance offspring inherits no copies of disease allele (not carrier)
iii. Parents of affected individual are not typically affected but are gene carriers
iv. Males and females equally affected
v. Often seen in consanguineous couples (related by blood)
Ie: sickle cell anemia, CF
x-linked dominant
i. One copy of disease allele on x-chromosome required for individual to be susceptible
ii. 50% chance for offspring to inherit disease allele from affected female
iii. affected male: all daughters will be affected but none of his sons
iv. Males and females affected (may be more severe or lethal in males)
Ie: Fragile X syndrome
x-linked recessive
i. Two copies of diseased allele on X chromosome are required for female to be affected; one copy for male
ii. Females are usually carriers because they have one copy of diseased allele
iii. Carrier female: 50% chance that sons will inherit disease from mom and 50% chance that daughters will be carriers
iv. Affected female: all sons will be affected, all daughters will be unaffected carriers
v. Affected men transmit disease to all daughters (who are then carriers) but none to sons
Ie: Duchenne muscular dystrophy, hemophilia A
What is mendel’s first law?
segregation; alleles segregate at meiosis into gametes
What is mendel’s second law?
law of independent assortment; segregation of each pair of alleles is independent (except linked genes)
How is penetrance like a light switch?
on/off (affected/unaffected)
i. Could have mutation but not be affected (no visible phenotype)
ii. 80% penetrance: 80% of individuals with mutation are affected
Fraction of individuals with trait (disease) genotype who show manifestations of disease
What is age-dependent penetrance?
likelihood of manifesting disease in mutation carriers depends on age
How is expressivity like a light switch?
light is on but you’re trying to figure out how severe (dimmer function)
i. Affected individual (gene mutation led to disease) looking at severity
Degree to which trait is expressed in an individual (severity)
What is the influence of sex on Mendelian inheritance patterns?
manifestation of a trait depends on individual’s sex
What is the influence of stochastic effects on Mendelian inheritance patterns?
random effects can influence expression of phenotypes
What are modifier genes?
genetic factors that influence phenotype
Ie: one gene affects eye color but another also influences it by changing amount or distribution of pigment in iris
What are phenocopies?
same phenotype (as a genetic condition) due to non-genetic factors Ie: some animals change fur color (phenotype) depending on temperature where they live
What is pleiotropy?
Some mutation leads to multiple and different phenotypes (different organ systems); genes that have multiple effects within the body
How frequent are SNPs?
1 per 1,000 base pairs between any human genomes
What are insertion-deletion polymorphisms?
lots of variation in genome comes from variation in these large blocks of small repeating segments instead of variation between important genes
Mini-satellites are tandem repeats of ________ base pairs of DNA
10-100
How many base pairs does the haploid human genome have?
3x10^9
Evolution and adaptation are fueled by __________
random genomic variation
How do individuals get new mutations?
shuffling of regions during meiosis (recombination)
VNTR (variable number of tandem repeats) are found in _________
minisatellites
Microsatellites contain ________ repeats
2-,3-,4-bp
STRP (short tandem repeat polymorphisms) are found in ____________
microsatellites
What is the primary type of structural variation in the human genome?
copy number variation
Genomic DNA copy numbers are measured using _____________
array comparative genomic hybridization (array CGH)
What protein coding sequence exhibits the greatest human specific copy number expansion?
DUF1220
Gene-rich genome
Chr19
how many genes (expressed segments) each contains
Gene-poor genome
Chr13,18,21
____% of the genome is G-C rich
38%
____% of the genome is A-T rich
54%
Euchromatic has (more/less) repeats and makes up (more/less) of genome
less, more
Categories and frequencies of genomic DNA sequences
a. 1.5% translated (protein coding)
b. 20-25% represented by genes (exons, introns, flanking sequences involved in regulating gene expression)
c. 50% “single copy” sequences
d. 40-50% classes of “repetitive DNA”
Tandem repeats are the basics for ________ techniques
cytogenetic banding
Tandem repeats are often found on _________ (hotspots for evolutionary change)
Chr1,9,16,Y
“Alpha satellite” repeats are found near the _________ region of all human chromosomes
centromeric
“Alpha satellite” repeats may play a role in _________ during mitosis and meiosis
chromosome segregation
What do retrotransposon elements in DNA do?
copy their own sequences into other locations in DNA (can cause inactivation of genes)
Two examples of dispersed repetitive elements are …
- Short interspersed repetitive elements (SINES)
- Long interspersed repetitive elements (LINES)
Short interspersed repetitive elements (SINES) are part of the ______ family
alu
Long interspersed repetitive elements (LINES) are part of the _________ family
L1
Alu’s and L1’s can lead to non-allelic homologous recombination (NAHR), which is ___________
aberrant recombination events between different copies of dispersed repeats leading to diseases
How many human genes are there?
