Exam 5 ALL Flashcards
(251 cards)
1
Q
Autosomal Recessive disorders
A
1) PKU - defective enzyme
2) Cystic fibrosis - defective transporter
2
Q
Autosomal dominant disorders
A
1) Nuerofibromatosis - penetrance and expressivity
2) Huntington Disease - late onset and anticipation
3) Achondrioplasia - importance of new mutations
4) osteogenesis imperfecta - dominant negative effect
5) familial hypercholesterolemia - haploinsufficiency
6) Li-Fraumeni syndrome - two hit model
3
Q
Achondroplasia
A
AD - dwarfism - defect in bone growth (gain of function, receptor always on, dominant negative effect (always on receptor) that inhibits chondrocyte proliferation) bc tyrosine kinase receptor gene (FGFR3) is mutated - used for growth signaling. low fitness individuals but disease remains in pop due to new mutation at mutation hotspots (CG repeats - cytosine methlated and then spontaneously deaminated to thymine)
4
Q
Cystic fibrosis
A
AR - defective chloride channel CSTR - difficult protein to fold and glycosylate - found in organs the make use of secretions
1/2000 - sweat chloride test used to check.
pulmonary problems (thick mucous =bacterial inf) and pancreatic malfunction (secretions are to thick to move and get into sm intestines).
Treat: chest percussion, antibiotics, and bronchodialators. pancreatic enzyme replacement. lung transplant
5
Q
duchenne and becker muscular dystrophy
A
XR - (1/3000 male births) Defect in dystrophin (connects plasma membrane& ECM to muscular fibers and without it the plasma membrane sort of falls apart. dystrophon gene is large so targeted for new mututations. wheelchair bound by age 12 - do not reach reproduction age
6
Q
ehlers-danlos syndrome
A
AR - collagen disorder bc enzymes required for collagen processing are mutated
AD - mutations in collagen genes - dominant negative effect
7
Q
familial hypercholesteremia
A
AD - defective LDL receptor - (1/500) - defects in the LDL receptor. not enough ldl receptors to clear ldl from serum. (haploinsufficiency) xanthomas of hands and feet (fat accumulation growths).
8
Q
fructose 1,6 bisphosphatase deficiency
A
AR - fasting hypoglycemia
9
Q
glucose 6-phosphate dehydrogenase deficiency
A
XR - sensitivity to H2O2 generating agents and fava beans
10
Q
glycogen storage disease
A
AR- hypoglycemia, accumulation of glycogen
11
Q
huntington disease
A
AD - 5/100000 - dimentia and uncontrolled movement of limbs - onset at around age 40. neurological disorder results from gain of function mutation in CAG triplet expansion. Normal repeat of CAG region is 9-35. Anywhere over 40 will get HD-full penetrance. 35 (reduced penetrance) are said to have premutation (offspring most likely to get more CAG repeats and HD - anticipation = waiting to see if CAG expands and if will get disease).
12
Q
Leber’s hereditary optic neuropathy
A
Mito - defect on mitochondrial DNA - (1/50000) - mutation in ND1 gene - its product is part of ETC - rapid deterioration of optic nerve and blindness soon after
13
Q
osteogenesis imperfecta
A
AD - defective type I collagen bc of mutations in genes (1/10000). skeleton deformity and bone breakage.
type I - null mutations in Pro-alpa1 chain so production of 1/4 chains but still making some good protein - haploinsufficiency
types II, III, IV - distortion of 1/4 protein so 3/4 collage assemblies will be non-functional=dominant negative effect
14
Q
Phenylketonuria
A
AR - defect in tyrosine metabolism leads to the accumulation of Phe in body fluids - damages brain and nerves.
1/2900 live births. Infants have musty odor
Treat: Phe free diet prevents mental retardation
15
Q
sickle cell anemia
A
AR - Hemolysis
16
Q
sucrase-isomaltase deficiency
A
AR - sucrose/glucose polymer intolerance
17
Q
Neurofibromatosis
A
AD - multiple tumors - complete penetrance and variable expressivity = everyone gets cancer but how many different types of cancer varies - NF-1 gene protein promotes GTP-ase activity of Ras - if not present Ras is constituitively on = cancer.
