Week 2 Flashcards
What enzyme deficiency causes Gaucher Disease?
Glucocerobrosidases
In gaucher disease, lipid accumulates predominantly in ___________
macrophages
What is the likelihood of having a child at risk for Gaucher disease when both parents are affected with Gaucher?
100%
Which therapy is currently used most frequently for patients with Gaucher disease?
Enzyme replacement therapy
Which glycosphingolipids principally accumulates in Gaucher disease?
Glucocerebroside
What type of Gaucher disease is non-neuropathic?
Type 1
What could be a sign of a type of type I gaucher disease?
- Chronic Fever
- Jaundice
- Hepatosplenomegaly
- Headache
- Visual disturbances
- Hepatosplenomegaly
Symptoms of gaucher disease can appear at…
ANY AGE - infancy, late adulthood, etc.
Gaucher disease is diagnosed when levels of glucocerebrosidase activity are below normal at _____%
30%
What is prevalence for type 1 Gaucher carriers in Ashkenazi Jews?
1/15
Characteristics of Complex Traits (5)
1) Incomplete Penetrance
2) Variable Expressivity
3) Allele Heterogeneity
4) Locus Heterogeneity
5) Presence of Phenocopies
Allele Heterogeneity
Several different mutations within one gene can cause the same disease
Locus Heterogeneity
Mutations in several different genes can result in the same clinical presentation
Phenocopy
environmentally caused phenotype that mimics the genetic version of the trait
Multifactorial Inheritance
combination of genetic and non-genetic factors
- Aggregate in families
- Do not follow simple Mendelian mode of inheritance
- EX) Cancers, Type 1 and 2 Diabetes, Alzheimer’s
Determining Importance of Genetic vs. non-genetic factors via ________, ________, and _________ studies
Twin, Adoption, and Immigration studies
Heritability
proportion of variance in trait that is due to genetic variation
Genetic Association Studies (2)
1) Candidate Gene Association Studies
2) Genome wide association study
Candidate Gene Association Studies
Studies gene directly
- Relies on a priori biological hypothesis or positional hypothesis
- BUT most a priori hypotheses are wrong → ALMOST ALWAYS yields false positives
- Compare Allele frequencies in cases vs. controls
Weaknesses of Candidate Gene Association Studies are ___________ and __________ almost always yielding _____________
Publication bias and population stratification
false positives
Genome Wide Association study
case-control association study, but tests hundreds of thousands/millions of marker SNPs across the ENTIRE genome
Weaknesses of Genome Wide Association studies are _________, __________, and __________
Population stratification
Lots of follow up
big sample size
Strengths of Genome Wide Association studies are __________, __________, and __________ and are best used for ______________ with ________ effect sizes
- no publication bias
- can discover new genes (no prior hypothesis required)
- Fine localization
Best for common alleles with small-moderate effect sizes
Genetic Linkage Study
Search genome for segments disproportionately co-inherited along with disease in “multiplex families”
Genetic linkage analysis measures ____________ and uses ________ the statistical measure of linkage
likelihood of recombination between two loci in meiosis based on genetic distance
Log of Odds (LOD)
If LOD is > 3.0 then…
proof of linkage/gene localization
1cM (centiMorgan) = ____% recombination between two ______ per ______
1%
loci per meiosis
Strengths of Genetic Linkage studies are _______ and ________, and are best for _________ with ______ effect
- can discover new, unknown genes
- can provide fine localization
best for Mendelian traits (uncommon alleles with strong effects)
A weakness of genetic linkage studies is that it isn’t good for ___________
complex traits
Strength of Exome/Genome Sequencing Study
can get big snapshot of a person’s entire genome sequence
Weaknesses of Exome/Genome Sequencing Studies include _______, _______, and ______.
- difficult to distinguish between causal variants and non-pathological variation
- requires follow-up analysis
- Data interpretation difficult (variant of unknown significance, VUS)
3 most commonly used DNA polymorphisms for finding genes
1) Microsatellites
2) SNPs
3) Copy Number Variants
Microsatellites
Simple sequence repeats
multi-allelic
used in forensics
Single Nucleotide Polymorphisms (SNPs)
Single NT change
Haplotype
local context surrounding SNPs
Copy number variants
common genomic deletions/insertions hundreds to tens of thousands of nucleotides in size
- Tens of thousands known
- Most not causal for human disease
Compound Heterozygote
an individual who carries two different mutant alleles of the same gene
Alpha Globin Gene Cluster: order of genes 5’–>3’ (spatial = temporal order of expression)
Located on chromosome ____ and has ____ copies
Zeta-Alpha2-Alpha1
2 copies on chromosome 16
Beta Globin Gene Cluster:
order of genes 5’–>3’ (spatial = temporal order of expression)
Located on chromosome ____ and has _____ copies
Epsilon-Gamma-Delta-Beta
1 copy on chromosome 11
HbF
apha2gamma2
Adult Hemoglobins:
1) HbA: a2B2 (97%)
2) HbA2: a2d2 (2%)
Qualitative Hemoglobinopathies
structural variants, normal synthesis but altered globin property
-HbS, HbC, HbKempsey, HbKansas
Trinucleotide Repeat Disorders what are they, and what are 3 characteristics
- Expansion of a segment of DNA consisting of three or more nucleotides
1) Slipped Mispairing
2) Genetic Anticipation
3) Parental Transmission Bias
Slipped Mispairing
mispairing of bases in regions of repetitive DNA coupled with inadequate DNA repair systems
-Longer repeat → more chance of subsequent mispairing
Genetic Anticipation
Severity and/or onset of disease increases in the next generation (usually due to lengthening of repeat)
Parental Transmission Bias
repeat expansion more prone to occur in gametogenesis of the male or the female
Unique characteristics of mitochondrial inheritance (4)
1) Inheritance only through maternal lines
2) Affected males do NO pass on the genes
3) Replicative segregation
4) Heteroplasmy
Replicative Segregation
- At cell division, multiple copies of mtDNA replicate and sort randomly among newly synthesized mitochondria
- This could be normal or mutated DNA
Heteroplasmy
presence of more than one type of organellar genome within a cell or individual
X chromosomal inactivation is typically ________ somatic cells of females and occurs _________.
