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
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)
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
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)
5
Q
autosomal disorders
A
affect males and females equally
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
7
Q
mosaicism
A
phenotype is only expressed in a subset of cells
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
9
Q
pure dominant disorder
A
when both homo- and hetero-zygotes for dominant gene exhibit identical severity in phenotype
-rarely happens
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
11
Q
codominant
A
blood groups, ABO
12
Q
penetrance
A
probability that a mutant gene will have phenotypic expression
-when % of individual s demonstr8 phenotype but >100% have disease
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
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)
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
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)
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)
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
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
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
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
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)
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
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)
25
X linked inheritance
EX: hemophilia A caused by mutations in coagulation factor (X-linked recessive)
-all daughters of an affected male are carriers
26
X inactivation, dosage compensation, & expression of X-linked genes
-females determine the trait outcome for male
| EX: duchennes muscular dystrophy
27
manifesting heterozygotes
when female heteroZ for Xlinked DO demonstrate a disease phenotype
-often due to X inactivation
28
X linked dominant
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
29
y linked dominant
- only 20 genes on Y chromosomes
- SRY genes are sex determining
- usually DOs w/ Y =infertility/reproductive abnormalities
30
osteogenesis imperfecta
- father is unaffected but both children are
| - must have mosaicism of a new mutation that he passed on
31
unstable repeat expansion DO
-mutation changes from generatino to generation
unstable triplet repeat expansions
EX: fragile X, HUNTINGTONS, Myotonic Dystrophy, & Friedrich Ataxia
32
Restrn Fragment Length Polymorphism (RFLP)
- 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
33
VNTR variable number of tandem repeats
-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`
34
SNPs single nucleotide polymorphisms
use as polymorphic biomarkers & disease association
| -snp chips can detect 1000s of snps
35
haplotypes
- 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
36
epigenetics
non-mutational (no change in gene sequence) phenomenon that can affect gene expression and its inheritance
EX: X inactivation or Imprinting
37
Imprinting
differential expression of a gene allele depending on parental origin
-imprint=silence
EX: Prader Willi & angelman syndrome; IGF2 & cancer
38
Prader Willi Syndrome
On chromos 15, caused by deletion of SNORD116
-imprinted (silenced) maternally
-paternal (only active gene) gets deleted
=PW Syndrome
39
Angelman Syndrome
On chromos 15, caused by deletion of UBE3A
Paternally (silenced) imprinted
-maternal (only active gene) gets deleted
=AW syndrome
40
clinical cytogenics
study of chromosomes, their structure & inheritance, as applied to medical genetics
41
karyotyping
looking at all the chromosomes (physically, not sequence)
42
metacentric
central chromosome and = size arms
43
submetacentric
off-center centromere & diff size arms
44
acrocentric
centromere near 1 end
45
telocentric
only in mice, single arm
46
FISh
- molecular cytogenetics
| - multichromatic flourescent probes can target chromos, chromosome regions or genes
47
cytogenetics in cancer
BCR-AL= philadelphia chromosome in chronic myelogenous leukemia (CML) is a classic example
48
trisomy & monosomy
trisomy: usually lethal, Downs SYndrome trisomy of chromo 21
monosomy: usually lethal, X chromosome in Turner's Syndrome
49
Downs syndrome risk
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
50
Maternal Serum screening!
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]
51
genetic polymorphism
-1/300-1/100 bp diff between ppl
| EX: Rh system, Rh- (doesn't express) & Rh+(expresses specific cell surface protein)
52
alpha1-antitrypsin:
- has 5 alleles and if have ZZ you dont make enough protein =early onset emphysema
- example of eco-genetics
53
ecogenetics
genetic variation in susceptibility to environmetal agents
| EX: alpha1-AT, lactase deficiency , ALDH deficiency w/ alcohol, fair complexion w/ light, G6PD deficit & fava beans
54
heterozygous advantage
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
55
who is resistant to HIV
those with delta CCR5 variant
56
hardy weinberg
```
p^2+2pq+q^2
Assumptions:
-pop is large
-random matings
-allele frequencies remain constant : no mut., no (-) selexn, no genetic influx
```
57
what does HW disequilibrium indicate?
that a particular allele is associated w/ a disease
58
loss of fxn mutations
-arise from a variety of mutations; pt, delete, insert etc
| EX: B-globin, PAH (PKU), p53 (cancer)
59
gain of fxn mutations
-can arise from increased dosage or increased protein fxn
| EX: DOwn's, achondroplasia: increased axn of FGFR
60
novel properties?