1/3500 - mult benign tumors on skin, pigmented skin lesions (cafe au lait spots), benign tumors on iris, tumors on nerve cells= mental retardation
18
Q
Recessive inheritance- affects & explanation:
A
- enzymes
- proteins involved in transport and storage
-if heterozygous for recessive - you can make up for lost protein with other functional allele
19
Q
dominant inheritance- affects & explanation
A
- structural proteins
- proteins involved in growth, differentiation, and development
- receptor and signaling proteins
- haploinsufficiency
- dominant negative effect
- gain of function mutation
- lack of back up
20
Q
haploinsufficiency
A
half of gene dosage may not be sufficient for cell to carry out its function. Ex) good and bad collagen forming proteins come together and the whole protein falls apart thing
21
Q
dominant negative effect
A
- competition with normal protein
- deformed protein incorporated into larger structure causes instability
22
Q
gain of function mutation
A
evolution - new function may have advantage and effect will be seen regardless of normal protein concentration. ex) signal transduction proteins-mutation may turn signaling receptor constituitively ON
23
Q
lack of back up
A
two-hit model. inactivation of both alleles esp with cell cycle control proteins ex) Rb
24
Q
sex chromosomes
A
Males - hemizygous - XY - Y has sex determining region of Y (SDY) that determines sex
Females - XX - but one is inactivated at random = mosaicism
25
compound heterozygote
recessive disease in which the two recessive alleles are NOT identical due to different mutations
26
pseudoautosomal region of Y
part of Y chromosome that is similar to X for aligning with X during meiosis
27
recurrence risk
parents want to know what the probability is of having another child with said risk. Each childs risk is independent of previous children
28
characteristics of AR disease pedigree
- affected children have normal parents
- both sexes equally affected
- consanguinity is often present
29
coefficient of inbreeding
describes the degree of homozygosity. the smaller the number the more distant the relationship
30
sweat chloride test
Tests NaCl content in sweat of infant - tests for cystic fibrosis - 2-5x greater NaCl concentration in cystic fibrosis - can be done 48 hrs after delivery
31
characteristics of AD pedigree
- affected child has at least one affected parent
- both sexes affected equally
- disease CAN be transmitted from father to son
- if LOW penetrance then disease may skip generations
- IF Huntington Disease - premutations may result in affected child WITHOUT affected parent
32
penetrance
the degree to which a disease genotype develops disease symptoms - incomplete, complete or inbetween. Can lead to skipping of generations in pedigrees for AD disorders
33
expressivity
describes how strong a disease phenotype shows - low, med, high
34
allele heterogeneity
one gene at one particular spot (locus) on a chromosome. different mutations show the same phenotype - gain or loss of function
35
modifier genes
the individual genetic background modifies the phenotype - ALL CHANCE - dont always show phenotype = penetrance
36
premutation
Huntington disease example situation where parents may have 35 CAG triplet repeats (reduced penetrance) and be ok but child may get more than 35 (40+ =complete penetrance) and get HD because of more CAG repeat additions to the sequence during meiosis
37
anticipation
huntington disease example situation - repeats and severity increase with each generation
38
mutation hotspot
where mutations often occur - usually at CG repeats cytosine methylated and spontaneously deaminated to thymine - ex with achondroplasia
39
new mutation
explains for prevalence of genetic diseases that have reduced fitness. You'd think that the disease would kill itself off but bc of new mutations it persists in the population ex w/ achondroplasia
40
Rb is example of what inheritance type?
two-hit model with RB1 gene protein Rb - leads to cancers - E2F free to stimulate cell cycle
41
X-linked recessive pedigree characteristics
- skips generations
- more males affected than females
- no father to son transmission
- affected boys usually have unaffected parents
- skips generations via female carrier
42
x-linked dominant pedigree characteristics
- no father to son transmission
- daughters of affect father have condition
- females affected more frequently than males
- often lethal in males
43
RET gene
important signaling molecule for development - needs to be OFF when not signaled and ON when signaled. haploinsufficiency will cause upset development
- gain of function mutation = RET is always ON (Multiple endocrine neoplasia - proliferation of neuroendocrine cells)
- loss of function mutation = RET can't respond to stimulus (Hirschsprung disease - impairs dev of neurons that populate colon)
BOTH issues are dominant mutations and a decline in RET activity will ALWAYS upset development = haploinsufficiency
44
mitochondrial DNA
- only from mother
- affected males do not pass disease
- mitochon DNA mutates 10x faster than nuclear DNA
- multiple copies (1000s) of mitochon DNA = affected indiv have varying levels of mutated copies = heteroplasmy
45
heteroplasmy
refers to mitochondrial DNA - many copies - varying levels of mutated mitoch DNA show up in patients
46
Determining mode of inheritance:
1) Mitochondial? Y/N
2) IF N: Is there father to son transmission? Y/N
3a) IF Y: Autosomal: Do affected children have affected parents/grandparents? Y=A.DOMINANT/N=A.RECESSIVE
3b) IF N: X-linked: Are boys more freq affected than girls? Y=X-RECESSIVE/N=X-DOMINANT
47
null mutation
mutation that destroys the protein
48
life-time risk for single gene disease?
2% - single gene diseases = one or two mutant alleles present
49
Edward syndrome
Chromosome 18 trisomy
50
Patau syndrome
Chromosome 13 trisomy
51
Down syndrome
Chromosome 21 trisomy
52
Sex chromosome monosomy
X - Turner syndrome
53
Sex chromosome trisomy
XXY (male) - Kleinfelter syndrome
54
Sources of structural chromosomal alterations?
1) shoddy repair of DNA - end of DNA without telomere is found prepped (may lose some nucleotides) and ligated - usually after DNA-ases have already begun to degrade some of the DNA.
