the % chance that a mutated genotype will show a phenotype. 

% of mutant genotypes tha show an effect

reduced penetrance is <100%

all or none

3n (69) chromasomes

2 sperm 1 egg

rare

4n (92)

post fertilization event.  mitotic failure

non viable, result in pregnancy lost

46-> 0 and 92

due to nondisjunction in gametogenesis

(13 16 18 21 22) acount for 50% of miscarriages

• Chromasome 14, 21
• parent with robertsonian gene has high chance for child with DS
• 17% chance, age independent.

• some cells 46, some cells 47
• post fertilization event
• unequal chromosome segregation during fertilization.

Translocation

Reciprocal:

Robertsonian:

• Balanced rearangement
• genetic info transfered between 2 different (non-homologous) chromasomes

Reciprical: genetic info distal from break of 2 chromosomes switch places.

Robertsonian: breakage of 2 acrocentric chromosomes (13, 14, 15, 21, 22) near centromere, fusion of long arms = new chromasome.

• balanced rearangement
• 2 breaks in a chromosome, detached portion put back in reverse. 
• Chromosomal abnormal gametes may be produced in gametogenesis.

• risk of occurance of first degree relatives = √(population prevelance)

• higher = more genetic
• h = 2 (C_mz - C_dz). 
• All environmental C_mz = C_dz.
•  All environmental C_mz=1    C_dz=0.5

1. Measure of fetal produced analytes in maternal fluid.  AFP, HGG, UE "tripple screen" at 15 weeks.
2. Measure fetal produced analytes in amniotic fluid.  15-17 weeks
3. FISH or kariotype of fetal chromosomes from amniocytes. Test for aneuploidies.
4. DNA analysis from embryo .  (15-17 weeks), or chorionic villus sampling (10-11 weeks) to detect gene mutations.

if baby has NTD, AFP is high in maternal amnion and serum,

16 weeks of pregnancy

detect open NTD

safer,but less precise than sampling from amnion

also can detect down syndrome.

Mother tripple screan

quadra screen

AKA AFP test AKA second trimester test

detect down syndrome, trisomy 18, NTD.

(quadra screan also tests for inhibin A, and more acurate at detecting down syndrome)

• Inhibin A.  High 21, low 18 (tripple test)

• Low AFP (quadra test) High NTD

• Low PAPP-A (only first trimester)

• β-hCG.  High 21 low 18 (first & second trimester)

• High nuchal translucency: ultrasound scan

• Low uE3

Diagnostic Test

Predictive Testing

Diagnostic: rule out

Predictive: asymptomatic individuals with family history.  presymptomatic / predisposition

Carrier Testing: ID mutations. if family members have condition.

remove cell from 8-16 cell blastoma

amplify DNA

analysis or FISH to find aneuploidy

Gene therapy

Ex vivo

In vivo

Ex Vivo: cells taken out, gene therapy, cell put back into body.

In Vivo:  Cells modified while in body

Gene Therapy

Retroviral

Other viral

Nonviral

Retroviral: <+> High efficient, long duration, <-> mutagenesis, need dividing cell, limited DNA size.

Adenovirus: <+> broad rainge of target cells, not require cell division, low mutation.  <-> "transient expression, immunogenicity, virus cytopathic effect

Adeno associated virus: <+> not need cell division, site specific integrin.  <-> insertional mutation, limited DNA size

Nonviral: <+> no infectious risk, no size limit.  <-> low efficiency, low target range, transient expression.

Repetitive DNA

Satelite DNA

Satellite: highly repetitive, localized, not transcribed, associated with centrimere & telomere.

micro/mini satelites used for genetic maping.  maps STR

CODIS used by police to find bad guys,

Repetitive DNA

Dispersed repetitive DNA

moderately repetative

interspersed with unique sequence

transcribed into RNA

LINES: small length

SINES: long length

1. tissue specific alterations in chromatin structure

2. methylation of specific cytosines in the genome.

"epigenic"

Acetylation by modifying LYS residue on the histone weakens atraction.  (catalyzed by HATs) transcriptional activation.

Deacetylation (HDAC) tilences.

• Occurs at CYT base of DNA

• location is called CPG. 

• CPG spread out "CPG islands".  asymetrical

• CPG islands are the promoter regions where transcription starts.

