Genetics

Question 1

allele frequency

Answer 1

affected alleles in population/number of alleles in population

Question 2

x-chromosome inactivation

Answer 2

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)

Question 3

Duchenne’s Muscular Dystrophy (DMD)

Answer 3

• 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

Question 4

Becker Muscular Dystrophy (BMD)

Answer 4

• abnormal dystrophin gene

- less severe. Conserves reading frame. point mutation

Question 5

Bayesian: X-linked Recessive (i.e. DMD) with no family history (new mutation)

Answer 5

C: 1/3
NC: 2/3

observation (2 healthy sons): 1/2 * 1/2

Question 6

Bayesian: X-linked Recessive (+ fam hx)

Answer 6

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)

Question 7

Bayesian: AD + penetrance

Answer 7

C: 1/2
NC: 1/2

Use penetrance for observation (0.2) but multiple offspring affected by (0.8)

Question 8

Odds Ratio

Answer 8

“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)

Question 9

Concordance vs. correlation

Answer 9

use twins/sibs

concordance– both members of pair are alike
siblings reared together or apart have same concordance (based on relatedness)

Question 10

Recurrence Risk

Answer 10

sqrt(pop. risk)– sibling (first degree relative) risk

Question 11

multifactorial disease

Answer 11

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

Question 12

Hirschsprungs Disease (HSCR)

Answer 12

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

Question 13

IDDM

Answer 13

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

Question 14

NIDDM

Answer 14

• high concordance in MZ twins

- increased risk if sibling has NIDDM (high heritability)

Question 15

Monogenic (MODY)

Answer 15

Maturity onset diabetes of young. Glucokinase mutation. AD with 95% penetrance. onset before age 25

Question 16

Alzheimers

Answer 16

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

Question 17

Schizophrenia

Answer 17

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

Question 18

Huntington’s Disease

Answer 18

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.

Question 19

Fragile X Syndrome (FRAXA)

Answer 19

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

Question 20

Dystrophia Myotonica

Answer 20

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

Question 21

Fridreich’s Ataxia

Answer 21

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

Question 22

Linkage Analysis

Answer 22

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

Question 23

Association Analysis

Answer 23

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

Question 24

LOD score

Answer 24

assess strength of linkage between two loci

highest LOD score considered the estimate of the linkage distance.

LOD>3 = signficiant

Question 25

Complete Hydatidaform mole

Answer 25

“empty” egg fertilized by 2 sperm or 1 sperm that undergoes endoreplication
46XX
no fetus develops, only trophoblastic tissue

Question 26

Partial Hydatidaform mole

Answer 26

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

Question 27

Beckwith Wiedemann Syndrome (BWS)

Answer 27

IGF-2R (stimulates growth of fetus)
IGF-2R silenced by father
DELETION from MOM causes small offspring

Question 28

Russell Silver Syndrome (RSS)

Answer 28

IGF-2 (inhibits growth of fetus)
IGF-2 silenced from mom
DELETION from DAD causes small offspring

Question 29

Prader-Willi Syndrome (PWS)

Answer 29

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

Question 30

Angelman

Answer 30

“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

Question 31

underyling mechanism of iprinted syndromes

Answer 31

DNA modification- methylation (causes gene repression)

histone modification
acetylation = gene activation
deacetylation = gene repression/phosphorylation

Question 32

x-autosomal translocation… will she express disease if disease causing gene is on translocate chromo?

Answer 32

carrier of a balanced translocation will have most cells inactivating NORMAL x— if disease causing allele is on translocation chromosome she WILL EXPRESS DISEASE

Question 33

DMD pathophys

Answer 33

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.

Question 34

sib-pair analysis

Answer 34

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)