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FOM > Week 7 Cormier > Flashcards

Week 7 Cormier Flashcards

1
Q

What did ENCODE find about genes in 2012?

A

that 80% of what we used to call Junk DNA actually contains regions of DNA that regulate expression of genes

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2
Q

What is a kindred and a proband

A

kindred: extended faimly depicted in a pedigree
proband: 1st affected person who is brought to clinical attn, can be multiple
- -measure all others from the proband(s)

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3
Q

fitness(as described by cormier)

A

measure of impact a condition or genotype has on reproduction
-defined by # of offspring of affected individual who reach reproductive age

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4
Q

vertical transmission

A

transmission of a disease from one generation down the next & implies family history of disease (excludes sporadic cases, w/o family history)

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5
Q

autosomal disorders

A

affect males and females equally

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6
Q

X linked recessive disorders

A
  • more common for males to develop X linked recessive disorders due to hemizygosity (1 X)
  • females randomly inactivate 1 of their X’s , so if inherit dominant X linked disorder can still = mosaicism
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7
Q

mosaicism

A

phenotype is only expressed in a subset of cells

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8
Q

what do most recessive disorders do if a person inherits both recessive alleles?

A

acts a loss-of-fxn

-mutations in both alleles eliminates gene fxn

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9
Q

pure dominant disorder

A

when both homo- and hetero-zygotes for dominant gene exhibit identical severity in phenotype
-rarely happens

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10
Q

semidominance or incomplete dominance

A

when dominant disorder is more severe in homozygotes for the gene
-more common than pure dominant
EX: achondroplasia-short limbed dwarfism w/ large head (tend to marry each other and makes more severe or lethal to a fetus)
EX: familial hypercholesterolemia

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11
Q

codominant

A

blood groups, ABO

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12
Q

penetrance

A

probability that a mutant gene will have phenotypic expression
-when % of individual s demonstr8 phenotype but >100% have disease

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13
Q

expressivity

A

severity of expression of the phenotype among individuals w/ same disease causing genotypes
-severity of disease differs in people who have same genotype=variable expressivity of phenotype

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14
Q

NF1- neurofibromatosis

A
  • autosomal dominant disease of NS, eye & skin
  • multiple benign fleshy tumors of skin (neurofibromas)
  • hamrtomas on iris
  • cafe au lait spots: flat, diff colored skin
  • -100% penetrance (any heteroZ has some Sx’s)
  • -variable expressivity (severty of Sx’s)
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15
Q

age of onset

A

diseases usually have an avg age of onset

  • -can make diagnosis difficult/analysis of pedigree if individual hasn’t reached age of onset etc
  • -Example: parent dies b4 age of onset & kids still to young to know if they have it: HUntingtons disease
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16
Q

allelic heterogeniety

A

EX: cystic fibrosis & CFTR gene
EX: PKU & PAH gene
–many loci contain multiple mutant alleles in pop.
–tons of mutations w/ varying effects (some ppl only have lung condition, others have multiple afflictions: both caused by mutation in CFTR)

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17
Q

locus heterogeneity

A

many disease phenotypes caused by mutations in diff genes
-difficult to determine causative gene or therapy
-EX: retinitis pigmentosa=photoreceptor degeneration but via 70 diff genetic mutations
EX: hyperphenylalanemias(like PKU)

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18
Q

phenotypic heterogeneity

A

diff mutations in same gene cause diff diseases

  • EX: RET gene (for receptor tyrosine kinases)
  • 1 muation in Ret= colonic ganglia & constipation [Hirschprung’s disease], 2nd mutation causes thyroid & adrenal cancer [endocrine cancers], 3rd mutation causes both
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19
Q

sex influenced Autosomal recessive DO’s

A

-both sexes develop the disease, but 1 sex has higher frequency
EX: hemochromatosis- iron metabolism DO causing Fe overload & damage heart lungs etc (homoZ for Cys28tyr mutation in HFE gene for affected ppl)
-women 10-20% less likely then men to get hematochromatosis

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20
Q

Consanguinity

A

2 parents are related to each other
-EX; xeroderma pigmentosum is rare autosomal recessive DNA repair defect where <20% are born to parents who r 1st cousins

