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M > Lectures 38-47 > Flashcards

Lectures 38-47 Flashcards

1
Q

What produces G Banding?

A

G bands produced with Trypsin using Giemsa

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2
Q

Large highly identical repeats can catalyze recurrent genome rearrangements, causing diseases known as recurrent genomic disorders. Name a few.

A

All flanked by large, highly identical repeats:
Velocardiofacial syndome Angelman/Prader-Willi syndrome Charcot-Marie Tooth disease
X-linked Hemophilia

At least 40 human genetic diseases are caused by this mechanism of recombination between large high-identy repeats.

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3
Q

What are the types of variation in the human genome?

A

Single base-pair changes - point mutations
• Small insertions/deletions and microsatellites
• Mobile elements - retroelement insertions (300bp -10 kb in size)
• Large-scale genomic variation (>1 kb) eg. deletions and duplications
• Chromosomal variation - translocations, inversions, trisomy

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4
Q

SNPs are the most common cause of variation in the genome. What is their frequency?

A

Each individual harbors 3-5 million SNPs in their genome (approx 1 per 1000bp)
About 10,000 (0.3%) of these cause changes in protein sequence

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5
Q

What can be used to look at copy number variations (CNV)?

A

Microarray Comparative Genomic Hybridization. Fluorescently labeled DNA is hybridized to an array of probes immobilized on a glass slide that bind either the normal or variant DNA. This allows you to detect copy number variations too small to see with karyotyping.

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6
Q

What is epigenetics?

A

The study of reversible heritable changes in gene function that occur without a change in the sequence of nuclear DNA

Gene-regulatory information that is not expressed in DNA sequences but can be transmitted from one generation to the next (or to daughter cells within an organism)

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7
Q

What are types of epigenetic changes?

A
  • DNA methylation
  • Genomic imprinting
  • X-inactivation
  • Environment / nutrition and EWAS
  • In vitro fertilization
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8
Q

What are the molecular mechanisms that can mediate epigenetics?

A

-DNA methylation (CpG dinucleotides)
• Histone modifications and variants
• Non-coding RNAs (poorly understood)

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9
Q

What does methylation of a CpG nucleotide form?

A

Methylcytosine, the 5th base of DNA

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10
Q

Genome-wide DNA methylation patterns at gene promoters shows?

A

A bimodal distribution

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11
Q

What is the methylation status of most CpG’s outside promoters?

A

The majority (>80%) of CpGs outside of gene promoters are generally methylated

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12
Q

What happens in X inactivation?

A

To compensate for having two X chromosomes one X is silenced. Inactivation of X chromosome occurs randomly in somatic cells during embryogenesis. All progeny from this cells have the same x inactivated creating a mosaic of which X is expressed throughout the body.

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13
Q

How can you identify X linked inheritance on a family tree?

A

No male-to-male transmission, female carriers usually unaffected unless they show an “unfavorable” X-inactivation profile.

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14
Q

What is imprinting?

A

A phenomenon where the expression status of a gene is dependent on its parental origin

One allele of a gene is “imprinted” and silenced using methylation allowing for mono allelic expression.

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15
Q

If one parental gene is imprinted and there is a pathologic mutation on the other one, the person will have the disease. Give an example.

A

Prader-willi = paternal deletion on chromosome 15
Angelman’s Syndrome= Maternal deletion of Ch 15

So if they have the disorder the OTHER allele is imprinted or silenced.

Maternal deletion =overgrowth phenotype
Paternal deletion= undergrowth phenotype

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16
Q

What is the parental conflict hypothesis?

A

Hypothesized that the inequality between parental genomes due to imprinting is a result of the differing interests of each parent in terms of evolutionary fitness
Paternal genes&raquo_space;> promote offspring growth at the expense of the mother
Maternal genes&raquo_space;> limit growth to conserve resources for survival to produce additional offspring

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17
Q

Dietary effects of agouti expression?

A

Feeding mother “methyl donors” e.g. folic acid, vitamin B during pregnancy results in a skewed coat color distribution in offspring
This effect is due to hypermethylation of that of the neighboring IAP gene that causes increased expression of agouti

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18
Q

What does EWAS need to control for?

A

Therefore unlike GWAS, in order to be robust, EWAS need to control for age, and any other confounders such as gender, smoking, etc etc

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19
Q

Name types of replication errors.

