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BMB 462: EXAM 2
What color topped vacutainer is used to collect blood for karyotyping?
What is such a tube coated with. |
GREEN
Sodium heparin
|
What is the active ingredient in prekaryotyping treatment? |
colchicine
|
acrocentric |
centromere near end of chromosome
|
metacentric |
centromere near middle of chromosome
|
submetacentric |
centromere nearer to one end of chromosome than the other
|
karyogram |
picture of chromosomes
|
karyotype |
description of chromosome
|
euploidy |
cell with a set or sets of 23 chromosomes
|
aneuploidy |
chromosome number that is not an exact multiple of n (23 chromosomes)
|
triploidy |
double chromosome contribution from one parent
|
DIANDRIC triploidy |
extra set of chromosomes is paternal
aka: TYPE I triploidy
|
DIGYNIC triploidy |
extra set of chromosomes is maternal
aka: TYPE II triploidy (less common than type I)
|
aneuploidy |
cytogenetic abnormalities where all or part of one or more chromosomes is added or deleted
|
aneuploidy is the result of ______ |
nondisjunction (failure of chromosomes to separate normally during cell division)
|
viable autosomal trisomies |
Down syndrome (trisomy 21)
Patau syndrome (trisomy 13)
Edward syndrome (trisomy 18)
|
viable sex aneuploidies |
Turner's syndrome (45, X)
Kleinefelter syndrome (47, XXY)
47, XYY
|
MONOsomy is ____ tolerated than TRIsomy |
LESS |
Crossing over with PARAcentric inversion |
NOT viable
|
Corssing over with PERIcentric inversion |
VIABLE |
Robertsonian translocations |
two acrocentric chromosomes fusing at centromeres with loss of satellites and short arms - lost material (rRNA genes) is redundant
phenotypically normal
|
21q21q Transloaction (Robertsonian) |
all surviving progeny will have trisomy 21
|
isochromosomes |
mirror image chromosomes
two p arms or two q arms joined at the centromere
|
Obligate carrier |
individual who is assumed to be a carrier based on other affective relatives
|
Consanguinity |
parents share a common ancestor
|
Dosage compensation achieved by ____ |
X-inactivation in females
|
3 examples of X-lined recessive disorder |
Hemophilia A
Fragile X Syndrome
Duchenne Muscular Dystrophy
Red-green color blindness
|
Example of X-linked dominant conditio |
Rett syndrome
|
Homoplasmy |
all mitochondrial DNA are the same (either with or without a mutation)
|
Heteroplasmy |
proportion of normal and mutated mitchondrial DNA in a cell
(proportion can change as cells divide)
|
Clinical expression of mitochondrial inheritance depends on (3 things) |
amount of heteroplasmy
tissue distribution of mutatnt mtDNAs
threshold effect (vulnerability of each tissue ot impaired oxidative metabolism)
|
Key pattern for dominant inheritance |
vertical transmission
|
key pattery for recessive inheritance |
skipping generations
|
key pattern for X-linked recessive inheritance |
bias towards affected males
|
key pattern for x-lined dominant inheritance |
bias towards affected females
|
key pattern for mitochondrial diseases |
affected mothers with all children affected
|
What inheritance pattern rules out X-linked and mitochondrial disorders? |
father-to-son transmission
|
What inheritance pattern makes autosomal inheritance LESS LIKELY? |
gender bias
|
If males transmit the disease, you can rule out ____ |
mitochondrial inheritance
|
If an unaffected mother has affected children, or if an affected mother has unaffected children, you can rule out _____ |
homoplasmic mitochondrial inheritance
|
Penetrance |
probability that an individual with a specific genotype will express a phenotype to any degree
|
Complete penetrance |
everyone with a given genotype will express the phenotype to some degree
|
reduced penetrance |
not everyone with a particular genotype will express the phenotype
|
Example of reduced penetrance |
Hereditary cancer syndrome, e.g.: retinoblastoma
|
Causes of variability in phenotypic expression (6) |
(1) reduced penetrance
(2) variable expressivity
(3) pleiotropy