• methylation of CPG blocks transcription factors, inhibits transcription.  
• demethylation = activated.
• methylation controled by DNA methyltransferases. 

• Diseased gene at FMR1
• leading heredetary cause of retardation in males
• Long arm of X breaks at absense of folic acid
• Anticipation in father to daughter, not father to son.

• long arm of X breaks when folic acid absent
• 80% penetrance in males, 30% in females
• anticipation
• CGG repeat at FMR1.  repeat lengthened mother -> child, not father -> child  (father with pre mutation can't transfer disease to daughter)

glutamine

glycine

aspartate

ribos 5 phosphate -> PRPP

<+> Pi

<-> GDT GTP ADP ATP

purine

PRPP + glutamine -> 5 phospho..

<+> PRPP

<-> AMP GMP IMP

commiting for pyrimidine

<+> ATP PRPP

<-> UTP

NDP-> deoxy NDP

inhibited by hydroxyurea & dATP

preventative

xanthine oxidase

preventative

excrete uric acid, prevent reabsorption

block microtubule function

blocks inflamitary response

ARG

LYS

inhibit ribonucleotide reductase

cancer, HIV, sickel cell

inhibit IMP dehydrogenase

less guanine

inhibit growth of B/T

folate analog

inhibit dihydrofolate reductase

Aspartate

Glutamine

One X chromasome in every somatic cell at the 16-64 cell stage of XX is randomly and perminantly turned off.

so X linked gene products are = in males and females (Dosage compensation)

the % chance that a mutated genotype will show a phenotype. 

% of mutant genotypes tha show an effect

reduced penetrance is <100%

all or none

1.) Parents genotypically normal 1 child diseased

2.) parents genotypically normal multiple kids diseased

1,) probably due to new mutations of the child

2.) probably due to germline mosaicism

• Diseased gene at FMR1
• leading heredetary cause of retardation in males
• Long arm of X breaks at absense of folic acid
• degree of retardation higher in women
• Anticipation in father to daughter, not father to son.

• 2X more effected females than males
• no father -> son
• Fagile X syndrome
• Hypophosphatemic Rickets
• Incontenentia Pigmenti 1

• colorblindness
• Hemophelia
• G6PD deficiency
• muscular distraphy
• Lesh-Nihan

• Leber hereditary optic neuropathy
• Kearns-sayre disease
• Pearson syndrome

• leading cause of mental retardation in males
• long arm of X breaks when folic acid absent
• retardation less severe, and more varied in women
• 80% penetrance in males, 30% in females
• anticipation
• CGG repeat at FMR1.  repeat lengthened mother -> child, not father -> child  (father with pre mutation can't transfer disease to daughter)

3n (69) chromasomes

2 sperm 1 egg

rare

4n (92)

post fertilization event.  mitotic failure

non viable, result in pregnancy lost

46-> 0 and 92

due to nondisjunction in gametogenesis

(13 16 18 21 22) acount for 50% of miscarriages

• 95% complete trisomy 21 during non-disjunction during maternal gametogenesis
• problem in nondisjunction 1or 2
• after 1 baby with DS, next raises 1%

Chromasome 21

SOD1

COL6A1

ETS2

DYRK

APP

SOD1: acumulation of H2O2

COL6A1: heart defects

ETS2: Hypotonia (weak)

DYRK: retardation

APP: early Alzheimers

• Chromasome 14, 21
• parent with robertsonian gene has high chance for child with DS
• 17% chance, age independent.
• 3-4% of cases of DS

• 1-2% of DS
• some cells 46, some cells 47
• depending on location of 47 tissue dictates symptoms.
• variable
• post fertilization event
• unequal chromosome segregation during fertilization.

Translocation

Reciprocal:

Robertsonian:

• Balanced rearangement
• genetic info transfered between 2 different (non-homologous) chromasomes

Reciprical: genetic info distal from break of 2 chromosomes switch places.

Robertsonian: breakage of 2 acrocentric chromosomes (13, 14, 15, 21, 22) near centromere, fusion of long arms = new chromasome.  "derivitive (chromosomally abnormal gametes may be produced in gametogenesis)"

• balanced rearangement
• 2 breaks in a chromosome, detached portion put back in reverse. 
• Chromosomal abnormal gametes may be produced in gametogenesis.