A

PURINE - PYRIMIDINE
TRANSVERSION
PYRIMIDINE - PYRIMIDINE PURINE - PURINE
TRANSITION

Short Tandem Repeat Sequences (Microsatellites)
Di- and Trinucleotide Repeats Important in Gene Mapping, Pathogenesis

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20
Q

Common spontaneous mutation mechanism-

A

CpG Dinucleotide
• Frequently Methylated (80%)
• Deamination Reaction • Mutation Hotspot

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21
Q

What’s the difference between missense and nonsense mutations?

A

Missense- codes for another amino acid.

Nonsense- codes for nothing or something in the wrong place like a stop codon.

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22
Q

What’s Haploinsufficiency?

A

In a loss of function mutation the Activity of Single Allele is Insufficient
- Transcription Factors - Development

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23
Q

What is dominant negative?

A

A loss of function mutation where Presence of Mutant Allele is Pathogenic

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24
Q

Achondroplasia

A

AD Inheritance
• Mutations Cause Constitutive Activation of Fibroblast Growth Factor Receptor 3
• Recurrent Mutation of FGFR3 (G380R)
• Highly Mutable Locus (mutation hotspot)


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25
Q

FGFR3 Mutations:

A

Achondroplasia, hypochondroplasia, Thanatophoric Dysplasia

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26
Q

Neurofibromatosis1

A

NF1 Regulates RAS Signaling
• NF1 Loss of Function = Increased RAS Signalling

Variable expressivity and Pleiotropy

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27
Q

What is coenzyme supplementation not an effective treatment option for?

A

When there is a Altered Substrate Binding Site - Unresponsive.

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28
Q

What is the deficient protein in Gaucher Disease?

A

Acid β-Glucosidase

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29
Q

what is the enzyme used to treat gaucher’s?

A

intravenous recombinant glucocerebrosidase

30
Q

What are some therapies under study for future treatments of Lysosomal storage diseases?

A

Pharmacologic Chaperones • Stop Codon Read-Through
• RNA Interference • Gene Therapy
• Stem Cell Therapy

31
Q

What’s an anomaly?

A

A deviation from the usual, something different, peculiar, or abnormal
• A congenital anomaly is something that is unusual and different at birth

32
Q

What are the rates of anomalies?

A

Anomalies are Common
• Major anomalies in 2-3% newborns • Minor anomalies in 15% newborns
• 20-30% infant deaths and 30-50% deaths after the neonatal period are attributed to anomalies

33
Q

What are the differences btwn major and minor anomalies?

A

Major anomaly
– Significant cosmetic, medical & surgical consequence
– Examples: congenital heart disease, cataract
• Minor anomaly
– Insignificant consequence, normal variant
– Examples: skin tag, simian crease, overlapping toes

34
Q

What is a deformation?

A

Developmental Process is normal
• Mechanical force alters structure
• Examples:
– External forces – oligohydramnios can be secondary to renal hypoplasia, breech presentation
– Internal forces – neuromuscular abnormality

35
Q

What are examples of deformations?

A 
Potter’s facies
• flat nasal bridge
 -retrognathia 
Clubbed feet 
• spina bifida
36
Q

What’s a Disruption?

A

Developmental process is normal, but interrupted.
Examples: Amniotic band sequence
– Fetal cocaine exposure

37
Q

What is Dysplasia?

A

Abnormal tissue organization and development, microscopic structure
• Examples:
– Skeletal or connective tissue dysplasias – Ectodermal dysplasias

38
Q

What is Malformation?

A
  • Morphological defect from an intrinsically abnormal developmental process
  • Examples: holoprosencephaly, congenital heart disease, neural tube defect
39
Q

What is a syndrome?

A

• A recognizable pattern of anomalies, presumed to be causally related
– More than 700 human genetic syndromes have craniofacial abnormalities
– More than 500 human genetic syndromes have limb abnormalities

40
Q

What is a sequence?

A

A series of congenital anomalies derived from a single anomaly
• Can be part of a syndrome or an isolated event

Pierre Robin Sequence
• Primary anomaly is micrognathia
– Leads to superior displacement of tongue
– Leads to failure of palatal shelves to close
• Leads to “U” shaped cleft and
• glossoptosis

41
Q

what are the rates of causes of Human Congenital Anomalies

A 
unknown= 50-60%
multifactorial- 20-25
chromosomal- 7
mutant genes 8
environmental 7-10
42
Q

Symptoms of FAS?