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21
Q

inbreeding

A

similar to consanguinity but at the population level
(ppl w/in small pop choose ppl w/in that small pop)
EX: Tay-Sachs-fatal earlychildhood neurological DO
—comon in ashkenazi Jews

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22
Q

autosomal dominant inheritance

A
  • > 50% of mendelian disorders inherited this way
  • Sometimes homoZ for dominant traits are lethal (DD kills fetus, Dd lives)
  • trait is in every generation (unless due to new mutations)
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23
Q

new mutations of autosomal dominant DO’s

A

-spontaneous new mutations can arise (usually in gametes of parents)
EX: Down Syndrome, risk increases with age of parents

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24
Q

sex limited autosomal dominant DOs

A

sex ratio differs from 1:1
-hard to distinguish in pedigree–>usually need evidence of direct dad-son transmission
EX: male-limited precocious puberty- boys develop 2’ sex characteristics w/ growth spurt at age 4 (mut. in LCGR gene)

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25
Q

X linked inheritance

A

EX: hemophilia A caused by mutations in coagulation factor (X-linked recessive)
-all daughters of an affected male are carriers

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26
Q

X inactivation, dosage compensation, & expression of X-linked genes

A

-females determine the trait outcome for male

EX: duchennes muscular dystrophy

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27
Q

manifesting heterozygotes

A

when female heteroZ for Xlinked DO demonstrate a disease phenotype
-often due to X inactivation

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28
Q

X linked dominant

A

looks like autosomal dominant
-but no sons have disease and all daughters of an affected male have diseases
EX: rickets
EX: rett syndrome, only in girls though because lethal to males

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29
Q

y linked dominant

A
  • only 20 genes on Y chromosomes
  • SRY genes are sex determining
  • usually DOs w/ Y =infertility/reproductive abnormalities
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30
Q

osteogenesis imperfecta

A
  • father is unaffected but both children are

- must have mosaicism of a new mutation that he passed on

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31
Q

unstable repeat expansion DO

A

-mutation changes from generatino to generation
unstable triplet repeat expansions
EX: fragile X, HUNTINGTONS, Myotonic Dystrophy, & Friedrich Ataxia

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32
Q

Restrn Fragment Length Polymorphism (RFLP)

A
  • allelic variant that abolishes or generates a restrxn endonuclease recognition site or changes size of an RFLP
  • use 2 destinguish b/w 2 chromos
  • analyze via PCR & S. blot
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33
Q

VNTR variable number of tandem repeats

A

-tandem repeats make up a lot of genome and are not part of genes so not conserved
-polymorphic in size, used as biomarkers
analyze bia PCr`

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34
Q

SNPs single nucleotide polymorphisms

A

use as polymorphic biomarkers & disease association

-snp chips can detect 1000s of snps

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35
Q

haplotypes

A
  • can be any combo of alleles, loci, or markers on the same chromos but commonly refers to grps of nearby alleles or markers on a chromos that are inherited together
  • if you have a certain hap block, more susceptible to some diseases
  • the larger a hap block, the more likely it arose around a hap block recently
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36
Q

epigenetics

A

non-mutational (no change in gene sequence) phenomenon that can affect gene expression and its inheritance
EX: X inactivation or Imprinting

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37
Q

Imprinting

A

differential expression of a gene allele depending on parental origin
-imprint=silence
EX: Prader Willi & angelman syndrome; IGF2 & cancer

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38
Q

Prader Willi Syndrome

A

On chromos 15, caused by deletion of SNORD116
-imprinted (silenced) maternally
-paternal (only active gene) gets deleted
=PW Syndrome

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39
Q

Angelman Syndrome

A

On chromos 15, caused by deletion of UBE3A
Paternally (silenced) imprinted
-maternal (only active gene) gets deleted
=AW syndrome

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40
Q

clinical cytogenics

A

study of chromosomes, their structure & inheritance, as applied to medical genetics

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41
Q

karyotyping

A

looking at all the chromosomes (physically, not sequence)

