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M2M > Genetics > Flashcards

Genetics Flashcards

1
Q

Chiasmata

A

Physical linkages between homologs (maternal & paternal sister chromatids) during meiosis I

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2
Q

Bivalents

A

During Prophase I of meiosis, maternal and paternal homologs become synapsed along their entire length

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3
Q

Synaptonemal complex

A

Proteinaceous complex binding together maternal & paternal homologs, allowing for crossover.
Degrades at the end of Prophase I.

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4
Q

What is the most error-prone part of the process of meiosis?

A

Meiosis I - when homologs are segregated to opposite poles

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5
Q

Aneuploidy

A

The condition in which cells contain an abnormal number of chromosomes

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6
Q

Polyploidy

A

Extra copies of all chromosomes; e.g., triploidy (3n) or tetraploidy (4n)

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7
Q

Terminalization

A

Postulated model for abnormalities in aging maternal oocytes. As oocytes age, the cohesion complex between sister chromatids & homologs degrades –> chiasmata move towards the ends of the homologue pairs –> precocious separation of homologous chromosomes, leading to aneuploidy

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8
Q

Mosaicism

A

The presence of two or more populations of cells with different genotypes in tissues derived from a single zygote.

Mosaic phenotypes are highly variable & results are difficult to predict.

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9
Q

Down Syndrome

A

Trisomy 21

Characteristic facies, short stature, hypotonia, moderate intellectual disabilities

Congenital malformations – gastrointestinal anomalies, Hirschprung disease, early-onset Alzheimer’s

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10
Q

Edwards Syndrome

A

Trisomy 18

Intrauterine growth retardation, characteristic facies, severe intellectual disabilities

Clenched hands, narrow hips

Congenital heart disease, CNS abnormalities

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11
Q

Patau Syndrome

A

Trisomy 13

Normal or deficient growth, CNS abnormalities

Facial clefts, polydactyly

Renal dysplasia, congenital heart disease, omphalocele (midline defect –> abdominal organs develop externally in a sac)

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12
Q

Klinefelter Syndrome

A

47, XXY

Tall stature, hypogonadism, gynecomastia, sterility, language impairment

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13
Q

Turner Syndrome

A

45, X

Short stature, webbed neck, edema of hands and feet, broad shield-like chest, widely-spaced nipples, narrow hips, renal and cardiovascular anomalies, hormonal dysfunction, gonadal dysgenesis (failure of ovarian maintenance) = infertility

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14
Q

Charcot-Marie-Tooth Disease

A

Cause = duplication of the gene for peripheral myelin protein 22 (PMP 22) 17p11.2

Characterized by weakness of foot & lower leg muscles, hammertoes, & weakness & muscle atrophy of the hands in late stages.

Affects the function of peripheral nerves

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15
Q

Hereditary neuropathy with predisposition to pressure palsy (HNPP)

A

Cause by deletion of gene 17p11.2, containing gene for peripheral myelin protein 22 (PMP 22)

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16
Q

What is a contiguous gene syndrome?

A

Disorder caused by overexpression or deletion of several genes adjacent to one another.

Examples: velocardiofacial syndrome, DiGeorge Syndrome

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17
Q

Velocardiofacial syndrome

A

del 22q11

Cleft palate, septal defects

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18
Q

DiGeorge Syndrome

A

del 22q11

Absent or hypoplastic thymus and parathyroids
Outflow tract defects in the heart

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19
Q

What is the genetic basis for Prader-Willi Syndrome?

A

In 70% of patients, PATERNAL DELETION of homologue of Chr 15 (15q11-q13)

Maternal chr is methylated

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20
Q

Angelman Syndrome

A

Characterized by unusual facial appearance, short stature, severe intellectual disabilities, autism, spasticity, and seizures

Have a MATERNAL DELETION on homologue of Chr 15. Paternal copy is methylated & inactive

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21
Q

What is a horizontal inheritance pattern?

A

Disease shows up in siblings but not parents or offspring = autosomal recessive

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22
Q

Allele, carrier, & disease frequencies?

A

Allele frequency = q
Disease frequency = q^2
Carrier frequency = 2pq = 2q

q is for recessive diseases

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23
Q

What is allelic heterogeneity?

A

The presence of multiple common mutant alleles of the same gene in a population

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24
Q

What is a compound heterozygote?

A

An individual who carries 2 different mutant alleles of the same gene

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25
Q

PKU

A

Phenylketonuria = Have problems metabolizing phenylalanine in the blood

> 98% of time, defects in phenylalanine hydroxylase (PAH)

1-2% of time, defects in PAH cofactor BH4

High allelic heterogeneity. Compound heterozygosity leads to varied phenotype severity – depending on the allelic mutations, can be anywhere from 20-50% activity

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26
Q

What is PAH?

