Genetics Flashcards
allele frequency
affected alleles in population/number of alleles in population
x-chromosome inactivation
When one of the two copies of the X chromosome present in female cells is inactivated. The inactive X chromosome is silenced by being made into a transcriptionally inactive structure called heterochromatin (DNA methylation).
XIC- x inactivation center
XIST- non-coding mRNA (once complete, not needed)
TSIX- antisense transcript
the expected outcome is that females express half paternal and half maternal X OR skewed inactivation. (a female heterozytote for x-linked diseases will show symptoms of DMD)
Duchenne’s Muscular Dystrophy (DMD)
- caused by frameshift (70%)
- DELETION of dystrophin gene. longest protein, prone to spontaneous mutation
- 1/3 of cases involve new mutations
- DMD accelerates muscle breakdown
- high CK seen before clinical signs are obvious
- increased CK seen in 70% of female heterozygotes for DMD
Becker Muscular Dystrophy (BMD)
- abnormal dystrophin gene
- less severe. Conserves reading frame. point mutation
Bayesian: X-linked Recessive (i.e. DMD) with no family history (new mutation)
C: 1/3
NC: 2/3
observation (2 healthy sons): 1/2 * 1/2
Bayesian: X-linked Recessive (+ fam hx)
C: 1/2
NC: 1/2
if CK involved, need two observations– one for normal CK (~3/10) and one for offspring (1/2 * 1/2)
Bayesian: AD + penetrance
C: 1/2
NC: 1/2
Use penetrance for observation (0.2) but multiple offspring affected by (0.8)
Odds Ratio
“how much would risk increase for person if one allele is present vs. another allele in same gene”// how uch risk increases due to environmental effect (i.e. smoking)
lower odds ratio –> greater # genes needed for person to become sick
(dwarfism and macular degeneration have high odds ratio – i.e. allele frequency is lower)
Concordance vs. correlation
use twins/sibs
concordance– both members of pair are alike
siblings reared together or apart have same concordance (based on relatedness)
Recurrence Risk
sqrt(pop. risk)– sibling (first degree relative) risk
multifactorial disease
1) risk is higher if more than one fam member affected
2) risk is higher if affected person has severe symptoms
3) risk is higher if affected person belongs to the less commonly affected sex (i.e. son of alcoholic moms have greatest risk for disease if alcoholism affects men>women)
4) risk of 1st degree relative is ~sqrt(pop risk)
5) can’t use linkage analysis for multifactorial traits
Hirschsprungs Disease (HSCR)
megacolon
high heritability (familial)
Long [CODING region mutation–increased penetrance]
Short [male>female; more common; less familial occurance; mutation in ENHANCER – decreased penetrance]
RET gene (receptor tyrosine kinase, GDNF is ligand)
RET defect = distruption in migration of neural crest cells
IDDM
genetic factors:
1) HLA-DR3//HLA-DR4
2) Aspartic acid in pos 57 of DQ protects against IDDM (crossovers never happen in HLA area of chromosomes. IDDM is partly autoimmune– virus can trigger immune reaction)
3) Insulin gene on Chromo 11
NIDDM
- high concordance in MZ twins
- increased risk if sibling has NIDDM (high heritability)
Monogenic (MODY)
Maturity onset diabetes of young. Glucokinase mutation. AD with 95% penetrance. onset before age 25
Alzheimers
Abnormal cleavage of APP protein (alpha-secretase/preesilin 1 & 2). Causes increases of Abeta42 (40 and 42 aa protein products)
APP gene is on chromosome 21 (down syndrome)
ApoE4 allele is main known genetic risk factor
AD form of Alzheimers is 10-15% (amyloid or presenliin mutation) = major genes
minor genes= multifactoral inheritance
Schizophrenia
physician variation in what constitutes schizophrenia
concordance rates are 47% in MZ
overall heritability is 6–80%
risk factor = age of father
common in people with DiGeorge
Huntington’s Disease
Type I Trinucleotide Repeat Disorder– Gain of Function
CAG repeat expansion– increased glutamine in protein (polyglutamine)
usually htt sequesters repressor element (RE1) so BDNF can be transcribed which helps with microtubule transport (brain//neurons)
when defective, decreased transcription of neuronal genes
The larger the CAG repeats, the earlier onset.