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42
Q

metacentric

A

central chromosome and = size arms

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43
Q

submetacentric

A

off-center centromere & diff size arms

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44
Q

acrocentric

A

centromere near 1 end

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45
Q

telocentric

A

only in mice, single arm

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46
Q

FISh

A
  • molecular cytogenetics

- multichromatic flourescent probes can target chromos, chromosome regions or genes

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47
Q

cytogenetics in cancer

A

BCR-AL= philadelphia chromosome in chronic myelogenous leukemia (CML) is a classic example

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48
Q

trisomy & monosomy

A

trisomy: usually lethal, Downs SYndrome trisomy of chromo 21
monosomy: usually lethal, X chromosome in Turner’s Syndrome

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49
Q

Downs syndrome risk

A

1/800 live births have DOWns

  • over 45 yrs old= 1/15 have downs
  • 8 fold increase in risk if you have already had1 baby w/ downs
  • —if over 45 & have one DoWNs baby already= 1/2 or 50% chance of another DOWNs baby
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50
Q

Maternal Serum screening!

A

Downs: increased B-hcg, PAPP-a decrease 1st tri
-decreased AFP & UE3, increased B-hCG & inhibin A in 2nd tri
Neural Tube defects: increased AFP [spina bifida]

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51
Q

genetic polymorphism

A

-1/300-1/100 bp diff between ppl

EX: Rh system, Rh- (doesn’t express) & Rh+(expresses specific cell surface protein)

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52
Q

alpha1-antitrypsin:

A
  • has 5 alleles and if have ZZ you dont make enough protein =early onset emphysema
  • example of eco-genetics
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53
Q

ecogenetics

A

genetic variation in susceptibility to environmetal agents

EX: alpha1-AT, lactase deficiency , ALDH deficiency w/ alcohol, fair complexion w/ light, G6PD deficit & fava beans

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54
Q

heterozygous advantage

A

Deleterious allele maintained in pop cuz heteroZ increases fitness
Ex: B-globin
-B^s causes sickle cell when homoZ
-B^s heteroZ are resistant to malaria

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55
Q

who is resistant to HIV

A

those with delta CCR5 variant

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56
Q

hardy weinberg

A 
p^2+2pq+q^2
Assumptions:
-pop is large
-random matings
-allele frequencies remain constant : no mut., no (-) selexn, no genetic influx
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57
Q

what does HW disequilibrium indicate?

A

that a particular allele is associated w/ a disease

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58
Q

loss of fxn mutations

A

-arise from a variety of mutations; pt, delete, insert etc

EX: B-globin, PAH (PKU), p53 (cancer)

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59
Q

gain of fxn mutations

A

-can arise from increased dosage or increased protein fxn

EX: DOwn’s, achondroplasia: increased axn of FGFR

60
Q

novel properties?

A

EX: sickle cell disease: sickled Hb chains aggregate when deoxygenated

61
Q

inappropriate expression

A

many examples in cancer; genes normally silenced are turned on

62
Q

modifier genes

A

ppl [even w/in same family] w/ same mut. present w/ drastically diff phenotypes due to modifier genes
EX: ApoE4, if u carry 1 or 2 (worse) alleles you are more susceptible to a rang eof neurological DOs…like ALzheimers (e4/e4 is most detrimental, any other # w/ e4 is not as bad but not good)

63
Q

enzyme defects

A

EX: PAH gene in PKU where phenylalanine accumulate in body fluids & damages CNS

64
Q

Super IMportant about PKU!

A

defect occurs in 1 tissue (liver & kidney) but where the phenotype is manifested deleteriously is elsewhere (brain)

65
Q

lysosomal storage defects

A

EX: TAy SACHs–> buildup of GM2 (ganglioside sphingolipids)

66
Q

defect in protein trafficking

A

-possibly due to faulty post-translational modification
EX: I-cell disease- lysosomal storage disease caused by falty protein trafficking, acid hydrolases are not properly modified and get sent o/ of cell instead of to lyso

67
Q

defect in co-factor metabolism

A

EX: alpha1-AT, involved in breakdown of various proteases that can damage lung tissue if not regulateed

68
Q

defects in receptor proteins

A

EX: LDL receptors cant bind or internalize LDL & cholesterol= hypercholesterolemia