Females are therefore _____________
random
in the first week of embryogenesis
mosaic for their X chromosome
Mechanism for X inactivation
1) XIST gene expressed by inactive X chromosome (RNA expressed that coats inactivated X)
2) methylation of promoter regions prevents transcription
NonRandom X inactivation occurs when __________
there is a structurally abnormal X chromosome
If there is a:
1) abnormal X chromosome
2) Balanced translocation (involving X)
3) Unbalanced translocation (involving X)
THEN non-random inactivation of…
1) Abnormal X chromosome → non-random inactivation of abnormal X chromosome
2) Balanced translocation between X and autosome → non-random inactivation of NORMAL X, this preserves the balance
3) Unbalanced translocation between X and autosome→ nonrandom inactivation of der (X) and activation of the normal X
4 Characteristics of epigenetics
1) Different gene expression pattern/phenotype from an identical genome
2) Inheritance through cell division, even through generations
3) Like a switch: ON/OFF
4) Erase-able (inter-convertible)
Maintenance Methyltransferases
add methylation to newly synthesized strands, propogating epigenetic marks through somatic cell division
Epigenetics: DNA methylation of CpG cytosines results in ________ but does not effect _________.
gene repression (locks cell in this state)
does not effect base pairing
Epigenetics: Histone acetylation of chromatin results in ________ and is inherited because __________
gene activation
inherited because old histones influence new histones via enzymes to make new histones like the old ones
Epigenetics: Histone Deacetylases act to _________ by _________.
silence genes
removing chemical groups from lysines
TSG gene is typically ______ but can be silenced by _________. This is then stably maintained.
unmethylated/active
5meC causing aberrant methylation and silencing of tumor suppressor gene.
4 mechanisms of genetic mutation leading to disease
1) Loss of function of protein (MOST COMMON)
2) Gain of function of protein
3) Novel property by mutant protein
4) Heterochronic expression (wrong time) or Ectopic expression (wrong place)
Diagnostic Testing
Patient with signs or symptoms of genetic disease → positive genetic test result CONFIRMS diagnosis
Predictive Testing
- Patient with NO signs or symptoms of genetic disease → positive genetic test provides estimate of FUTURE disease risk
- Some underlying risk of disease due to family history or ethnic background
Informative results
- Information from a genetic test DEFINITIVELY diagnoses or excludes the disease in question
- Have family history of particular disease causing mutation, baby does NOT have mutation = informative
Non-Informative Results
- Situation where the genetic test result is normal, but it is not possible to definitively exclude disease/disease risk
- No family history, particular mutation not found in baby = non-informative – multiple possible mutations
Chromosomal Analysis tests for ________, and can only be used for _______ not ________
abnormality in chromosome number or structure
Used for BIG chromosomal changes (3-5Mb) and not for small scale issues
FISH is used to detect ______ but before testing you must __________
200 Kb changes (duplications, deletions, translocations, copy number, aneuploidies)
know/strongly suspect diagnosis and what exactly you are looking for
Sanger Sequencing/NextGen Sequencing is good for _________, but before testing you must _________. It cannot detect _________
small mutations or insertions/deletions
must know/suspect specific genetic diagnosis
cannot detect large deletions/insertions, rearrangements, etc.
Microarrays (DNA based) can be used to identify ____________ but cannot diagnose __________
100-200Kb (aneuploidies, unbalanced chromosomal rearrangements, chromosome deletions/duplications, nucleotide)
Cannot diagnose: balanced chromosomal rearrangements, anything below 100-200 Kb, or nucleotide mutations
3 Requirements of gene therapy:
1) Targeting: must be delivered/targeted to appropriate cells and NOT inappropriate cells
2) Expression: must lead to adequate expression and duration
3) Toxicity: side-effects must be acceptable
Retroviral Gene therapy uses _________ and integrates into ____________. One issues is that you risk _________. Retroviruses are limited by ___________.
- RNA viruses
- cell genome of dividing cells (efficient)
- risk insertional mutagenesis (can be passed on to daughter cells)
insert size (7-9kb max)
Adenoviral Gene Therapy uses ________ and can infect _________. It does NOT ________, and therefore only has _______.
There is also a risk of ______
DNA viruses
- any cell (not just actively dividing cells)
- does NOT integrate into cell genome
- transient expression
- Severe immune reaction
Non-viral gene therapy can use _____ .
It is good because it can have _________, _______, and ________, but is limited because it has _________ and _________.
direct DNA
large insertion sizes, minimal host response, and no risk of getting passed on to daughter cells
Limited because it has low efficiency and transient expression
WNT4
-signaling factor for the development of ovaries
promotes female sex development and represses male sex development
Mesonephric ducts develop into….
fallopian tubes
Recombinant 8 syndrome
derives from parental carrier with balanced pericentric inversion 8 p23.1q22.1
Severity of phenotype in mosaic down syndrome is related to…
the timing of mitotic non-disjunction event during development of zygote
DNA methyltransferases and histone deacetylases could be used to treat…
anti-cancer therapy that disrupts inheritance of malignant epigenetic changes
Chromatin state is maintained in what stage of the cell cycle?
S phase - during DNA replication
DAX1 gene
SRY inhibitor