25,000-30,000
The three types of human genes are…
- protein-encoding
- RNA-encoding
- pseudogenes
Gene families arise through __________
gene duplication
Meiotic recombination involves ________ crossing-over between _________
homologous; non-sister chromatids
What is the most common contiguous gene syndrome in humans?
del 22q11 (overexpression of multiple loci next to each other)
Methylation binding proteins attract ________ to _______ transcription and compact ________
HDACs, silence, chromatin
DNA methylation marks are established in the _______
gamete
DNA methylation is stably maintained in ______ cells after fertilization
somatic
Methylation in somatic cells is maintained by ____________
methyltransferase
Prader-Willi and Angelman Syndromes involve deletions in long arm regions of chromosome _____
15
Prader-Willi causes (%s)
- 70% deletion of paternal chromosome
- 28% maternal uniparental disomy
- 2% mutation on imprinting center
Angelman Syndrome causes (%s)
- 70% deletion of maternal chromosome
- 4% paternal uniparental disomy
- 18% (ish) imprinting center mutation on maternal allele
- 8% mutated gene
FISH Probe: Centromere (name, use, example)
Name: cen
Use: enumeration of chromosomes
Example: ALL panel, prenatal dx
FISH Probe: Locus specific identifier (name, use, example)
Name: LSI
Use: deletion/duplication of gene (loci)
Example: p53, cancer
FISH Probe: Fusion (name, use, example)
Name: F, DF
Use: detecting translocation
Example: BCR;ABL, PMR;RARa
FISH Probe: Break apart (name, use, example)
Name: BAP
Use: detecting translocation and rearrangement
Example: MLL (cancer)
FISH Probe: Whole chromosome point (name, use, example)
Name: WCP
Use: identifying translocations or markers
Example: WCP 1-22, X, Y
The target DNA in chromosomal microarray is …
a single-stranded oligomer
CMA can only detect ________ and _________
gains, losses
CMA cannot detect _________________
balanced rearrangements (limited mosaicism)
The CYP450 enzyme is active in the _______ and ___________
liver, intestinal epithelium
Cyclosporine is a(n) ________ of _______ gene.
immunosuppressant, CYP3A
Grapefruit juice and ketoconazole are _________ of CYP3A gene
inhibitors
Rifampicin is a(n) ________ of CYP3A gene
inducer
tricyclic antidepressants and opioids such as codeine act on _______ gene
CYP2D6
Warfarin acts on _______ gene
CYP2C9
Proton pump inhibitors and fluoxetine act on ________
CYP2C19
__________ drugs act on NAT gene
isoniazids for TB
TMPT gene experiences _______ mutations that destabilize the genome
missense
If you give kids with ALL a standard dose of ________, it will kill them.
6-mercaptopurine (for TMPT gene)
Butyrylcholinesterase hydrolyzes _________, which acts on BCHE gene
succinylcholine
G6PD is a ________ enzyme
x-linked
people are susceptible to hemolytic anemia after exposure to _________ drug
sulfonamide, dapsone
Rare mutations in RYR1 lead to _________
malignant hyperthermia
Warfarin acts on the _______ gene by reducing vitamin K so it can be recycled and used to make more coagulation factors
VKORC1
Hardy Weinberg assumptions
- large population, random mating
- constant allele frequencies
- no mutation rate
- all genotypes equally fit
- no significant immigration/emigration
Turner and Klinefelter’s syndromes are normally driven by ____________
meiotic nondisjunction
Centromeres (are/are not) repeat rich
are
The classes of DNA include __________ and _________________
tandem repeats, dispersed repetitive elements
Types of DNA variation (3)
- insertion/deletion polymorphisms
- SNPs
- copy number variation
Increases in DUF1220 copy number led to an increase in _________ instability
1q21.1
1q21.1 duplications lead to ________ and _________
macrocephaly, autism
1q21.1 duplications lead to _______ and __________
microcephaly, schizophrenia
Aneuploidy can occur…(3)
- meiosis I
- meiosis II
- post-zygotically
What percent of Turner’s Syndrome karyotypes are pure 45X?
50%
75% of Klinefelter Syndrome comes from errors in _____________
maternal meiosis I
Mosaicism is most commonly caused by ___________
nondisjunction
In chromosomes, which are more common: structural rearrangements or numerical aberrations?
numerical aberrations
75% of Robertsonian translocations involve chromosomes ____ and ____
13, 14
Inversions with chromosomes 1,9,16, and Y are almost always ______ in nature
familial
Pericentric inversions give rise to ___________
two complementary recombinants
Imprinted genes make up less than ___% of the human genome
10%
During crossing over, deletions are caused by __________________
low copy repeat misalignment
Cytogenetics are important in diagnosing ________ while CMA are important in diagnosing __________
leukemia, lymphoma; children with delays
APML is caused by gene fusion of ___________ and CML is caused by gene fusion of ____________
PML-RARalpha (t(15;17))
BCR-ABL (t(9;22))
CML is treated with ___________
Gleevec
Gleevec (CML treatment) binds at the ____ binding site in the BCR/ABL ___________ and the effect is __________
ATP, tyrosine kinase, inhibited cell proliferation
DS infant and children have a _______ increased risk for developing AML or ALL and a _______ increased risk for developing AMKL
20-100 fold
500x
Cytogenetics detects ____________ while CMA detects _____________
balanced rearrangements, runs of homozygosity
CMA determines the _________ and _________ of deletions/duplications
size, location
T/F You can see mutations in FISH
false (identifies number of a specific chromosome or translocation)
What is inverted duplicated isodicentric 15Q (IDIC15)?
autism, not dysmorphic, often hypotonic seizures
What are 15Q interstitial duplications?