  • autosomal dominant disorder
  • **like PKU, LDLR deficiency is localized to liver but see effects elsewhere (cardiovascular disease )
69
Q

defects in transport

A

EX: CF an autosomal recessive disease

-mut. in CFTR [delta 508=3 bp deletion] eliminates phenylalanine that causes misfolding of proteins

70
Q

Defects in structural proteins

A

EX: duchennes muscular dystrophy, mutation in the dystrophin gene (huge protein) which is supposed to maintain muscle membrane integrity & link actin skeleton to ECM

71
Q

mitochondrial DO’s

A

-most often found in tissues w/ high demands
-only inheritted maternally
EX: Leber’s hereditary optic neuropathy

72
Q

multifactorial inheritance

A

like height, multiple factors/genes can play a role in phenotypes

73
Q

4 characteristics of inheritance of complex diseases

A
  1. no simple mendelian pattern of inheritance (instead grades of expressivity & penetrance)
  2. familial aggregation
  3. environmental factors
  4. complex diseases are more common close to proband
74
Q

Gene for intestinal cancer

A

Pta2g2a (in mouse)

75
Q

physical mapping

A

actual sequence & location on chromos

76
Q

genetic mapping

A

based on following a phenotypic trait in families

-indicates relative position of genes by linkage analysis

77
Q

linkage analysis

A

2 genetic loci are transmitted together from parent to offspring more then expected (>50%)

78
Q

recombination frequency

A

liklihood of seperation
>50% = not linked
<50% =linked
RF 1%=1cM =2 MB of sequence

79
Q

determining phases

A

specific alleles & markers on a chromos are “in phase” when coinherited from same parent
-need @ least 3 generations to determine

80
Q

What is the best and most common mapping method?

A

linkage analysis (for single-trait genes)

81
Q

SNP haplotypes helped map which monogenc disease gene?

A

EHlers-Danlos VIII

  • involves collagen defect
  • mapped to chromos 12, now narrowed to 7 cM on it
82
Q

where was huntingtons disease gene mapped?

A

Lake MAracaibo, Venexzuela
1980s
Nancy Wexler

83
Q

Association analysis

A
  • start w/ candidate gene
  • then look in families and/or population to determine if ppl w/ disease carry a mut. or polymorphism
  • GWAS are a type
  • more commonly used in complex disease genetic analysis
84
Q

GWAs

A

?

EX: complement factor H & risk for macular degeneration

85
Q

mapping complex trait diseases

A
  • most common method used is association analysis

- can use Sib-pair as well

86
Q

benzo[a]pyrene

A
  • an aromatic polycyclic hydrocarbon and carcinogen

- causes the formation of bulky DNA adducts that commonly result in A to G mutations.

87
Q

what is calpain 10 (CAPN10)?

A

a type II diabetes gene (T2D)

-1st T2D susceptibility gene

88
Q

Oji-Cree and T2D relationship

A
  • highest population % of T2D (40%)
  • 1 mutant allele= 5x gr8r risk of T2D
  • 2 mutant alleles=25x greater risk
  • HNF-1alpha=homeodomain gene
89
Q

3 most common cancers

A

1) prostate (men); breast (women)
2) lung
3) colorectal

90
Q

neoplasia

A

disease process associated w/ uncontrolled cell proliferation leading to a mass or tumor

91
Q

carcinoma

A

epithelial (intestine, breast, & lungs)

92
Q

hematopoetic & lymphoid

A

leukemias & lymphomas

93
Q

sarcomas

A

mesenchymal origin, bone, muscle, & CT

94
Q

natural selection

A
  • neoplastic cells evade cellular constraints on growth & proliferation
  • acquired over time
  • changes are selected for that confer a selective advantage
95
Q

clonal evolution hypothesis

A
  • every tumor cell is capable of initiating neoplastic growth
  • genetic & epigenetic changes occur over time in individual cancer cells allows genetic events to occur
96
Q