2) non-homologous recombination - usually between similar sequenced chromosomes. X and Y may cross over too (pseudoautosomal region of Y)
55
Cri-du-chat
Del5p (p=short) - Cat's cry syndrome - microcephaly, hypertelorism (wide-set eyes), micrognathia (small jaw), severe mental retardation, heart defects. New mutation disease since children with dont usually survive
56
Di-George Syndrome
del22q (q-long arm) - usually a new mutation - congenital heart defects, immunodeficiency, hypoparathyroidism, mental retardation, cleft palate
57
deleteions
lose some part of a chromosome or non-homologous cross-over - results in haploidy or partial monosomy - affects multiple organ systems.
58
duplications
relocation of part of a chromosome to another = partial trisomy
59
Philadelphia Chromosome
part of 9 to 22. BCR and ABL combined - constituitively on tyrosine kinase receptor = chronic myelogenous leukemia
60
Robertsonian translocation
the long and short arms of two chromosome are exchanged - the chromosome that had a short arm and got the short arm usually gets lost in cell division. loss results in 3 chromosome trying to line up in meisosis - results in balance or unbalanced separation
61
inversions
invert two loci on a chromosome (ABCD to ACBD). causes issues during meiosis when chromosomes try to line up - looping occurs to match up and recomb results in a chrosomsome without centromeres and a chromosome with 2 centromeres
62
frequency of chromosomal aberations @ conception and birth
0.5% of pregnancies and 0.2% of live irths
63
percent of perfectly normal zygotes lost spontaneously?
15%
64
Inheritance of chromosomal aberration pedigree
many children show up dead (diamonds)
65
karyotype procedure
draw blood and isolate WBC. arrest them in mietosis. stain stuff up
66
% of pregnancies with abn chromosomes and how many of this 1% dies spontaneously?
just under 1% and 94% of the 1% do not make it
67
trisomy 21 survival rate
22% survive
68
sex trisomy survival rate:
79% survive (barr bodies - X inactivation)
69
balanced rearrangement survival rate
84% survive (issue is with their kids of these patient's who may not get complete set of genes)
70
why do cytogenics (karyotyping)?
1) problems of early growth/development
2) stillbirth/neonatal death
3) fertility problems
4) pregnancy with advanced maternal age
71
epigenetics
study of gene expression that does not involve changes in DNA sequence (methylation on cysteine and acetylation on histones-lysine)
72
heterochromatin
tightly compact - lots of methylation and little acetylation
73
euchromatin
not compacted - less methylated and a lot acetylated
74
CpG islands
Methylation on cytosine residue - silences DNA
1) if upstream from genes CpG islands mostly un-methylated.
2) if in repetitive DNA - mostly methylated.
75
hypomethylation
unwanted genes are not silence because nothing is methylated
76
de-novo methylation
introduced methalation onto unmethylated strand by denovo DNA methyltransferases (DNMT3a and b)
77
maintenance methylation
pattern of DNA methylation is copied to the new strand after S-phase of cell cycle (DNMT1)
78
acetylation
HATS used (can also modify by Ub, phosphorylation, and methylation)
79
methylation of histones
1) deacetylated histones are methylated
2) methylated histones bind to HP1 proteins (READ THE CODE)
3) HP1 proteins bind histone methylases (WRITE THE CODE) - methyaltion spreads until a boundary element is reached
80
imprinting timing and effects
DNA silencing that marks the maternal or paternal chromosome. Marks some genes inactive and other active -transcriptional control. During meiosis imprinting is re-done to have chromosomes resemble maternal (if female) or paternal (if male).
81
parent of origin effect diseases
Prader-Willi Syndrome- deletion on paternal chromosome 15 = excessive food seeking behavior, hypogonadism, mental retardation
Angelman syndrome- deletion on maternal chromosome 15 = unusual facial features, seizures, movement and gait disorders, & mental retardation
82
uniparental disomy
a triploid zygote loses a chromosome from the parents who only gave one. Now the child is diploid but for only maternal or paternally imprinted homologues. effects gene dosage since you may have lack of one or the other gene or the same imprinting on each which results in double of on gene product (Beck Wiedemann Syndrome - chromosome 11 from father times two.)
83
epigenetics and cancer
CAUSE GENOMIC INSTABILITY: hypermethylation - cant transcribe genes that we can to control the cell cycle
hypomethylation - we are transcribing genes that we dont want that are pushing cell cycle forward
84
5-azacytidine treatment
DNA methyltransferase (DNMT) inhibitor. Causes hypomythylation of the genome to counteract malignancies associated with hypermethylation
85
boundary elements
chromatin barrier that prevents spreading of methylation inactivation
86
methylcytosine binding proteins (MBPs)
join the party after DNA methyltransferases add the methylation. MBPs interact with repressors of transcription and histone deacetylases (HDACs) -- tighten up DNA.