- maternally inherited
- within one arm of chromosome
- autism, not dysmorphic, hypotonic seizures
Pharmacogenetics looks at variable responses due to ____________
individual genes
Pharmacogenomics looks at variable responses due to ____________
multiple loci across the genome
Pharmacokinetics describes the ___________ of drugs
absorption, distribution, metabolism, and excretion
Pharmacodynamics describes the relationship between ___________
concentration of a drug (at active site) and biological effects
Expected DNA mutations for poor metabolizers (4)
- frameshift
- missense
- nonsense
- splicing
Expected DNA mutations for ultrafast metabolizers (2)
- increased copy number
- missense
Mendelian disease looks at the _____ of genetic effect and population genetics looks at the _________ of disease
size, frequency
What can NextGen DNA sequencing determine?
if estimates of mutation rates from Hardy-Weinberg are correct
Genes present for development of testes
SRY, SOX9, SF1, DAX1
SF1/NR5A1 cause the genital ridge to differentiate into ___________ and __________
- sertoli cells (AMH, spertm)
- Leydig cells
Production of anti-mullerian hormone (AMH) is stimulated by…(2)
SRY, SOX9
________ is important for differentiation of the testes
FGF9
WNT4 protein is important in females for __________
differentiation of ovary
WNT4 is inhibited by _______
SOX9
CYP2D6 inhibitors (3)
- quinidine
- fluoxetine
- paroxetine
How are imprinting patterns maintained in offspring?
maintain methylation
_______% of babies with DS have congenital heart defects
30-50
Copy number variations are often enriched with __________ and __________
- specific duplications
- sequence gaps
First degree relatives include __________
parents, siblings, children
Patau syndrome is trisomy ____
13
Edwards syndrome is trisomy ____
18
In adjacent 1 segregation, homologous centromeres go to _________ daughter cells
different
In adjacent 2 segregation, homologous centromeres go to _________ daughter cells
the same
Individuals with androgen insensitivity have _____________
extra female genitalia with male gonads
The incidence of inversion is as high as ___%
1%
Leydig cells produce _________ and Sertoli cells produce ________
testosterone, anti-Mullerian hormone
Androgen insensitivity syndrome is caused by a _______________ gene
x-linked
What is 5-alpha reductase deficiency?
inability to convert testosterone to dihydrotestosterone
5-alpha reductase deficiency is caused by a ________________ gene
autosomal recessive
allelic heterogeneity
existence of multiple alleles of a single gene causing a similar phenotype
compound heterozygote
person who carries different mutant alleles at the same gene locus
Alpha1-antitrypsin deficiency (ATD) is (early/late) onset
late
Tay-Sachs has a defect in the ability to get rid of ___________, which makes up 5% of brain mass
ganglioside
Qualitative hemoglobinopathies (3)
HbS, HbC, HbE
Quantitative hemoglobinopathies (4)
alpha, beta, gamma, delta thalassemias
Patients with Denys-Drash and Frasier Syndromes are genetically ______ but exhibit sex reversal because of a mutation in the _____ gene
male, WT1
WT1 is a ____________ for the SRY gene
transcription factor
Salt wasting in the first few weeks of life and metabolic stress are symptoms of ____________
congenital adrenal hyperplasia
What is a genetic linkage study?
search genome for segments disproportionately co-inherited along with diseases in multiplex families
What is log of odds?
a statistical measure of the likelihood that loci are linked together given the inheritance/disease pattern
Gene linkage studies are most powerful for…
uncommon risk alleles with strong effects
most commonly used DNA polymorphisms for finding genes (3)
- microsatellites
- SNPs
- CNVs
Candidate gene association studies are best for…
common risk alleles with small to moderate effects
In sickle cell (HbS), the amino acid change is _______ to _________
glu(-) to val(neutral)
In HbC, the amino acid change is ________ to ____________
glu(-) to lys(+)
Alpha-thalassemias are usually caused by ________ and beta-thalassemias are usually caused by __________
deletions, point mutations
4 main characteristics of epigenetic phenomena
- different gene expression pattern/phenotype, identical genome
- inheritable through cell division
- on/off switch
- erase-able (therapeutic potential)
In a person with PWS, treatment with GH should be started….
at onset of excessive eating symptoms
Paternal errors in meiosis I result in …
XXY (Klinefelter’s)
What is the recurrence risk for Trisomy 21?
1/100 + maternal age risk