A

Phenylalanine hydroxylase; converts phenylalanine into tyrosine

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27
Q

What is BH4?

A

A cofactor for PAH. Also cofactor in creation of dopamine and serotonin – pts with deficiency have trouble making these neurotransmitters

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28
Q

Explain maternal PKU

A

Women went off PKU (low-protein) diets during pregnancy; led to increased miscarriage & babies with developmental delays.

They had too much Phe in blood –> gets to baby, is toxic for developing brain of baby

Solution: low-Phe diet lifelong, esp during pregnancy

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29
Q

How & when do you screen newborns for PKU?

A

Screen by measuring ratio of Phe:Tyr (babies with PKU have high Phe, low Tyr)

Need to screen multiple times to make sure you don’t miss critical window; once 1-2 days after birth & once 10-14 days after birth

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30
Q

Clinical features of alpha-1 antitrypsin?

A

Increased risk for emphysema, liver cirrhosis, liver cancer

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31
Q

Which enzyme is the primary target for alpha-1 antitrypsin, and what does it do?

A

Elastase - helps break down elastin in lungs & maintain proper lung turnover

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32
Q

Mutant alleles involved in AAT?

A

Z allele is the most common

  • Individuals with ZZ genotype have ~15% of normal SERPINA1 level (gene for AAT)
  • Z allele makes a protein that isn’t folded properly & tends to accumulate in the ER of liver cells –> liver damage

S allele makes unstable protein (lower enzyme activity)
- Individuals with SS genotype have 50-60% of normal level

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33
Q

Tay-Sachs Disease

A

Lysosomal storage disorder caused by abnormal accumulation of GM2 ganglioside in lysosomes. Caused by a defect in HEXA gene, leading to faulty α subunit in Hexosaminidase A enzyme

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34
Q

What is GM2?

A

Lipid found in neuronal cell membranes

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35
Q

What is the molecular pathway of Tay-Sachs Disease?

A

GM2 gets removed from cell membranes by GM2AP in lysosomes. GM2AP transports it to Hex A (enzyme composed of α and β subunits). Subunits are encoded for by HEXA & HEXB genes, respectively

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36
Q

Sandhoff Disease

A

Caused by mutation in HEXB gene –> faulty β subunits –> defects in enzymatic activity –> accumulation of GM2 & other substrates acted upon by enzymes with β subunits

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37
Q

AB variant of Tay-Sachs Disease

A

Mutation in gene encoding for GM2AP protein = proper enzymatic function but no carrier protein –> accumulation of GM2 in lysosomes

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38
Q

What is the layout of the α- and β-globin gene clusters?

A

Two copies of α on Chromosome 16
One copy of β on Chromosome 11

α-cluster: zeta-alpha2-alpha1 (ζ-α2-α1)
β-cluster: epsilon-gammaG-gammaA-delta-beta (ε-γG-γA-δ-β)

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39
Q

What are the different forms of hemoglobin expressed during development?

A

Embryonic:

  • Hb Gower 1: ζ2ε2
  • Hb Gower 2: α2ε2
  • Hb Portland: ζ2γ2

Fetal:
Hb F: α2γ2

Adult:
>95% Hb A: α2β2
3.5% Hb A2: α2δ2
1% Hb F

ζ to α (zeta during embryo –> at 6 weeks post-conceptual age (fetus) all α)

ε to γ (epsilon during embryo –> same as above)

Levels of γ start to decrease simultaneously with levels of β starting to increase (at birth)

Levels of δ (delta) start to increase during adulthood

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40
Q

What is the Locus Control Region?

A

Upstream promoter ~10kb away from coding sequence

Deletions of the entire LCR of the beta cluster cause beta-thalassemias

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41
Q

Mutation that causes sickle cell anemia?

A 
Mutation in one codon (6)
Changes Glu (charged) --> Val (hydrophobic) on β6

HbSS = someone who has 2 alpha & 2 beta with sickle cell mutation

Hb S, when it becomes deoxygenated, loses solubility –> forms polymers –> sickle shape

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42
Q

Mutation that causes Hemoglobin C disease?

A

Mutation in same codon as sickle cell anemia (6)

Changes Glu –> Lys (neg charge –> pos charge)

HbCC = β subunit tends to form crystals & causes lysis of RBCs

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43
Q

How do you diagnose sickle cell anemia?

A

Mst II restriction enzyme recognizes a site on normal β subunits, cuts into pieces. Because of point mutation, it no longer recognizes site on βs subunit = longer fragments are obtained

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44
Q

What are the genotypes of α-thalassemias?