87
obstacle to cloning
hard to copy the imprinting when doing invitro - skipping meiosis and fertilization - organism will have developmental problems
88
X-chromosome inactivating center (XIC)
each X has this region - transcription of the inactive x specific transcript - XIST gene in XIC on the chromosome to be inactivated. RNA made then mediates the inactivation.
89
regulative development
cells are functionally equivalent and the loss of a cell will not matter
90
mosaic development
Once primivite streak is formed: cells are NOT functionally equivalent and the loss of a cell will lead to a loss of some tissue
91
pre-implantation diagnosis
in regulative development - a cell can be removed from the morula and examined for chromosomes and the remaining 15 cells will develop into a normal embryo.
92
first visible axis in emryo
the primitive grove - anterior posterior IE HEAD AND BUTT - (NOT LIKE IN ANATOMICAL TERMS FRONT AND BACK SIDE)
93
function of the node:
- the node is required for the formation of the primitive streak - gene "nodal" makes nodal protein that diffuses and forms gradient for the formation of the primitive streak
- nodal cells also secrete noggin and chordin for formation of dorsal ventral axis (top/bottom axis)
- left sided expression of nodal- initiates the left-looping of the heart tube
(Left-right symmetry is done by Sonic hedgehog - from the notochord - important for organ placement and cardiovascular system)
94
three germ layers:
ectoderm: skin and nervous system
mesoderm: bone muscle and most internal organs
endoderm: cells of gut and lung epithelium
95
patterning=
after axes ave been assigned - patterning determines which parts become head, thorax, abdomen...etc.
Anterior/posterior = Homeobox genes (HOX)
96
Homeobox (HOX)
family of transcription factors that activate DNA - follows down chromosome. Signal for cell fate in patterning
- small# HOX= early - Hox-a for proximal distal, Hox-d for anterior posterior.
- large # HOX= late - tail/distal
depending on the hox gene activated determines cell fate.
97
Five processes that drive development
1) gene regulation
2) cell-cell signaling
3) dev of a cell shape and polarity
4) movement and migration of cells
5) Programmed cell death
98
malformation:
results from an intrinsic abnormality in the development process- EX) HOX gene mutation results in an extra finger
99
deformation:
results from an extrinsic influence on development- forms well but then respondes to extrinsic influence EX) lack of amniotic fluid so lungs couldnt expand
100
disruption
results from the destruction of developing tissue - forms well but then gets destroyed by second extrinsic factor - EX) amniotic band wraps around hand and kills it by cuting blood supply
101
syndromes:
ONLY APPLIES TO CASES WITH MULT DEFORMATIONS: caused by a single defect that simultaneously affects the development of different tissues - EX: DOWN
102
sequences
ONLY APPLIES TO CASES WITH MULT DEFORMATIONS: caused by a single defect that starts a cascade of events- EX: Pierre Robin sequence - lack of space in utero = face doesnt have room so get cleft lip and palatebc tongue is squished due to mandible not having enough room
103
First 1-4 week problems:
(blastogenesis) multiple major abnormalities in entire embryonic regions
104
Weeks 5-8 problems:
(organogenesis) abnormalities in specific organs, single major abnormality
105
Week 9+ problems:
(after organ formation) mild effects
106
axes in the developing limb:
shoulder to fingertip = proximal-distal
thumb to fifth finger = anterior-posterior
dorsum to palm = dorsal-ventral
107
anterior posterior axis
head-butt
108
dorsal ventral axis
back-front
109
noggin & chordin
secreted by nodal and induces dorsal-ventral development
110
blastocyst
hollow sphere containing inner and outer cell mass
111
cinical dysmorpology
study of birth defects and how they came to be
112
period of emryonal development
after the egg is fertilized this stage begins with 4 cell divisions without growth
113
epiblast
formed from the inner cell mass - around the time of implantation - day 7-12 - epiblast will = the emryo
114
gastrulation
process that forms the three germ layers -
115
homeodomain
special DNA binding domain on HOX transcription factors
116
isolated anomalies
affect a single boy region during development-sporadic or mulifactorial in origin. 60% of defects are this
117
major anomalies
anomalies with surgical or cosmetic consequences - large impact on well-being of patient
118
minor anomalies
anomalies with little impact on well-being of the patient
119
morula
solid ball of 16 cells - no size change
120
polydactyly
result of malformation
121
Robin's Sequence
a sequence that causes a sequence ofevents (ha). spacial constraint on jaw = tongue squished = cleft palate and lip
122
situs invertus
due to Shh issue = organs are all in mirrored location
123
situs ambiguous
due to Shh issue = organ location is randomized
124
time of implantation
7-12 days
125
Treacher Collins Syndrome
small jaw, downslanting eyes and malar hypoplasia -AD
126
VACTERL association
```
Brith defects that occur together for unknown reasons:
V-Vertebral defects
A-anal atresia
C-cardiac issue
T& E- Traceho-esophageal fistula
R - Renal abn
L - Limb abn
```
127
five cellular processes that constitute development:
1) transcriptional regulation
2) morphogen and cell to cell signaling
3) changes in cell shape and organization
4) cell migration
5) programmed cell death
128
5 most common birth defects:
1) heart (1/100-1/200)
2) pyloric stenosis (1/300)
3) neural tube defects (1/1000)
4) orofacial clefts (1/700-1/1000)
5) clubfoot (1/1000)
129
5 most identifiable causes for genetic defects
50% of cases cause is unk- in the rest where known:
50% complex inheritance - combo of 3-4 factors
25% chromosomal defects
20% single gene mutations
5% non-genetic cause ie smoking or drinking, maternal infections...