• unbalanced rearangement
• chromosomal breakage, and not repaired. 

• unbalanced rearangement
• duplicate gene info due to unequal crossing over meiosis

• each trait is addative
• normal distribution

• Threshold traits
• "Exclusive" traits 
• Incidence is greatest among relatives of most severe
• If more common in men, then relatives of a woman with it = more risk.
• risk of occurance of first degree relatives = √(population prevelance)

• higher = more genetic
• h = 2 (C_mz - C_dz). 
• All environmental C_mz = C_dz.
•  All environmental C_mz=1    C_dz=0.5

Neural tube defect

(NTD)

happens because neural tube won't close during early development.

genetic & environmental

1 type will raise risks for other types

take folate.

1. Measure of fetal produced analytes in maternal fluid.  AFP, HGG, UE "tripple screen" at 15 weeks.
2. Measure fetal produced analytes in amniotic fluid.  15-17 weeks
3. FISH or kariotype of fetal chromosomes from amniocytes. Test for aneuploidies.
4. DNA analysis from embryo .  (15-17 weeks), or chorionic villus sampling (10-11 weeks) to detect gene mutations.

if baby has NTD, AFP is high in maternal amnion and serum,

16 weeks of pregnancy

detect open NTD

safer,but less precise than sampling from amnion

also can detect down syndrome.

Mother tripple screan

quadra screen

AKA AFP test AKA second trimester test

detect down syndrome, trisomy 18, NTD.

(quadra screan also tests for inhibin A, and more acurate at detecting down syndrome)

• Inhibin A.  High 21, low 18 (tripple test)

• Low AFP (quadra test) High NTD

• Low PAPP-A (only first trimester)

• β-hCG.  High 21 low 18 (first & second trimester)

• High nuchal translucency: ultrasound scan

• Low uE3

Diagnostic Test

Predictive Testing

Diagnostic: rule out

Predictive: asymptomatic individuals with family history.  presymptomatic / predisposition

Carrier Testing: ID mutations. if family members have condition.

remove cell from 8-16 cell blastoma

amplify DNA

analysis or FISH to find aneuploidy

Gene therapy

Ex vivo

In vivo

Ex Vivo: cells taken out, gene therapy, cell put back into body.

In Vivo:  Cells modified while in body

Gene Therapy

Retroviral

Other viral

Nonviral

Retroviral: <+> High efficient, long duration, <-> mutagenesis, need dividing cell, limited DNA size.

Adenovirus: <+> broad rainge of target cells, not require cell division, low mutation.  <-> "transient expression, immunogenicity, virus cytopathic effect

Adeno associated virus: <+> not need cell division, site specific integrin.  <-> insertional mutation, limited DNA size

Nonviral: <+> no infectious risk, no size limit.  <-> low efficiency, low target range, transient expression.

1. in stomach H-H broken
2. in Intestine enzymes free up ribose & deoxyribose.
3. most purines (G A) turned into uric acid and excreted, Pyrimidines excreted or metabolized.  Ribose & Deoxyribose is metabolized

in cytoplasm of all tissue

need ATP, Glutamine, GLY, Aspartate, Folate

1. Ribose 5 Phosphate + ATP -> AMP + PRPP

by enzyme PRPP synthase.  activated by phosphate.

2. PRPP + Glutamine -> 5 phosphoribosyl amine + Glutamate + PiPi

by enzyme PRPP aminotransferase (comiting)

driven by hydrolysis of PRPP

inhibited by AMP, GMP, IMP

Purine ring built up bit by bit on the ribose

AA provide the N and carbon skeleton

folate derivative 10-formyl-tetrahydrofolate donates a carbon at 2 steps

happens in cytoplasm of all tissue

needs energy, AA, Folate

made as separate bases, then attached to activated ribose.  final base attached to activated ribose PRPP

PRPP synthetase

inhibited by:

activated by

important for purine/pyrimidine synthesis

inhibited by: GDP, GTP, ADP, ATP

activated by: Phosphate

PRPP amidotransferase

which reaction?

regulated by:

inhibited by:

comiting step for purine synthesis

Regulated by: Substrate availability

Feedback Inhibition: AMP, GMP & IMP

CPS II

which reaction?

activated by

inhibited by

comiting step for pyrimidine synthesis

Activated by: ATP and PRPP

Inhibited by: UTP (end product of pathway)

UMP-> UDP -> dUDP -> dUMP -> dTMP

UDP -> dUDP

broad substrate specificity

makes all DNA nucleotides

NDP + NADPH + H -> deoxyNDP + NADP

substrates: CDP, UDP, ADP, GDP.