A
  1. αα/αα = 100% ; normal
  2. αα/α- = 75% ; silent carrier
  3. αα/– (α-thal 1) = 50% ; mild anemia
    a. Southeast Asia
  4. α-/α- (α-thal 2) = 50% ; mild anemia
    a. Africa, Mediterranean, Asia
  5. α-/– = 25% ; severe anemia
    a. = Hb H (β4)
  6. –/– = 0% ; fetal death (hydrops fetalis)
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45
Q

What are the geographic locations of the different types of α-thals?

A

α-thal 1 = αα/– = Southeast Asia

α-thal 2 = α-/α- = African, Mediterranean, Asia

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46
Q

What is the genotype of Hb H?

A

α-/– = 25% ; severe anemia (β4)

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47
Q

What is β-thalassemia minor (intermediate)?

A

You have one functional β allele and one either missing or mutant. Have 50% β globin amount and >50% β allele, respectively.

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48
Q

What is β-thalassemia major (Cooley’s anemia)?

A

You either have 2 missing β alleles (β0-thal) or 1 missing and 1 mutant (β+-thal). End up with 0% β globin or <50% β globin, respectively.

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49
Q

What is a simple β-thalassemia?

A

Mutations affects only a single gene = β-globin chain gene

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50
Q

What is a complex β-thalassemia?

A

Affects expression of multiple genes in a cluster – caused by large deletions that remove β-globin gene plus genes in the β-cluster, or the LCR

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51
Q

Hereditary persistence of fetal hemoglobin (HPFH)

A

There is no δ or β synthesis because of deletions of both genes (which are typically expressed in adults). 100% of hemoglobin is HbF (α2γ2), which is ~17-35% of normal level of Hb production.

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52
Q

What mutations cause increased γ-globin expression?

A
  1. extended deletion of additional downstream sequences, which likely brings a cis-acting enhancer element closer to the γ-globin gene
  2. mutations in the promoter region of one of the two γ-globin genes that destroy the binding site of a repressor, thereby indirectly upregulating expression of γ
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53
Q

What is the geographic distribution of hemoglobinopathies?

A

SE Asia & West Pacific: α, β thalassemias & E

Africa: S, C, α, β thalassemias

East Mediterranean: β thalassemias and S

High prevalences:

  • Africans = S
  • SE Asians = E
  • SE Asians & Mediterraneans = β-thal
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54
Q

What are reticulocytes?

A

Young RBCs

sign of increased RBC production

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55
Q

What are the clinical features of Cooley’s anemia?

A
  • dense skull/marrow expansion
  • osteopenia
  • enlarged spleen
  • iron overload
  • growth & endocrine failure
  • death usually results from iron deposition
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56
Q

Achondroplasia - basics

A

Most common form of dwarfism
- AD -
Skeletal dysplasia: 1 in 15,000-40,000 newborns

De novo mutations occur exclusively in paternal germline, and occur more with increasing age (>35 years)

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57
Q

What are the clinical characteristics of achondroplasia?

A
  • small stature
  • rhizomelic limb shortening (proximal limbs shorter than distal)
  • short fingers
  • trident hands
  • large head/frontal bossing
  • midfacial retrusion
  • small foramen magnum
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58
Q

What is the mutation involved in achondroplasia?

A

FGFR3 = encodes fibroblast growth factor receptor 3

Inhibits bone growth –> this is a GAIN-OF-FUNCTION mutation

(Nucleotide on this gene has the highest new mutation rate known in man)

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59
Q

Neurofibromatosis Type I

A

Disease causing benign tumors on nerve tissues.
- AD -

1 in 3000 births
50% new mutation rate

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60
Q

What are the diagnostic criteria of neurofibromatosis Type I?

A

Two or more of following:

  • 6 or more café-au-lait spots
  • 2 or more neurofibromas = benign tumor of nerve sheath
  • 1 plexiform neurofibroma = involving more than one nerve
  • freckling in the axillary or inguinal area
  • optic glioma
  • 2 or more Lisch Nodules (brown spots in eyes)
  • distinctive osseous lesions
  • affected first degree relative
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61
Q

What is the mutation involved in neurofibromatosis Type I?

A 
Protein = NF1
Gene = Neurofibromin-tumor suppressor gene on Chr 17

Loss of function mutation

> 1000 mutations have been described. Although dominant, must have a mutation in both genes to demonstrate the phenotype

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62
Q

Polycystic Kidney Disease - basics

A

Causes large cysts on kidneys & occasionally other organs

  • 1 in 1000 births
  • 5% new mutation rate
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63
Q

What are the clinical manifestations of PKD?

A
  • bilateral renal cysts
  • cysts in other organs
  • vascular abnormalities
  • end stage renal disease in 50% by 60 years old
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64
Q

What are the mutations in PKD?