130
% children born with defect
2-3%
131
% birth defects account for infant death:
20% ( 40% if premature birth is included)
132
robustness
a mutation does not mean that you will 100% get the disease... it only increases the risk of something going wrong. The environment is the deciding factor
133
general transcription factors:
your regular hodgpodge of transcription factors used anytime needed
134
specific factors
activated in a certain cell at a certain time
135
morphogens
EX is SHH - morphogens are secreted by cells to signal to nearby cells their relative position - forms morphogen gradient and cells will determine their developmental programing based on the concentration of morphogen around them
136
HOX transcription factors
tells cells where they are anterior-posterior
137
two functions of Shh morphogen
development of brain and spinal chord and development of posterior limb elements
138
what does shh need for correct functioning?
needs to be post translationally mod-ed with cholesterol
139
shape and orientation of a cell is determined by
(polarizing secretion) the environment! Ex) kidney tubule responds to detection of a fluid stream
140
development of cerebral cortex
neural tube cells on ventricular side divide and generate neuronal precursor cells which migrate outward. Migration occurs in waves gonig past previous waves.connections are made once the cell waves are done and cells are in order
141
five developmental processes that need programmed cell death
- development of heart
- development of individual digits
- perforation of anal and choanal membranes
- connection bw vagina and uterus
- development of immune system
142
hermaphrodites
both testes and ovaries
143
pseudohermaphrodites
have either testes or ovaries but it doesnt match genetic sex
144
development of embryo into male
Y chromosome has sex determining region of Y (SRY) that has a gene - testes determining factor (TDF) that stimulates formation of testes. Testes produce androgens which form male external genetalia
NO Y= is default to ovaries forming and female genetalia
145
female pseudohermaphroditism
pathway that makes cortisol from cholsterol is broken and so cholesterol is diverted into androgen forming pathway = male genetalia but female genetic sex
146
male pseudohermaphroditism
mutation on SRY means no TDF
OR
mutation in androgen synthesis pathway so cant make adrogens
= = automatic default to female external genetalia but male genetic sex
147
epigenetics on development
cell lineages develop to have stable pattern of gene expression = permanent and irreversible!
148
tumor progenitor cell model
1) tumor prog cells arise during development due to epigenetic changes and the action of tumor progenitor genes (TPG)
2) a gatekeeper mutation (GKM) in a tumor suppressor gene (TSM) or oncogene (ONC) generate a benign tumor
3) Epigenetic and genetic plasticity help evolve the benign tumor into a metastatic, invasic, and drug resistant tumor
149
apoptosis in dev of immune system
whole bunch of t-cells make a whole bunch of antibodies for everythnig - even self - cells that react are destroyed.
150
congenital adrenal hyperplasia
leads to pseudohermaphroditism in females - blocks formation of cholesterol to cortisol due to mutation in enzyme so cortisol is made into androgens
151
formin and renal aplasia
experiment with mice that showed robustness exists
152
LIS1 disorder
if there is a muation in LIS1 gene the migration of neuronal precursor cells is screwed up = smooth cerebral cortex (lissencephaly) = mental retardation
153
lissencephaly
smooth looking cerebral cortex
154
polycystic kidney disease
kidney cells do not get orientation shape signal from flow due to mutation in polycystin gene receptor product so they keep growing into a cyst
155
segmental overgrowth
just one cell in a segment divides once too much and you get a larger body bad at that segment
156
smith-Lemli-Optiz Syndrome -
defect in cholsterol synthesis so Shh cannot be properly mod-ed = midline defects
157
statins and birth defects
statins are cholsterol lowering drugs - less cholsterol interferes with Shh = midline defects in child
158
transcriptional regulatory modules
transcriptional factors that are expressed together for the same purpose form this
159
polymorphisms
an allele that is present in more than 1% of the population - allele is just different - not necessarily good or bad
high polymorphism = everyone has different sequence = diversity
low polymorphism = everyone has the same - conserved sequence
160
Hardy Weinberg equations
p^2+2pq+q^2 = 1
p+q=1
If x-linked allele freq=(affected males/total males)
161
genetic drift
people entering or leaving population can remove or add allele to the mix without any specific selection for or against that allele - disappearance or amplification of rare alleles
162
assortative mating
similar individuals tend to mate (not random) and therefore homozygosity is the population.more homozygous pople = more homozygous diseases
163
founder effect/population bottleneck
community begins from a few people/wcommunity wiped out and a few remain and all people are descendants of these founders --> leads to amplification of rare alleles
164
heterozygote advantage
CFTR helps with typhoid fever
B-globin helps with malaria
HFE helps with plague
165
diseases that are in genetically isolated populations:
Ellis van Creveld Syndrome - Amish
Tay_sachs Disease - Jewish
Tyrosinemia - French Canadians
166
linkage disequilibrium
two close markers are associated much more frequently than expected by chance - not enough meiosis events to separate the linkage markers which are close enough together - overtime they will separate
YOUNG POPULATION with HIGH LINKAGE DISEQUILIBRIUM
167
genome wide association studies
compare single nucleotide polymorphism (SNPs) in patients and controls to calculate odds ratio for each SNP - this will show the link between the polymorphism and the disease genotype.