EX: sickle cell disease: sickled Hb chains aggregate when deoxygenated
61
inappropriate expression
many examples in cancer; genes normally silenced are turned on
62
modifier genes
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
enzyme defects
EX: PAH gene in PKU where phenylalanine accumulate in body fluids & damages CNS
64
Super IMportant about PKU!
defect occurs in 1 tissue (liver & kidney) but where the phenotype is manifested deleteriously is elsewhere (brain)
65
lysosomal storage defects
EX: TAy SACHs--> buildup of GM2 (ganglioside sphingolipids)
66
defect in protein trafficking
-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
defect in co-factor metabolism
EX: alpha1-AT, involved in breakdown of various proteases that can damage lung tissue if not regulateed
68
defects in receptor proteins
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
defects in transport
EX: CF an autosomal recessive disease
| -mut. in CFTR [delta 508=3 bp deletion] eliminates phenylalanine that causes misfolding of proteins
70
Defects in structural proteins
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
mitochondrial DO's
-most often found in tissues w/ high demands
-only inheritted maternally
EX: Leber's hereditary optic neuropathy
72
multifactorial inheritance
like height, multiple factors/genes can play a role in phenotypes
73
4 characteristics of inheritance of complex diseases
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
Gene for intestinal cancer
Pta2g2a (in mouse)
75
physical mapping
actual sequence & location on chromos
76
genetic mapping
based on following a phenotypic trait in families
| -indicates relative position of genes by linkage analysis
77
linkage analysis
2 genetic loci are transmitted together from parent to offspring more then expected (>50%)
78
recombination frequency
liklihood of seperation
>50% = not linked
<50% =linked
RF 1%=1cM =2 MB of sequence
79
determining phases
specific alleles & markers on a chromos are "in phase" when coinherited from same parent
-need @ least 3 generations to determine
80
What is the best and most common mapping method?
linkage analysis (for single-trait genes)
81
SNP haplotypes helped map which monogenc disease gene?
EHlers-Danlos VIII
- involves collagen defect
- mapped to chromos 12, now narrowed to 7 cM on it
82
where was huntingtons disease gene mapped?
Lake MAracaibo, Venexzuela
1980s
Nancy Wexler
83
Association analysis
- 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
GWAs
?
| EX: complement factor H & risk for macular degeneration
85
mapping complex trait diseases
- most common method used is association analysis
| - can use Sib-pair as well
86
benzo[a]pyrene
- an aromatic polycyclic hydrocarbon and carcinogen
| - causes the formation of bulky DNA adducts that commonly result in A to G mutations.
87
what is calpain 10 (CAPN10)?
a type II diabetes gene (T2D)
| -1st T2D susceptibility gene
88
Oji-Cree and T2D relationship
- highest population % of T2D (40%)
- 1 mutant allele= 5x gr8r risk of T2D
- 2 mutant alleles=25x greater risk
- HNF-1alpha=homeodomain gene
89
3 most common cancers
1) prostate (men); breast (women)
2) lung
3) colorectal
90
neoplasia
disease process associated w/ uncontrolled cell proliferation leading to a mass or tumor
91
carcinoma
epithelial (intestine, breast, & lungs)
92
hematopoetic & lymphoid
leukemias & lymphomas
93
sarcomas
mesenchymal origin, bone, muscle, & CT
94
natural selection
- neoplastic cells evade cellular constraints on growth & proliferation
- acquired over time
- changes are selected for that confer a selective advantage
95
clonal evolution hypothesis
- 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
cancer stem cell hypothesis
growth & progression of many cancers are driven by small subpoplations
97
cancer stem cells
CSCs-lead to proliferation of cell population
98
familial cancers
- several close relatives w/ common cancers
- several close relatives w/ (related cancers)
- etc (inherited)
99
oncogenes
- abnormal stimulation of cell division & proliferation
- dysregulated version of endogenous genes
- turn "on" a stimulatory pathway
100
proto-oncogene
converted into an oncogene
- regulatory mutation
- gene amplification
- chromosome rearrangement
101
tumor suppressor genes
p53, RB1, BRCA1 or 2
102
LOH
| loss of heterozygosity
- many cancers result from loss of fxn of 1 allele
| - loss of 2nd wildtype allele is called LOH
103
Microinstability (MIN)
arises most often from defects in mismatch repair (MMR) or nuclear excision repair (NER)
-chromosomal instability (CIN)
104
burkitts lymphoma
caused by chromosomal translocation
| -affects MYC proto-oncogene
105
Chronic myelogenous leukemia
- chromosomal translocation b/w chromos 9 & 22
| - causes proto-oncogene BCR-ABL to be affected
106
what is MLH1 mutation an example of?
mismatch repair defect & MIN
107
colorectal cancer
APC mutation in CRC (a TSG)
108
Familial Adenomatous Polyposis (FAP)
inherited form of CRC
- families carry a mutant copy of APC
- CRC requires at least 6-10 genetic mut's & epigenetic events
109
name the oncogenes and TSG's associated with colorectal cancer
K-Ras & B-catenin (oncogenes)
| Apc, p53, TGFbeta recepto, Smad4, * MLH1
110
What is the primary role of APC in prevention of colorectal cancer?