(4) allelic heterogeneity
(5) locus heterogeneity
(6) delayed age of onset
|
Variable expressivity |
manifestation of a disease is variable amongst individuals that have the same genotype
|
Example of disease displaying variable expressivity |
tuberous sclerosis
|
Pleiotropy |
a single gene producing diverse phenotypic effects; a pleiotropic ds gene could have multiple adverse effects in different organ systems/body areas
|
Example of pleiotropic genetic diseases |
Marfan's syndrome
Cystic fibrosis |
Allelic heterogeneity |
several different mutations of one gene that all cause the same disease
|
Example of disease displaying allelic heterogeneity |
cystic fibrosis
|
Locus heterogenity |
mutations at different loci (in different genes) causing the same disease or phenotype
|
Example of locus heterogenieity |
hearing loss
|
Example of disease displaying delayed age of onset |
Huntington ds
|
Variability caused by interactions of genes (4 things) |
(1) incomplete dominance
(2) codominance
(3) epistasis
(4) sex-influenced conditions
|
Incomplete dominance |
expression of heterozygote (Aa) is different from and intermediate to both homozygotes (AA, aa)
|
2 examples of disease showing incomplete dominance |
achondroplasia
familial hypercholesteremia
|
Co-dominance |
different alleles have an equal effect on the phenotype - both are expressed
|
Example of co-dominance |
ABO blood groups
|
Epistasis |
expression of one gene is prevented or modified by another gene (at a different locus)
|
Example of epistasis |
H gene codes for the H antigen on teh surface of RBCs
|
Sex-influenced diseases are expressed ... |
in both genders, but with significantly different frequencies
|
Example of sex-influenced traits |
male-pattern baldness (not an X-linked trait)
|
Sex-limited condition |
expressed exclusively in one gender
|
Phenocopies |
an environmental influence mimicking a genetic disorder
|
Somatic mosaicism |
mutation occurs AFTER fertilization, affecting a subpopulation of cells
Individual manifests ds if percentage of affected cells is high enough
|
Example of somatic mosaicism |
segmental neurofibromatosis
|
Germ line mosacisim |
Subpopulation of gametes have mutation that individual does not himself express
|
In germ line mosacisim, mutation occurs ___ fertilization in the process of ____, not ____ |
AFTER fertilization
in the process of MITOSIS
(not meiosis)
|
2 examples of germ line mosaicism |
DMD
osteogenesis imperfecta
|
Skewed X inactivation |
one cell line (paternal X chr or maternal X chr) is preferentially inactiviated
|
Hereditary hemochromatosis |
increased iron absorption leads to multiple manifestations
|
Mechanism for microdeletions
|
recombination error leading to duplication and deletion of chromosomes
|
Wolf-Hirschhorn syndrome - genetic etiology |
loss of terminal material from shot arm of chromosome 4
|
Symptoms of Wolf-Hirschhorn syndrome |
profound mental retardation
seizures
ocular hypertelorism
broad or beaked nose
micrognathia
|
Cri-du-chat syndrome - genetic etiology |
5p deletion
|
Cri-du-chat syndrome: phenotype |
newborns have weak, high pitched cat cry
micrognathia
microencephaly
hypertelorism
epicanthal folds
low set ears
slow growth
severe developmental delay
mental retardation
|
VeloCardial Facial Syndrome (DiGeorge Syndrome) - genetic etiology |
Chromosome 22q11 microdeletion
|
VeloCardial Facial Syndrome - embryology |
abnormalities affect 3rd and 4th branchial arches of embryonic development, leading to developmental abnormalities in parathyroid and thymus glands, and heat
|
VeloCardial Facial Syndrome - phenotype |
parathyroid hypoplasia - hypocalcemia
thumic aplasia - immune deficiency
conotruncal heart defects
dysmorphic facial features
cleft lip, cleft palate
developmental delay
increased risk for schizophrenia
genital abnormalities
|
William's syndrome - genetic etiology |
Chromosome 7q11.23 microdeletion (elastin gene)
|
Overarching theme of William's syndrome phenotype |
Connective tissue disorder!