1) find SNPs that are strongly associated with a disease
2) plot relevant chromosome of people and where ever that graph peaks shows that all the people have that same SNP
168
estimating the number of genes involved in the inheritance of a quantitative trait
Bell curve
The more genes that are involved = lower probability of an offspring inheriting all or none of the contributing alleles
The higher the number of genes involved, the lower the fraction of extreme phenotypes at the fringes of the bell curve
169
concordance rate
study of a trait shared by twins
170
liability distribution
distribution of multifactorial diseases shown by a bell curve
171
threshold of liability
can only get the disease if you cross the threshold
172
same environment
proves strong environmental conditions at play
173
different environment
proves strong genetic components at play for disease
174
model free linkage analysis
for the mapping of complex traits with an unknown number of contributing alleles. use SNP markers in affected families and see which markers are connected to disease
175
incidence
(how many new cases are recorded in a given time)/(size of population)
176
prevelance
proportion of the population that is affected by the disease at any given time
177
empirical risks
doctors can provide this to families who want to know risks regarding complex diseases. includes incidence and prevalence
178
relative risk ratio (lamda) of sibblings parents or general relatives
=(prevalence of disease in relative of affected person)/(prevalence in general population)
describes the likelihood of the pt getting the disease if has sibling/rel/parents with compared to not having the disease
179
recurrence risk for multifac diseases changes why?
Changes because each time a family member is affected with the disease you can assume the number of contributing alleles in the parent generation is higher than expected -- risk goes up
180
pedigrees of multifactorial diseases
pretty much look like AD with incomplete penetrance.
- do not follow mendelian
- familial aggregation=higher # alleles in affected families
- show incomplete penetrance due to environmental factors (ex-MZ twins)
- disease is much more common among close relatives of the proband
181
pyloric stenosis
narrowing of exit from stomach into sm intestines - more common in boys than in girls so if a GIRL in the family ends up having the disease then more likely for the boy to get - assumed to be more affected alleles in the population
182
prevalence for multifactorial diseases: general population:
0.5%
183
prevalence for multifactorial diseases: second degree relative affected
0.7-2%
184
prevalence for multifactorial diseases: first degree relative affected:
3-4%
185
prevalence for multifactorial diseases: two first degree relatives affected:
5-8%
186
prevalence for multifactorial diseases: three first degree relatives affected:
9-12%
187
prevalence for multifactorial diseases: identical twins:
20-30%
188
determining genetic and environmental factors of multifactorial diseases
adopted studies and MZ and DZ twins.
If concordance (share the same trait) is higher in MZ than in DZ then train has a strong genetic component
189
RR of 1.5 for an allele means?
patient is a carrier of allele so your risk is 1.5x the risk for a non-carrier
190
relative risk
describes the diseases association of an allele - how much more likely a carrier of an allele is to develop the disease than a non-carrier
191
haplotypes
transmission of a particular region as a unit - ex MHC region regarding HLA transferred as a unit. expressed in a codominant manner - both genotypes expressed
each parent transmits one haplotype to the children
192
susceptibility alleles/protective alleles
alleles that increaseor decrease the risk of diease - EX) DR-DQ haplotypes may increase or decrease getting T1D
193
human leukocyte antigens
class 1 and 2 genes that play a role in the initiation of immune response - important for organ transplant matching. inherrited together - haplotypes. variation in this region account for 40% of genetic risk for diabetes (Specific DR-DQ haplotypes - can be protect or be more susceptible to disease)
194
HLA-B
haplotypes that determine risk in spondyloarthropathy
195
HLA-C
can predict risk for psoriatic arthritis
196
direct sequencing
know where the disease causing mutation is so you test for it - only works when you know the precise mutation location and since genes can be so large it may be hard to find or it could just be a SNP
197
indirect sequencing
need to know the genomic locus of mutant allele and you follow the inheritance of a polymorphic marker linked to that mutant allele- BUT good polymorphic markers are hard to find and if the distance between the marker and mutant allele is high then recomb is more likely making your prediction less accurate
198
Whole genome sequencing
a huge technical challenge for sequencing because the complete human genome consists of 3 billion bps, therefore it is impractical for clinical practice
199
Whole exome sequencing
just sequencing the part of the genome that is expressed approx 3% of genome
200
SNP typing
just sequencing the parts of the genome that vary with SNPs related to the disease
201
limits of DNA sequencing
- sequencing will not show which chromosome the heterozygous or momzygous mutation is on
- cant deduce if SNPs are linked
- will not show deletions or duplications
202
PCR and uses
- used to amplify DNA fragments 94, 60, 72 repeat.