A
  • 2 different ones, on 2 different genes! = locus heterogeneity
  • PKD1 (Chr 16)
  • PKD2 (Chr 4, 15%)
  • Polycystin 1 & 2
  • Produces a truncated protein
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65
Q

What are the clinical manifestations of familial hypercholesterolemia?

A
  • high cholesterol (>310) and LDL levels (>190)
  • xanthomas
  • premature CAD & death
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66
Q

What are the mutations in familial hypercholesterolemia?

A

Locus heterogeneity –> mutations in 3 genes known to cause this:

  • LDLK
  • APOB
  • PCSK9
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67
Q

What is anticipation in AD diseases?

A

Appearance of the disease at an earlier age as it is transmitted through a family, or severity of disease increases

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68
Q

What are the clinical manifestations of Huntington’s Disease?

A
  • progressive neuronal degeneration causing motor, cognitive, and psychiatric disturbances
  • age of onset 35-44
  • death approximately 15 years after onset
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69
Q

Huntington’s Disease - basics

A

Trinucleotide repeat disorder (CAG)
Occurs 1 in 10,000
Anticipation & paternal transmission

70
Q

What are the mutations involved in Huntington’s Disease?

A 
Gene = HTT (Chr 4)
Protein = Huntingtin

Expansion of glutamine may cause altered structure of biochemical property of the protein

Repeat count:
o 39 = full penetrance
o >60 = juvenile onset

71
Q

What is a hemizygous chromosome?

A

The special case where a male has an abnormal allele for a gene located on the X chromosome and there is no other copy of the gene

72
Q

Fragile X Syndrome - basics

A

X-linked dominant
Trinucleotide repeat disorder – CGG repeats in 5’ UTR of FMR1 gene
(>200 repeats = full mutation)

More common in males

Most common cause of inherited developmental delay

anticipation
maternal transmission bias

73
Q

Fragile X Syndrome - clinical manifestations

A 
intellectual disabilities
dysmorphic features: large ears, long face, macroorchidism
autistic behavior
social anxiety
hand flapping/biting
aggression
74
Q

What are the mutations involved in Fragile X Syndrome?

A

FMR1 & FMRP (protein); on X chromosome (obvs)

Protein is essential for normal cognitive development and female reproductive function

Increase in the trinucleotide repeats –> methylation of gene –> protein is not made

75
Q

Duchenne’s Muscular Dystrophy

A
  • progressive muscular weakness, going from proximal –> distal
  • calf hypertrophy
  • dilated cardiomyopathy
  • Creatine kinase levels 10x normal (indication of inflammation of muscles = myositis)

Onset before the age of 5
Wheelchair bound before 13
Death in their 30’s

Absence of Dystrophin protein

76
Q

Hemophilia A

A

X-linked recessive

1 in 4,000 male births; about 10% of female carriers are affected

Clinical: spontaneous bleeds, excessive bruising, prolonged bleeding, delayed wound healing

Mutation in gene F8, encoding Factor VIII (a coagulation factor)

77
Q

What is ataxia?

A

Lack of voluntary coordination of muscle movements

Leads to a jerky, unsteady, to-and-fro motion of the middle of the body (trunk) and an unsteady gait (walking style). It can also affect the limbs.

78
Q

Difference between X-linked dominant and X-linked recessive?

A

X-linked dom:

  • displays in male hemizygous and female heterozygotes
  • much more likely to actually see the phenotype in females

X-linked recessive:

  • phenotype is expressed in all males & homozygous females
  • heterozygous females are carriers
79
Q

Mitochondrial inheritance

A

Mother passes on to all her children. Men pass on to none of their children

Replicative segregation - multiple copies of mtDNA will segregate randomly during replication to mitochondria

Heteroplasmy - mitochondria will have more or less copies of mutated mtDNA

Threshold effect - once enough mutated mtDNA is present, disease phenotype presents

80
Q

What are the clinical manifestations of mitochondrial diseases?

A

Heavily affect organs that require a lot of oxidative phosphorylation: brain, eyes, skeletal muscle, heart

81
Q

What is a haplotype?

A

A given set of alleles at a locus or cluster of loci on a chromosome

82
Q

What is linkage disequilibrium?