helps control B-catenin (oncogene in Wnt signalling) levels via degradation
111
lumping & splitting
b4 genetic etiologies traditionally have been lumped together
-new technology permits "splitting"
112
diffuse large B-cell lymphoma (DLBCL)
- most common form of noon-Hodgkins lymphoma
| - made up of 2 diff cancers: germinal center B-cell DLBCL & activated B-cell like DCBCL
113
germinal center B-cell DLBCL
patients w/ cancers that responded to chemo
114
activated B-cell like DLBCL
pt's that failed chemo & had poor survival
115
next generation sequencing (NGS)
perform whole genome, whole exome, whole transcriptome & whole epigenome sequencing w/in single day for cheap
-electronic medical record
116
3 complications in treating monogenic DO's
- gene may not b identified
- fetal damage
- most severe clinical phenotypes are less amenable to intervention
117
allelic heterogeneity
- diff mutant alleles of same gene give rise to diff disease phenotypes
- PKU is an example
118
locus heterogeneity
hyperphenylalaninemia: can be caused by defects in PAH or biopterin metabolism enzymes
119
Gaucher's disease
- most prevalent lysosomal storage disease
- ashkenazi jews
- autosomal recessive deficiency in enzyme that degrades glucocerebrosidase (get build up)
- TX: protein targetting or BMT
120
hematopoetic stem cell transplantation (HSC)
effective TX for SCID, thalassemias etc
| -cord blood transplants can happen too
121
gene therapy
modify cells to produce a therapeutic effect
- compensate for LOH
- replace a dominant mutant gene
- pharmacological effect
122
target cell
- long lived cell: stem cell
| - bone marrow is only regularly used
123
ex vivo gene therapy
- 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
in vivo gene therapy
direct injection into the body using a vector
- quick & easy;
- disadvantages: many including targeting proper cells, immune responses, safety
125
retrovirus (vector)
- RNA
- enveloped
- only acts on dividing cells
- most have permanent expression/persistent gene transfer
- can enter virtually all target cells
- retroviral ex: HIV
126
lentivirus (vector)
- RNA
- enveloped
- acts broadly
- integration might induce oncogenesis in some applications
- persistent gene transfers in most tissues
127
AAV (adeno-associated vector)
-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
adenovirus (vector)
- dsDNA
- broad action
- non-enveloped
- no mutations: failure due to strong immune respose
- cant integrate into host genome
129
herpes virus (vector)
-CNS tropism
- (+) can package large genes
(-) strong inflammation/immune response
130
non-viral vectors
(+) lack biological risks
(-) havent been very successful
EX) naked DNA, liposomes, protein-DNA conjugates, artifical chromosomes, & nanoparticles
131
siRNAs gene therapy
- can b designed to target a range of tissues
| - lots of knockdowns
132
hemophilia B
- factor IX replacement (FIX)
- liver specific
- AAV2, AAV9 vectors
- watch liver for problems
133
FIX
- expressed in hemophilia B
| - helps?
134
Lysosomal storage diseases (LSDs)
- recessive diseases
| - caused by mutations in genes involved in lysosomal degradation
135
Parkinson disease
main CNS application for gene therapy
136
leber congenital amaurosis
- early onset photoreceptor degeneration
- 10 diff mutations cause this
- RPE65 is gene targetted (involved in retinoic acid metabolism of retina
- trials of AAV2
137
risks for gene therapy
- 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
X-SCID "bubble babies"
- kids born w/o immune response (IR)
- kids had complete rescue of IR
- some developed leukemia (from LMO2 gene inserts)
- b cell lymphoma
139
what have lentiviral hematopoetic SC gene therapies been used for lately?
- new therapies
- metachromatic leukodystrophy (MLD) is a lysosomal storage disease
- helped reduce symptoms
140
Wiskott-Aldrich Syndrome
SC therapy
- immunodeficiency caused by mutations in WASP protein
- using lentivirus vectors--> helped a lot
141
embryonic stem cells
toti/pluripotent
- isolated to inner mass of blastocyst
- capable of unlimited replication in cell culture
- can cause cancer sometimes & ethical dilemmas
142
somatic stem cells
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
reprogramming somatic cells into pluripotent stem cells
- 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
What is xeroderma pigmentosum
Skin cancer w/ uv sensitivity and neurological abnormalities
Caused by defective nucleotide excision repair process
145
Ataxia telangiectasia
Causes leukemia, lymphoma, yray sensitivity, genome instability
Defective ATM protein kinase that fixes double strand breaks
146
Werner syndrome
Premature aging, cancer at several sites, genome instability
Defect in accessory 3' expo nuclease and DNA helicase
147
Benzo[a]pyrene affects
Aromatic polycyclic hydrocarbon and carcinogen from cigs
Cause bulky adducts
Cause g to a transition mutations!!!!
Commonly attacks p53