Inhibited: by dATP & hydroxyurea

enzyme requires NADPH (from oxidative branch of hexos monophosphate)

Enzyme

H2folate -> H4folate

acts after thymidylate synthase.

targeted by methotrexate to starve the cell of folate

salvage pathway

purine

enzyme HGPRT

catalyzes 2 reactions

hydroxanthine + PRPP -> IMP + pyrophosphate

guanine + PRPP -> GMP + pyrophosphate

enzyme APRT

adenine + PRPP -> AMP + Pyrophosphate

salvage pathay

Pyrimidine

enzyme: pyrimidine phosphoribosyltransferase

pyrimidine base + PRPP -> pyrimidine nucleotide + PiPi

catabolism

pyrimidines

Purines

pyrimidines: can break down into acetyl COA & succinyl COA.  (not worth the trouble)

Purines: can;t turn it into ATP.  turned into uric acid and excreted.

too much serum urate

males > 7 mg/dl age 30-50 onset

females > 6 mg/dl age 50-70

sodium urate: neutral PH

Uric acid: acidic

treatment:

allopurinol: preventative, inhibits xanthine oxidase

probenicid: preventative, excrete uric acid, prevent reabsorption

Colchicine: blocks inflamitory response

Indocin: NSAID

Repetitive DNA

Satelite DNA

Satellite: highly repetitive, localized, not transcribed, associated with centrimere & telomere.

micro/mini satelites used for genetic maping.  maps STR

CODIS used by police to find bad guys,

Repetitive DNA

Dispersed repetitive DNA

moderately repetative

interspersed with unique sequence

transcribed into RNA

LINES: small length

SINES: long length

1. tissue specific alterations in chromatin structure

2. methylation of specific cytosines in the genome.

"epigenic"

Acetylation by modifying LYS residue on the histone weakens atraction.  (catalyzed by HATs) transcriptional activation.

Deacetylation (HDAC) tilences.

• Occurs at CYT base of DNA

• location is called CPG. 

• CPG spread out "CPG islands".  asymetrical

• CPG islands are the promoter regions where transcription starts.

• methylation of CPG blocks transcription factors, inhibits transcription.  
• demethylation = activated.
• methylation controled by DNA methyltransferases. 

How is neurofibromatosis I inherited?

Autosomal Dominant

Ribonucleoside Diphosphates

(2000-5)

uridime

(2000-8)

hypoxanthine guanine phosphoribosyl transferase

(HGPRT)

(2000-9)

a purine/pyrimidine, a sugar, and 1 or more phosphates

(2000-10)

deoxyuridine monophosphate

(dUMP)

(200-12)

dihydrofolate reductase

(2001-2)

probenicid

(2001-7)

Adenosine Deaminase

(ADA)

(2001-9)

UMP

(2001-11)

ribonucleoside diphosphate to deoxyribonucleoside diphosphate

(2001-12)

adenosine monophosphate

(2001-13)

nucleoside

(2001-15)

double stranded DNA and 8 histones

(2001-19)

Xanthine

(2002-2)

pyrimidine catabolism

(2002-5)

thimadilate synthase

(2002-10)

Cytosine

(2002-18)

ribonucleotide reductase

(2003-24)

addition to acetyl group to histones

(2003-31)

1000

(2003-34)

repeats dispersed within the genome

(2005-16)

guanine

(2005-17)

PRPP synthase

(2005-24)

Hydroxyurea

(2005-25)

• autosomal dominant
• trinucleotide repeats

Autosomal Dominant

Pleitropy

• autosomal dominant
• variable expression

autosomal dominant

penetrance

Hurler Syndrome

autosomal recesive

lysosomal storage

Autosomal dominant

Homozygous more extreme

X linked dominant

trinucleotide repeats

X linked recesive

genetic defect HGPRT

can't salvage purines

autosomal recesive

can't make pyrimidines

treated with uridine

deficient in ADA

no B/T cells

lacks enzyme for purine catabolism