A

Certain alleles within chunks tend to stay together, because recombination within those chunks is uncommon

LD blocks (=chunks) 2x smaller in African populations than Caucasian or Asian b/c African pop. is more ancient

83
Q

Candidate gene association studies

A

You guess what gene is relevant to a disease, and you test SNPs/sequencing in that gene

Depends on a priori biological/positional hypothesis

Best for common risk alleles with small-moderate effects

FATAL FLAWS:

  • Publication bias
  • True multiple-testing correction must include all tests, even those that never made it to publication
  • Background genetic variation may vary among populations – your controls will never be identical to one another
84
Q

Genome-wide association studies (GWAS)

A

Tests hundreds of thousands/millions of markers (SNPs) across entire genome

You know the number of tests performed genome-wide; can perform appropriate multiple-testing correction

Still need to match cases & controls ethnically; but because entire genome is represented, can detect & correct for population stratification

Create a Manhattan Plot to find statistically sig signals

Difficult to distinguish potentially causal variants from non-pathological

85
Q

Genetic linkage study

A

Search genome for segments disproportionately inherited along with disease in family members that have a disease vs. family members that don’t have the disease

Best for Mendelian traits (uncommon alleles with strong effects); less powerful for “complex traits”

Functionality depends on recombination = loci close to each other undergo less separation by recombination, whereas the ones further apart undergo more recombination

86
Q

Genetic recombination

A

Unit of genetic recombination = centiMorgan (cM)
1 cM = 1% recombination between two loci per meiosis
Statistical measure is LOD (log of odds) score
Significance level: LOD >= 3.0 is considered proof of linkage/gene localization

87
Q

Allelic heterogeneity

A

Multiple mutations in a particular gene can cause disease

88
Q

Genetic heterogeneity

A

Mutations in multiple genes involved in a particular phenotype

89
Q

Chromosomal analysis

A

= Karyotyping. Used for suspected abnormalities of chromosome number or structure. Can diagnose aneuploidies, deletions, insertions, rearrangements, and duplications.

90
Q

Fluorescence in-situ hybridization (FISH)

A

Can diagnose deletions, translocations, and abnormalities of copy number. Often used to detect cytogenetic changes that are not visible by chromosomal analysis.

You need to know the chromosomal deletion/etc. that you’re testing for in order to correctly pick the probe!

91
Q

Chromosomal microarray analysis

A

Look for chromosomal DNA losses & gains, small deletions & insertions. Great resolution.

92
Q

DNA sequencing analysis

A

Used to identify sequence changes in specific genes - novel, polymorphic, etc. Only assays one region of a gene, though. Doesn’t sequence promoters, introns –> not 100% sensitive.

93
Q

What are the advantages/disadvantages of retroviral gene therapy?

A

Advantages: integrate into cell genome, minimal host immune reactions

Disadvantages: small max size of transgene, infect only dividing cells (not quiescent), risk of insertional mutagenesis/germline integration

94
Q

What are the advantages/disadvantages of adenoviral gene therapy?

A

Advantages: wide variety of cell types can be infected; large insert size; stable & easy to get to high titers

Disadvantages: does not integrate into genome, expression can be transient, some risk of malignant transformation, immune reactions can be severe

95
Q

What are the advantages/disadvantages of non-viral gene therapy?

A

Advantages: insert size can be very large (even mini-chromosomes), minimal immune response

Disadvantages: low efficiency, transient expression

96
Q

Fabry Disease

A

X-linked disorder caused by deficiency of alpha-galactosidase A activity, which removes galactose from glycosphingolipids

97
Q

Multiple Endocrine Neoplasia

A

AD

RET mutation –> high risk of thyroid cancer, but you can prophylactically remove thyroid & risk goes away

98
Q

Aphasia

A

Damage to the part of the brain that regulates speech. Present with inability to speak, read, or write.

99
Q

Hereditary hemorrhagic telangiectasia

A

A disorder that results from abnormalities in the blood vessels. Arteries go directly to veins, without intervening capillaries (arteriovenous malformations, or telangiectases). These can occur near the skin, leaving pink marks.

Hemorrhages can occur in the brain, liver, lungs, or other organs.

100
Q

What is the amino acid substitution that occurs in achondroplasia?

A

Gly380Arg substitution

101
Q

Syndromic deafness - types and causes

A

Retinitis pigmentosa –> Usher
Thyroid goiter –> Pendred
Arrhythmia or sudden death –> Jervell and Lange-Nielson syndrom
White forelock –> Waardenburg
8th nerve schwannomas –> Neurofibromatosis type II

102
Q

What is the most common cause of congenital deafness?

A

Genetic, autosomal recessive, nonsyndromic deafness due to GJB2 mutation

103
Q

What happens with the different amounts of repeats in Fragile-X Syndrome?

A

CGG repeats!

5-50 repeats –> normal
50-200 repeats –> increased expression of mRNA (bizarrely)
>200 repeats –> no mRNA –> no FMRP

104
Q

What is Fragile X-associate tremor/ataxia syndrome (FXTAS)?

A

X-linked, lesser number of repeats than full Fragile-X Syndrome (50-199)

Adult onset –> ataxia, tremor, parkinson’s symptoms, peripheral neuropathy.

More in men than women

105
Q

When does premature ovarian failure occur?

A

When there’s a pre-mutation number of CGG repeats (50-199; pre-Fragile-X Syndrome)

Women’s ovaries fail early, before 40

106
Q

What are some examples of loss-of-function mutations that lead to disease?