cancer stem cell hypothesis

A

growth & progression of many cancers are driven by small subpoplations

97
Q

cancer stem cells

A

CSCs-lead to proliferation of cell population

98
Q

familial cancers

A
  • several close relatives w/ common cancers
  • several close relatives w/ (related cancers)
  • etc (inherited)
99
Q

oncogenes

A
  • abnormal stimulation of cell division & proliferation
  • dysregulated version of endogenous genes
  • turn “on” a stimulatory pathway
100
Q

proto-oncogene

A

converted into an oncogene

  • regulatory mutation
  • gene amplification
  • chromosome rearrangement
101
Q

tumor suppressor genes

A

p53, RB1, BRCA1 or 2

102
Q

LOH

loss of heterozygosity

A
  • many cancers result from loss of fxn of 1 allele

- loss of 2nd wildtype allele is called LOH

103
Q

Microinstability (MIN)

A

arises most often from defects in mismatch repair (MMR) or nuclear excision repair (NER)
-chromosomal instability (CIN)

104
Q

burkitts lymphoma

A

caused by chromosomal translocation

-affects MYC proto-oncogene

105
Q

Chronic myelogenous leukemia

A
  • chromosomal translocation b/w chromos 9 & 22

- causes proto-oncogene BCR-ABL to be affected

106
Q

what is MLH1 mutation an example of?

A

mismatch repair defect & MIN

107
Q

colorectal cancer

A

APC mutation in CRC (a TSG)

108
Q

Familial Adenomatous Polyposis (FAP)

A

inherited form of CRC

  • families carry a mutant copy of APC
  • CRC requires at least 6-10 genetic mut’s & epigenetic events
109
Q

name the oncogenes and TSG’s associated with colorectal cancer

A

K-Ras & B-catenin (oncogenes)

Apc, p53, TGFbeta recepto, Smad4, * MLH1

110
Q

What is the primary role of APC in prevention of colorectal cancer?

A

helps control B-catenin (oncogene in Wnt signalling) levels via degradation

111
Q

lumping & splitting

A

b4 genetic etiologies traditionally have been lumped together
-new technology permits “splitting”

112
Q

diffuse large B-cell lymphoma (DLBCL)

A
  • most common form of noon-Hodgkins lymphoma

- made up of 2 diff cancers: germinal center B-cell DLBCL & activated B-cell like DCBCL

113
Q

germinal center B-cell DLBCL

A

patients w/ cancers that responded to chemo

114
Q

activated B-cell like DLBCL

A

pt’s that failed chemo & had poor survival

115
Q

next generation sequencing (NGS)

A

perform whole genome, whole exome, whole transcriptome & whole epigenome sequencing w/in single day for cheap
-electronic medical record

116
Q

3 complications in treating monogenic DO’s

A
  • gene may not b identified
  • fetal damage
  • most severe clinical phenotypes are less amenable to intervention
117
Q

allelic heterogeneity

A
  • diff mutant alleles of same gene give rise to diff disease phenotypes
  • PKU is an example
118
Q

locus heterogeneity

A

hyperphenylalaninemia: can be caused by defects in PAH or biopterin metabolism enzymes

119
Q

Gaucher’s disease

A
  • most prevalent lysosomal storage disease
  • ashkenazi jews
  • autosomal recessive deficiency in enzyme that degrades glucocerebrosidase (get build up)
  • TX: protein targetting or BMT
120
Q

hematopoetic stem cell transplantation (HSC)

A

effective TX for SCID, thalassemias etc

-cord blood transplants can happen too

121
Q

gene therapy

A

modify cells to produce a therapeutic effect

  • compensate for LOH
  • replace a dominant mutant gene
  • pharmacological effect
122
Q

target cell

A
  • long lived cell: stem cell

- bone marrow is only regularly used

123
Q

ex vivo gene therapy

A
  • transfer of a gene outside the body or a stem cell
  • reintroduced into a body
  • advantage: doesnt require an efficient means to enter cell (rare engineered cell can be selected for in culture)
124
Q

in vivo gene therapy

A

direct injection into the body using a vector

  • quick & easy;
  • disadvantages: many including targeting proper cells, immune responses, safety
125
Q

retrovirus (vector)