Fragile X Syndrome (FRAXA)
Type II disorder– loss of function
CGG 5’ UTR FMR1
CGG gets hypermethylated and promotor shut off (mRNA cannot transcribe gene).
without FMR1 protein: protein synthesis and internalization of AMPA and long term depression exagerated.
most comon form of inherited mental retardation.
has premutation allele 55-200 other premutaiton-related disorders: -- ovarian insufficiency -- gait ataxia -- frontal lobe dementia
Dystrophia Myotonica
Type II disorder– loss of function (progressive muscle wasting)
DM1 (35-50 CTG) vs. DM2 (no premutation)
Expansion of CCTG in first intron OR CTG repeat in 3’ UTR of two genes
Fridreich’s Ataxia
Type II disorder– loss of function
GAA expansion repeat in first intron of FRATAXIN gene
expansion prevents transciritpnon of gene
Frataxin– mitochondrial protein invovled with Fe homeostasis
Linkage Analysis
Families
tests for co-segregation of allesle within family members
if it is a rare variant withs trong affect on phenotype
Recombination is tracked using microsatellite markers
Association Analysis
Populations
searches for DIFFERENCES in ALLELE FREQUENCY between unrelated groups of affected and unaffected individuals or within families.
many genes contributing to problem
LINKAGE DISEQUILIBRIUM (bad allele is found together with specific marker allele in nealry all people carrying bad alleles)– association due to physical proximity of SNPs
LOD score
assess strength of linkage between two loci
highest LOD score considered the estimate of the linkage distance.
LOD>3 = signficiant
Complete Hydatidaform mole
“empty” egg fertilized by 2 sperm or 1 sperm that undergoes endoreplication
46XX
no fetus develops, only trophoblastic tissue
Partial Hydatidaform mole
Two sperm and one egg join or one sperm and one egg join and the sperm DNA undergo endoreplication
69XXY or 69XXX
fetus develops but does not survive
Beckwith Wiedemann Syndrome (BWS)
IGF-2R (stimulates growth of fetus)
IGF-2R silenced by father
DELETION from MOM causes small offspring
Russell Silver Syndrome (RSS)
IGF-2 (inhibits growth of fetus)
IGF-2 silenced from mom
DELETION from DAD causes small offspring
Prader-Willi Syndrome (PWS)
small deletion in PATERNAL chromosome 15 (no SNRNP- maternally imprinted, silenced)
“hungry all the time”
maternal imprinting lacking
symptoms; reduced motor function, obesity, mental deficiency
Angelman
“happy puppy syndrome” (hyperactivity, unusual seizures, repetitive muscle movements, mental deficiencies)
small deletion in MATERNAL chromosome 15 (no UBE3A- gene is paternally imprinted, silenced)
Paternal Uniparental Disomy
underyling mechanism of iprinted syndromes
DNA modification- methylation (causes gene repression)
histone modification
acetylation = gene activation
deacetylation = gene repression/phosphorylation
x-autosomal translocation… will she express disease if disease causing gene is on translocate chromo?
carrier of a balanced translocation will have most cells inactivating NORMAL x— if disease causing allele is on translocation chromosome she WILL EXPRESS DISEASE
DMD pathophys
1) you get ISCHEMIA
2) LACK OF PHYSICAL COUPLING OF CYTOSKELETON AND ECM.
sarcoglycans, dystroglycans, etc forms complex that falls apart with dystrophin missing. leads to accelerated muscle breakdown. Dystrophin helps anchor muscle fibers primarily in skeletal and cardiac muscles. It connects intracellular cystokeleton to transmembrane proteins which are connected to ECM
also NOS (nitric oxide synthase) is lacking– necessary for exercise induced vasodilation and you get ischemia if misising.
sib-pair analysis
choose fam where at least 2 sibs are affected
calculate ALLELE SHARING then average all pairs
if avg is above 50%, marker is near bad gene!
(only works if parents both have good and bad alleles)