A

Duchenne’s Muscular Dystrophy (and Becker’s), HNPP, Osteogenesis Imperfecta Type I

107
Q

Genetics of Duchenne’s Muscular Dystrophy?

A

Mutation/deletion of DMD on Xp21.2 (X-linked inheritance)

Large deletions of multiple exons or nonsense mutations –> LOSS-OF-FUNCTION

108
Q

What are the genetics of Becker muscular dystrophy?

A

In-frame deletions in the DMD XP21.2 gene - so instead of losing whole exons or nonsense, just lose a few aa. Milder form of disease than Duchenne’s.

109
Q

Hereditary neuropathy with liability to pressure palsies (HNPP)

A

Deletion of PMP22 gene –> LOSS-OF-FUNCTION

Autosomal dominant!!!

This protein is an integral glycoprotein in nerves –> repeated focal pressure palsies.

110
Q

Genetics of CMT1A phenotype?

A

3 copies of the PMP22 gene –> GAIN-OF-FUNCTION –> Charcot-Marie-Tooth

Autosomal dominant!!!!

Clinically: demyelinating sensory & motor neuropathy. Presents with weakness in lower extremity, sensory loss, & muscle atrophy.

111
Q

Osteogenesis Imperfecta Type I

A

AD!!

Collagen is made up of 3 chains, 2 proα1 and one proα2

Here, premature stop codon in COL1A1 –> mRNA unstable –> degraded –> only 1/2 as much COL1A1 & proper collagen produced

112
Q

Osteogenesis Imperfecta Types II, III, and IV

A

Normal amounts of collagen are produced, but 1/2 are normal, 1/2 are not. Phenotype is much more severe than Type I

113
Q

What are some disease examples of gain-of-function of the protein?

A

Hemoglobin Kempsey, Charcot-Marie-Tooth Syndrome Type 1A

114
Q

Hemoglobin Kempsey

A

Mutation in beta globin (Asp99Asn) –> higher oxygen affinity. Hemoglobin remains locked in the “relaxed” state. Does not release oxygen appropriately in tissues –> body creates more RBCs –> polycythemia

115
Q

What are some disease examples of novel property mutations?

A

Osteogenesis Imperfecta Types II, III, & IV; sickle cell anemia

116
Q

What are the three different classes of trinucleotide repeat disorders?

A
  1. Expansion of non-coding repeats and loss of function (Fragile X)
  2. Expansion of non-coding repeats and gain of function (FXTAS, myotonic dystrophy types I & II)
  3. Expansion of codons in exons (Huntington’s)
117
Q

Huntington’s Disease

A

CAG repeats

Normal number is =40
36-39 = incomplete penetrance
Paternally inherited in children

118
Q

Myotonic dystrophy

A

DMPK (gene that encodes a kinase)

Normal is 5-34 CTG repeats. Repeats expanded generationally. Maternal expansions more likely.

Clinically: myotonia, cataracts, cardiac arrhythmias, weakness, balding, respiratory defects, intellectual disability

119
Q

What classes can genomic DNA be assigned to and what is the frequency of each class?

A

1.5% translated (protein-coding)
20-25% genes (introns, exons, flanking sequences for gene expression, etc.)
50% “single copy” sequences
50% “repetitive DNA” (millions of repeated sequences)

120
Q

Describe the types of repetitive DNA that exist in the genome

A

Satellite DNAs (tandem repeats)

  • Microsatellites: 2, 3, or 4-nucleotide repeats
  • Minisatellites: 10-100 bp tandemly repeated blocks of DNA
  • “α-satellite” repeats (171 bp) found near centromeres; may be important to chromosome segregation

Dispersed repetitive elements

  • Short Interspersed Repetitive Elements (Alu family)
  • Long Interspersed Repetitive Elements (L1 family)
  • Medical significance: may facilitate non-allelic homologous recombination events, lead to aberrant genes
121
Q

How many human genes are there?

A

25,000-30,000

122
Q

What are the different types of genes?

A

Protein-coding genes
RNA-coding genes (rRNA, tRNA, etc.)
Psueodogenes: intron-containing, retroposed pseudogenes (cDNA from RNA)

123
Q

What is the advantage of gene duplication?

A

When a gene duplicates, it frees up the other gene to vary while it still carries out an essential function

124
Q

What are the some of the symptoms/diseases associated with aberrant CNVs on 1q21.1?

A

Deletions in this region lead to microcephaly & schizophrenia

Duplications in this region lead to macrocephaly and autism

125
Q

What is the “missing heritability” problem in genome sequencing?

A

Individual genes cannot account for much of the heritability of diseases.

Large studies implicating local SNPs account for only a fraction of the expected genetic contribution

126
Q

What does this mean?