- mutations can be detected with primers that exclusively bind to mutant or wildtype alleles (allele specific oligonucleotides - ASO)
- inversions or deletions become obvious bc of variation in length of amplified fragment (Amplification length polymorphism)
203
real-time PCR
meausres nucleotide usage each cycle so you can measure the amount of amplified DNA - can tell you how much template you started with if you plot. More cycles to reach threshold=less template that you started with
204
reverse transcriptase PCR
detects and quantifies RNA - product is copy (c) DNA- cDNA
- detects viruses (HIV)
- expression of oncogenes and tumor suppressor genes in cancer cells
205
ASO arrays
ASSESES GENOTYPE detect SNPs and can be used to detect mutant alleles. need to know details about the nucleotide sequence of the gene under study.
amplify PT DNA and label with marker. Then on a slide bind mutant and wildtype - can detect homocygosity if one or the other fluoresces or heterozygosity if both mutant and wild fluorese
206
DNA microarrays
a slide with a bajillion test sequences on it and you test patient DNA (w/marker) against it.
207
genome arrays
Can test for differences in gene expression by separating cancer cell RNA and normal cell RNA. Reverse transcriptase - make cDNA and label reg and cancer cDNA. put on chip full of oligonucleotides - where it hybridizes tells you what is present
208
pharmacogenomics
research to correlate an individual drug response to a certain genotype - adverse reactions in some patients and not others is due to polymorphisms - works towards figuring out an individual drug treatment plan based on genotype.
209
prenatal diagnosis
amnioxentesis and chorionic vilus sampling
210
amniocentesis
amniotic fluid taken 15/16 weeks which contains fetal cells
211
chorionic vilus sampling
cells are taken from the chorion@ 10/12 weeks - extraembryonic in origin - may miss mosicism
212
direct to consumer genetic testing
Good: can know if you or children have risk for relatively cheap
Bad: knowing could be bad. counseling is not always available. access to genetic information (insurance issues)
213
Copy number variation (CNV)
describes the observation that chromosomal regions can be present in the non-diploid states - most are benign but some cause medelian or chromosomal disorders. Can detect with comparative genome hybridzation and fluorescence in situ hybridization
214
comparitive genome hybridization (CGH):
samples of single stranded DNA from pt and a control and label with fluorescent dye. Mix with chromsomes in metaphase. looking for uneven labeling of chromosome=
-if hybridized to oligonucleotides of a chromosome region you can determine dup or del of DNA
215
fluorescent in situ hybridization
allow for the identification of the number of chromosomal locus on a metaphase chromosomal locus on a metaphase chromosone by hybridiz with a fluor probe
216
polyclonal antibodies
obtained by challenging animal with intravenously injected antigen, after several days withdraw blood that will have mixture of antibodies against different epitopes of antigen, and then examine the quality and specificity of antibodies in serum
217
monoclonal antibodies
obtained by first injecting animal with antigen, this stimulates B-lymphocytes to produce antibodies, then B-lymphocytes fraction from spleen is obtained and fused with myeloma cell line, hybridoma cells result and immortally produce antibodies, one cell line is selected based on quality and specificity of antibodies produced and this particular cell line can be cultured to produce one specific antibody
218
ELISA
detects antigens in-vitro - sandwich and indirect
219
Sandwich elisa
ANTIBODY COATED WELL - used to quantify an antigen by coating antibody to well, adding antigen, adding enzyme-linked specific antibodies, and then adding substrate to develop color or fluorescence
220
indirect ELISA
ANTIGEN COATED WELL - used to detect presence of antibodies by coating well with antigen, adding sample (i.e. blood) to well, add enzyme-linked antibody, and then adding substrate to develop color or fluorescence.
221
Western Blotting
used to indicate molecular weight of protein. Protein extracts are electrophoresed, which separates them by weight. Then they are transferred to a membrane and incubated with specific antibody. Antibody binds to protein of interest, and the position of the protein on the membrane is indication of its molecular weight.