A
  • RNA
  • enveloped
  • only acts on dividing cells
  • most have permanent expression/persistent gene transfer
  • can enter virtually all target cells
  • retroviral ex: HIV
126
Q

lentivirus (vector)

A
  • RNA
  • enveloped
  • acts broadly
  • integration might induce oncogenesis in some applications
  • persistent gene transfers in most tissues
127
Q

AAV (adeno-associated vector)

A

-ssDNA
-not enveloped
-acts broadly except for hematopoetic SC’s
-small packaging capacity
(until recently…still may not be able to fit whole genome)
-non-inflammatory, no side effects
***preferred viral vectors

128
Q

adenovirus (vector)

A
  • dsDNA
  • broad action
  • non-enveloped
  • no mutations: failure due to strong immune respose
  • cant integrate into host genome
129
Q

herpes virus (vector)

A

-CNS tropism
- (+) can package large genes
(-) strong inflammation/immune response

130
Q

non-viral vectors

A

(+) lack biological risks
(-) havent been very successful
EX) naked DNA, liposomes, protein-DNA conjugates, artifical chromosomes, & nanoparticles

131
Q

siRNAs gene therapy

A
  • can b designed to target a range of tissues

- lots of knockdowns

132
Q

hemophilia B

A
  • factor IX replacement (FIX)
  • liver specific
  • AAV2, AAV9 vectors
  • watch liver for problems
133
Q

FIX

A
  • expressed in hemophilia B

- helps?

134
Q

Lysosomal storage diseases (LSDs)

A
  • recessive diseases

- caused by mutations in genes involved in lysosomal degradation

135
Q

Parkinson disease

A

main CNS application for gene therapy

136
Q

leber congenital amaurosis

A
  • early onset photoreceptor degeneration
  • 10 diff mutations cause this
  • RPE65 is gene targetted (involved in retinoic acid metabolism of retina
  • trials of AAV2
137
Q

risks for gene therapy

A
  • some deaths w/ adenoviruses & retroviruses
  • XSCID= thought to b cured but caused big prblem
  • –started developing fatal leukemias from retroviral insertion mutations into LMO2
138
Q

X-SCID “bubble babies”

A
  • kids born w/o immune response (IR)
  • kids had complete rescue of IR
  • some developed leukemia (from LMO2 gene inserts)
  • b cell lymphoma
139
Q

what have lentiviral hematopoetic SC gene therapies been used for lately?

A
  • new therapies
  • metachromatic leukodystrophy (MLD) is a lysosomal storage disease
  • helped reduce symptoms
140
Q

Wiskott-Aldrich Syndrome

A

SC therapy

  • immunodeficiency caused by mutations in WASP protein
  • using lentivirus vectors–> helped a lot
141
Q

embryonic stem cells

A

toti/pluripotent

  • isolated to inner mass of blastocyst
  • capable of unlimited replication in cell culture
  • can cause cancer sometimes & ethical dilemmas
142
Q

somatic stem cells

A

multipotent

  • most tissues, even neurons can be made but are restricted in what they can make
  • often come from BM, liver, heart, intestine etc
  • adult BM SC’s & Umbilical cord blood stem cells are most often used
  • could b rejected
143
Q

reprogramming somatic cells into pluripotent stem cells

A
  • somatic cells can b reprogrammed in cell culture to induced pluripotent stem cells (iPSs)
  • uses transcription factors
  • epigenetic state of iPSs is very similar to ES cells
  • KLF4 & Myc
144
Q

What is xeroderma pigmentosum

A

Skin cancer w/ uv sensitivity and neurological abnormalities

Caused by defective nucleotide excision repair process

145
Q

Ataxia telangiectasia

A

Causes leukemia, lymphoma, yray sensitivity, genome instability

Defective ATM protein kinase that fixes double strand breaks

146
Q

Werner syndrome

A

Premature aging, cancer at several sites, genome instability

Defect in accessory 3’ expo nuclease and DNA helicase

147
Q

Benzo[a]pyrene affects

A

Aromatic polycyclic hydrocarbon and carcinogen from cigs

Cause bulky adducts
Cause g to a transition mutations!!!!
Commonly attacks p53

FOM (6 decks)

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