46,XX,ins(2)(p13q21q31)

A

An insertion of segment 2q21-q31 into the breakpoint at 2p13

127
Q

What does this mean?

46,XY,t(2;6)(q35;p21.3)

A

A reciprocral translocation with breakpoints in chromosomes 2q35 and 6p21.3

128
Q

What does this mean?

45,XY,der(14;21)(q10;q10)

A

A Robertsonian translocation: fusion with breaks near the centromeres in acrocentric chromosomes 14q10 and 21q10

der = derivative chromosome

129
Q

What are paracentric and pericentric inversions?

A

Paracentric: inversion does NOT include centromere (can lead to acentric or dicentric chromosomes during meiosis)

Pericentric: inversion includes centromere (can lead to duplications or deletions)

130
Q

What are the ways that reciprocal translocation can go wrong during segregation in meiosis?

A

Adjacent-1: two chromatids with partial monosomy – unbalanced, total loss of crucial genetic material

Adjacent-2: two chromatids with partial trisomy - duplication of genetic material. Can lead to CML

131
Q

What is a Robertsonian translocation?

A

Fusion of two acrocentric chromosomes within their centromeric regions, resulting in the loss of both short arms (these short arms contain rDNA repeats, so the loss of these is not deleterious)
“pseudo di-centric”

132
Q

What is an interstitial deletion?

A

A deletion that contains the centromere (goes from one arm to the other)

Can form into a ring chromosome

133
Q

What is an isochrome?

A

A chromosome in which one arm is missing and the other is duplicated in a mirror-like fashion

134
Q

What happens to the offspring of a carrier of isochrome 21?

A

100% are abnormal - either they have trisomy or monosomy (which is not compatible with life)

135
Q

What does DNMT1 do?

A

It’s a maintenance methyltransferase - it recognizes hemi-methylated DNA after duplication & re-methylates appropriately

136
Q

What on earth is Waddington’s epigenetic landscape?

A

Basics: a ball at the top of the hill; can roll down and enter many different valleys.

Biological: a stem cell has the potential to differentiate into many different types of cells, follow many different pathways. Potential for differentiated cells to de-differentiate into something else is decreased (hills on either side of valleys). Each cell state is a stable “low energy” state.

137
Q

What turns histones on? ;)

A

Acetylation of lysines

Phosphorylation of serines

138
Q

Tumor Suppressor Gene (TSG)

A

Methylation (silencing) of this can lead to cancer.

Potential therapies are un-methylating it.

139
Q

What is cytogenetics?

A

Study of the structure & number of chromosomes

140
Q

What are the two most common leukemia translocations?

A

t(9;22) is diagnostic for chronic myelogenous leukemia (CML). Treated with tyrosine kinase inhibitors (Gleevec)

t(15;17) is diagnostic for a specific acute promyeloid leukemia (APML).

141
Q

Acute promyeloid leukemia (APML)

A

Result of translocation of 15;17.

Auer rods visible on slides

Treated with retinoic acid –> acts on RARα (retinoic acid receptor) to enable DNA coactivators –> differentiation therapy –> cure

142
Q

How do the cytogenetic findings in childhood B-cell leukemia affect prognosis?

A 
Low hyperdiploidy (47-50 chr) = poor prognosis
High hyperdiploidy (>50 chr) = good prognosis
143
Q

What are the different types of FISH probes?

A

Centromere – used for enumeration (ALL panel, prenatal dx)

Locus specific – deletion/duplication (p53, cancer)

Dual fusion, fusion – translocation (BCR:ABL, PML:RARα –> cancer)

Break apart – translocation rearrangement (MLL –> cancer)

Whole chromosome paint (identifying markers, translocations)

144
Q

Chromosomal microarray analysis

A

DNA from patient and from control is oligomerized and hybridized onto plate. One is labeled red, one labeled green. If everything’s yellow, they exist in equal amounts. Can detect duplications, deletions – but not translocations, as DNA is chopped up.

145
Q

What is uniparental disomy?

A

In PWS, for example, 2 methylated copies from mom are inherited, nothing from dad.

146
Q

What are the clinical features of Prader-Willi Syndrome?

A

Newborn: hypotonia (floppy babies), almond-shaped eyes, undescended testicles, lighter skin pigmentation than sibs

Child: early course of difficulty feeding & failure to thrive - until preschool, when child develops hyperphagia and gains weight dramatically

Mild-moderate developmental delays; ophthalmologic problems: strabismus (lazy eye), nystagmus (jiggly eyes); scoliosis; OSA

147
Q

What is ptosis?

A

Falling or drooping of the eyelid

148
Q

What is spasticity?

A

Stiff or rigid muscles. May also be called unusual tightness or increased muscle tone.