222
ELISA vs WESTERN BLOT
ELISA gives quantitative info about antigen. WESTERN BLOT distinguishes between different isoforms of an antigen
223
Direct sequencing works on and detects:
DNA - detects: point mutations, sm insertions and deletions
224
whole exome sequencing works on and detects:
DNA- detects SM insertions and deletions in exons - not introns or intergenic regions
225
SNP typing works on and detects:
DNA - detects: single nucleotide polymorphs in the entire genome
226
PCR works on and detects:
DNA - detects small insertions and deletion
227
Reverse Transcriptase PCR works on and detects:
RNA - detects expression levels for a small number of genes 8-12
228
allele specific oligonucleotides works on and detects:
DNA - detects point mutations, small insertions and deletions
229
gene expression arraysworks on and detects:
RNA - detects expression levels of thousands of genes - in intergenic regions or introns
230
methylated DNA PCR works on and detects:
DNA - detects epigenetic changes and DNA methylation
231
comparative genome hybridization works on and detects:
DNA - insertions, deletions and aneuploidies in the kilo to megabase range
232
fluorescence in situ hybridization works on and detects:
DNA - detects copy number of a selected chromosomal region
233
ELISA works on and detects
proteins - detects the amount of protein in sample
234
Western blot works on and detects:
proteins - amount and size of protein in sample
235
Principles of gene therapy:
- Mutation to be curd must be recessive; only when mutation is recessive, adding functional copy of gene will remedy defect
- Cells in question must be accessible to therapy
- Repairing genome of differentiated cells of body is somatic gene therapy, could also be done to genome of reproductive cells (germ-line therapy). This second form is prohibited because one would alter genetic makeup of future generations without their consent.
- Gene delivery is an obstacle because one must find a way to insert a fragment of DNA into the chromosomal DNA of billions of cells. Usually achieved by constructing viral or non-viral vectors.
236
methods of gene therapy
virus, non-virus, exvivo, invivo
237
Virus method for gene therapy
Viruses are able to insert their genetic material into a host cell. By turning them into vectors, harmful part of genome removed and replaced with gene of interest, virus is able to insert its genome into cells with its own machinery still intact. The goal is to find a virus that has an aggressive spread to deliver through the whole body without being too aggressive to trigger a massive immune response. Also effective integration of viral NA into host genome should be accomplished stably so that they are not integrated randomly which could cause cancer.
238
non virus method for gene therapy
- Liposomes are lipid vesicles with DNA payload that fuse to cell membranes and release DNA into cells. Advantages: easy to use, commercially available, can accommodate large DNA molecules. Disadvantages: slow entry into cells, low integration rate of DNA into genome
- Naked DNA is easy to prepare in large amount and has no size limit. Disadvantages: DNA is quickly degraded and entry into cells is inefficient
- Complexed DNA is more stable than naked, has no size limit and relatively easy to prepare. Disadvantages: entry of DNA into cells is inefficient
- Artificial Chromosomes are autonomously replicating gene delivery vectors. Advantages: no insertion into genome required for stable expression and no size limit. Disadvantage: unpredictable chromosomal events happen during mitosis.
239
ex vivo method for gene therapy
- Requires: removal of cells from patient, manipulation of cells in lab (with retrovirus for example), and reimplantation of modified cells.
- Safe than in vivo bc altered outside the body
240
in vivo method for gene therapy
1. Treats cells directly avoiding harvesting and reimplanting. Reaching every affected cell is a difficult task, and therefore this therapy works best on epithelial cells that are exposed to surface of tissues EX) used for Cystic fibrosis
241
describe the use of antibodies in cancer therapy
Herceptin is a monoclonal antibody approved for therapy of metastatic breast cancer. Used in treatment of ERB2 overexpressing breast cancer. ERB2 gene is amplified and becomes oncogene, but normally it encodes epidermal growth factor (EGF) receptor with is a protein tyrosine kinase located on the cell surface. The antibody is directed against the extracellular domain and inhibits proliferation of tumors. The antibody is trade-named Trastuzumab and has been modified to deliver a chemotherapeutic agent directly to cancer cells.
242
somatic line gene therapy
repairs the genome of differentated cells in the the body
243
germ line gene therapy
alters the genome of reproductive cells, which would permanently alter the genetic composition of an individual and their offspring (this gene therapy is prohibited due to ethical reasons)
244
5 viruses that have been used as vectors:
```
retrovirus
adenovirus
adeno-associated virus
herpes simplex virus I
baculovirus
```
245
first successful gene therapy trial for ADA SCID
done by ex vivo
246
Down syndrome characteristics
smaller mouths, low set ears-posteriorly rotated, up slanting palpebral fissures, small jaw, small neck, brushfield spots (iris thing), sandle gap deformity (wide first and second toe), single palmar crease, heart conditions
247
Edward Syndrome characteristics
two vessel cord, horeshoe kidney, limb abnormalities: finger overlap & prominent posterior hindfoot, meningomyelocele, prominent occiput, heart conditions
248
Patau Syndrome characteristics
midline cleft, HEART, polydactyly, CNS issues (holoprosencephaly - smooth brain), cutis aplasia (lesion on head)
249
Turner syndrome characteristics
edema in feet, arms not bending, posterior neckline, broad spaced nipples, murmur heard posteriorly, notching - of descending part of aorta, fingers are webbed, infertile, renal
250
Kleinfelters syndrome characteristics
tall, small testes and penis, gynecomastia (breast formation), learning and beh problems
251
some other issue
bulbus shaped nose, upslanting eyes, low set ears, long upper lip thingy, wide spread eyes