A 
0.2 to 1.5 per 1000 births
• Growth retardation
• Microcephaly
• Mental retardation
• Short palpebral fissures
• Short nose
• Smooth philtrum
• Thin upper lip
• Small distal palanges and hypoplastic finger nails
• Cardiac defects
43
Q

Cardiofaciocutaneous Syndrome?

A 
General CF syndrom= defecient raf or mek
Noonan- deficient Shp2
Costello syndrome- deficient Ras
Autosomal dominant
• Sparse, brittle hair
• ASD, pulmonic stenosis
• Ectodermal skin changes • Mental retardation
44
Q

Holoprosencephaly?

A

cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres. Normally, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of human pregnancy. The condition also occurs in other species.

The condition can be mild or severe. According to the National Institute of Neurological Disorders and Stroke (NINDS), “in most cases of holoprosencephaly, the malformations are so severe that babies die before birth.[1]

When the embryo’s forebrain does not divide to form bilateral cerebral hemispheres (the left and right halves of the brain), it causes defects in the development of the face and in brain structure and function.Genetic heterogeneity single phenotype caused by
different mutations or different genetic factors
• Chromosome abnormality (50%)
• Autosomal dominant Mutations in SHH, Patched,
ZIC2, SIX3

45
Q

Draw the SHH pathway.

A

Screenshot 12.

46
Q

What goes wrong when SHH mutations occur causing halopsrocencephaly?

A

Basically when SHH binds to PITCH1 on the membrane, this releases PITCH1’s inhibitory effect on SMOH. When That inhibition is lifting the signaling cascade proceeds stimulating GLI 1, 2, 3 entering the nuclease and stimulating the transcription of SHH targets. That doesn’t happen with mutated SHH.

47
Q

Fibroblast Growth Factor Receptor (FGFR) Craniosynostosis Disorders?

A

Autosomal dominant
• Genetic heterogeneity • Phenotypic variability
• Gain of function mutations

Craniosynostosis is Premature fusion of skull bones.

48
Q

Draw the FGFR pathway

A

Screenshot 13 and 14.

49
Q

What are the two GLI3 related disorders?

A

Greig Cephalopolysyndactyly- thumb/ preaxial polydac

Pallister-Hall syndrome- PINKI Post axial polydac

50
Q

Which are the short and long arms of chromosomes?

A

P=short (like a little pee!)

q=long

51
Q

Can only look at chromosomes in what phase?

A

Metaphase.

52
Q

How do Aneuploidies happen?

A

MEIOSIS-1 NONDISJUCTION (75% maternal)



53
Q

Turner syndrome

A

45X. 80% due to paternal meiotic error. The incidence is about 1 in 5000 female births but this is only the tip of the iceberg because 99% of Turner syndrome embryos are spontaneously aborted.
 Individuals are very short, they are usually infertile. Characteristic body shape changes include a broad chest with widely spaced nipples and may include a webbed neck.

54
Q

Klinefelter syndrome

A

47,XXY The incidence at birth is about 1 in 1000 males.
 50% maternal in origin/50% paternal in origin
 Testes are small and fail to produce normal levels of testosterone growth resulting in gynaecomastia in about 40% of cases and in poorly developed secondary sexual characteristics. No spermatogenesis.
 Taller and thinner than average and may have a slight reductioninIQ. ManyKlinefeltermalesleadanormal life.
 Very rarely more extreme forms of Klinefelter’s syndrome occur where the patient has 48,XXXY or even 49, XXXXY karyotype. These individuals have severe intellectual disability.

55
Q

Robertsonian translocation

A

Translocation between acrocentric chromosomes. Short arms are lost and long arms fuse at centromere (5% of Down syndrome cases) *[46,XX,der(14;21)(q10;q10),+21]
1 in 1,000 individuals has a Robertsonian translocation
A normal karyotype has 45 chromosomes eg; 45,XX,der(13;14)(q10;q10)

56
Q

What is an inversion?

A

An inversion consists of two breaks in one chromosome. The area between the breaks is inverted (turned around), and then reinserted and the breaks then unite to the rest of the chromosome. If the inverted area includes the centromere it is called a pericentric inversion. If it does not, it is called a paracentric inversion.