Reflexes (for example, a knee-jerk reflex) are stronger or exaggerated

149
Q

What are the mechanisms that lead to Down Syndrome?

A
  1. meiosis I nondisjunction (maternal) - 95% of cases
  2. Robertsonian translocation (4%)
  3. Isochromosome (21q21q translocation)
  4. mosaic DS - phenotype typically milder, wider variability
  5. partial trisomy 21 (very rare)
150
Q

What is the phenotype of a patient with Down Syndrome?

A

Normal growth parameters

Midfacial hypoplasia (middle 1/3 of face develops slower than eyes, jaw, etc.)
Upslanting palpebral fissures
Epicanthal folds
Small ears, large-appearing tongue

Low muscle tone, increased joint mobility

Transverse palpebral fissures

Clinically: heart defects, diabetes, thyroid problems, GI structural abnormalities, OSA, increased risk of leukemia, early Alzheimer’s

151
Q

Fitness calculations

A

Autosomal dominant: μ = ½ F (1-f)
Autosomal recessive: μ = F (1-f)
X-linked recessive: μ = 1/3 F (1-f)

  • μ = mutation rate/gene/generation
  • F = frequency of disease
  • f = reproductive fitness
152
Q

What is the difference between pharmacogenetics and pharmacogenomics?

A

Pharmacogenetics: assessing pharmaceutical efficacy based on allelic variation in genes affecting drug metabolism. Looking at individual genes

Pharmacogenomics: assessing common genetic variants in the aggregate for their impact on drug responsiveness

153
Q

Phase I & II drug metabolism steps?

A

Phase I: attach a polar group onto the compound to make it more soluble; usually a hydroxylation step

Phase II: attach a sugar/acetyl group to detoxify the drug and make it easier to excrete

154
Q

What is the difference between pharmacokinetics and pharmacodynamics?

A

P-kinetics: the rate at which the body metabolizes, etc. the drug = whether or how much of the drug reaches its target

P-dynamics: the after-effects of the drug binding to its target (downstream effects) = what happens when the drug successfully reaches its target

155
Q

CYP450 enzyme system

A

CYP450 genes encode enzymes that are active in liver, small intestine. Metabolize 90% of commonly used meds

156
Q

CYP3A

A

Acts on cyclosporine.
Inhibited by ketoconazole, grapefruit juice.
Elevated (activity) by rifampin

157
Q

CYP2D6

A

Acts on tricyclic antidepressants, opioids (codeine)

Inhibited by quinidine, fluoxetine, paroxetine

158
Q

VKORC1 and CYP2C9

A

Act on Warfarin

159
Q

NAT

A

N-actyltransferase enzyme

Acts on Isoniazid (drug for TB)

160
Q

TMPT

A

1 in every 300-400 children do not have this enzyme – if you give these children with ALL (leukemia) the standard chemotherapeutic dose, you will kill the child due to immunosuppression

161
Q

G6PD

A

Most common disease-producing enzyme defect in the world – 400 million ppl worldwide & 10% of African-American males are G6PD deficient

X-linked

Deficient individuals are susceptible to hemolytic anemia after drug exposures

Acts on sulfonamide, dapsone

162
Q

What is a Barr body?

A

A clump/cluster of inactivated X chromosome

163
Q

XIST

A

= a gene located on the X chromosome

Expressed only from the inactive X; inactivation can’t occur in its absence

Majority of genes on inactivated X chr have promoters that have been methylated

164
Q

Klinefelter’s Syndrome

A

47, XXY

Learning disability, delayed speech & language, tall stature, small testes, reduced facial & body hair, gynecomastia

165
Q

Jacobs Syndrome

A

47, XYY

Learning disability, speech/developmental delays, autism spectrum, tall stature

166
Q

Triple X Syndrome

A

47, XXX

May have tall stature. Increased risk of learning disabilities, delayed speech, seizures, kidney abnormalities

167
Q

What do Sertoli cells & Leydig cells turn into?

A

Sertoli = sperm

Leydig = interstitial cells; produce testosterone

168
Q

Genital development in women

A

Paramesonephric (Mullerian) ducts result in female structures

169
Q

Hormones involved in female genital development?

A

WNT4 = responsible for differentiation of ovaries; inhibited by SOX9

DHH = upregulated by WNT4; inhibits SOX9

RSPO1 = coactivator of WNT pathways

170
Q

Genital development in men

A

Mesonephric (Wolffian) ducts results in male structures.

Ducts elongate to form vas deferens, epididymus, and seminal vesicles

171
Q

Hormones involved in male genital development?

A

SRY & SOX9 = responsible for AMH hormone, regression of paramesonephric ducts

FGF9 = differentiation of testes

SF1/NR5A1 = stimulate differentiation of Sertoli & Leydig cells

M2M (4 decks)

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