57
Q

Wolf-Hirschhorn syndrome?

A

Wolf-Hirschhorn syndrome is the deletion of 4p16.3

58
Q

What is the most common cause of turner syndrome?

A

Ring Chromosomes

59
Q

What is FISH?

A

FISH is a physical DNA mapping technique in which a DNA probe labeled with a marker molecule is hybridized to chromosomes on a slide, and visualized using a fluorescence microscope
 The marker molecule is either fluorescent itself, or is detected with a fluorescently labeled antibody.

60
Q

Limitations of Array CGH?

A

Cannot detect balanced rearrangements

 Does not give information about the type of rearrangement

61
Q

What is the equation for heritability?

A

h^2=2*(r^2MZ-r^2DZ)

62
Q

What is the HardyWeinbergEquilibrium(HWE)?

A

HardyWeinbergEquilibrium(HWE)analyzeswhether there is equilibrium between the frequencies of alleles in a population
• HWEstatesthatallelicfrequencieswillremainconstant over time if certain conditions are met.
• HWEusesasimpleequationtoestimateallelic frequencies:

63
Q

HWE equation?

A

Freq. of all alleles = 1 p = dominant allele A q = recessive allele a
p + q =1

Freq. of all genotypes= 1
p2 = homozygote genotype AA
2pq = heterozygote genotype Aa q2 = homozygote genotype aa
p2 + 2pq + q2 =1

64
Q

How to calculate when given # of genotypes?

A

pA= (2pAA+pAa)/2Ntotal
Same for aaa

Take those values you get…
plug them into the equation. So square p and q and multiply pq by 2.

Then plug those values into percentages of the whole. so if the total is 31 percent of 100, the expected hardy weinburg number is 31.

65
Q

What can cause deviation from the Hardy Weinburg?

A 
Genotypingerror
• Mutation
• Migration(immigrationandemigration) • Naturalselection
• NonrandomMating/Inbreeding
• Geneticdrift
66
Q

What are the types of natural selection?

A

Stabilizing
Types of selection
– Extremes have
decreased fitness (Example: birth weight)
• Disruptive
– Intermediates have
decreased fitness (Example: fur color, peppered moth)
• Directional
– Extremes have increased
fitness
(Example: usually seen in environments 13 that have changed over time)

67
Q

Potential of Pharmacogenetics?

A

Can be used CLINICALLY to: 1. Improvedrugselection
– May predict responders vs. non-responders 2. Predictadversedrugreactions(ADRs)
– 2 million hospitalizations/year due to ADRs
3. Doseadjustmentformaximumefficacyandsafety
– Some drugs are difficult to safely dose due to a narrow therapeutic range
4. Decreasehealthcarecosts
– Pharmacogenetic testing may reduce hospitalizations due to ADRs

68
Q

What are CPY450s?

A

CYP450s: a large diverse superfamily of hemoproteins that catalyze hydroxylation and other metabolic reactions.
– exogenous and endogenous compounds
– major enzymes involved in drug metabolism and bioactivation

CYP2C191 = Wild-type
CYP2C192 - *28
= Variant alleles (most reduced function)

69
Q

CYP2C9 metabolizer combinations?

A

CYP2C91 X2 =Extensive Metabolizer (EM)
CYP2C91 and CYP2C92= Intermediate Metabolizer (IM):
CYP2C92 X2= poor metabolizer

70
Q

CYP2D6 ?

A

CYP2D6 metabolizes ~20-25% of all medications.
– antidepressants, antipsychotics, antiarrhythmics, opiates,
antiemetics, β-adrenoceptor blockers, tamoxifen, etc.

Increased Activity Alleles: *1xN, *2xN,
• Normal Activity Alleles: *1, *2, *35
• Reduced Activity Alleles: *9, *10, *17, *29, *41, *41xN
• Non-functional Alleles: *3, *4, *4xN, *5, *6, *7, *8, *11, *15

71
Q

VKORC1 (warfarin) sensitivity?

A

Low Sensitivity: -1639 G/G
• Intermediate Sensitivity: -1639 G/A
• High Sensitivity: -1639 A/A

72
Q

CYP2C19* 2 patients associated with what?

A

CYP2C192 (c.681G>A) associated with platelet aggregation in healthy subjects:
CYP2C192 patients more likely to have a cardiovascular ischemic event or death during 1 yr follow-up.

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