|
Symptomes of William's syndrome |
microcephaly and elfin-like facial features
supravalvular aortic stenosis
bladder diverticula
hypercalcemia
|
Inheritance pattern for Neurofibromatosis: Type 1 (NF1) |
autosomal dominant inheritance (single gene mutation) with complete penetrance, but pleiotropy and variable expressivity
1/2 all new cases = de novo mutation
no ethnic, geographical, sex, etc. bias
|
Diagnostic criteria for NF1 |
six or more cafe au lait macules
skinfold freckling
2+ neurofibromas
optic glioma (w/ tunnel vision, HA, etc)
2+ Lisch nodules
osseous lesion
|
Pts w/ NF1 have a high risk for ___ |
CA - NF1 is an overgrowth syndrome!
|
NF2 is due to mutations in what gene (nickname)? |
Merlin gene
|
Key phenotypic sign of NF2 |
bilatera CN8 vestibular schwannomas (symptoms of tinnitus, hearing loss and balance dysfunction)
|
Penetrance of NF2 |
100% (complete penetrance), with variable expressivity and sometimes delayed age of onset
|
Inheritance pattern for Marfan syndrom |
Autosomal dominant with 100% penetrance
|
Marfan syndrome caused by mutation to what gene |
FBN-1 gene (fibrillin)
|
Diagnostic criteria for Marfan's |
skeletal manifestations
cardiovascular
optic
dural ectasia
family
(NOT DNA testing)
|
Three means of determining relative importance of genes vs. environment in ds etiology |
Twin studies
Concordance rates
Heritability
|
If concordance rates are similar, heritability is ____ |
LOW |
concardance rates |
how often two individuals share the same trait/conditio
|
traits mostly determined by genes will have a heritability close to ___ |
1.0
|
heritability does NOT tell you anything about |
how many genes could be involved
how much each gene contributes to phenotypes
mode of inheritance
|
Genetic anticipation |
aka: Sherman paradox
increased frequency of affective relatives, severity of phenotype or earlier age of onset in successive generations
|
Etiology of genetic anticipation phenomenon |
trinucleotide expansion of a CGG repeat triplet sequence normally presents in the promoter of the FraX gene - greater number of repeats, greater chance individual is affected
|
Premutation |
expansion of a trinucleotide repeat, not significant enough to cause phenotype
unstable - may expand to full mutation in next generation
|
Is expansion usually maternal, paternal or both in FraX syndrome? |
maternal |
threshold CGG repeat number for phenotype manifestation in FraX |
200 |
2 classes of trinucleotide repeat disorders |
repeats in noncoding regions of a gene
repeats in exonic region of gene
|
2 clinical entities relative to FMR-1 locus |
premature ovarian failure
FraX-associated Tremor/Ataxia Syndrome
|
genetic description of Myotonic dystrophy |
CTG expansion in 3' UTR of DMPK gene (codes for a myotonin-protein kinase)
|
protein-level problem with DTG expansion in 3' UTR of DMPK gene |
protein levels unaffected
problem apparently with expanded mRNA and its processing
|
CTG premutation repeat can ___ after MATERNAL transmission and ____ after PATERNAL transmission |
maternal: expand
paternal: contract
|
In Huntington's ds, expansion preimary occurs after ___ inheritance |
paternal
|
define polyglutamine diseases |
CAG repeats (CAG = dodon for glutamine)
|
polyglutamine causes ____ in the ____ |
polyglutamine causes protein aggregation in the nucleus
|
CAG repeats in HD are considered __-of-function mutations |
GAIN-of-function
|
GENETIC IMPRINTING |
different expression of genetic material, at either the chromosomal or allelic level, depending on whether the geneitc materal is inherited from the male or female parent
|
5 disease indicating genetic imprinting |
HD
myotonic dystrophy
Fragile X
autosomal dominant spinocerebellar ataxia
NF1
|
hydatidiform mole |
occurs when chromosomes in fertilized egg are mostly or all paternal in origin
trophoblastic proliferation with little to no embyronic development
|
Imprinting pattern of an individual is established ____ fertilization and ____ during life |
Imprinting pattern of an individual is esatblished BEFORE fertilization and remains established during life.
|
What biochemical phenonemenon is strongly associated with imprinting |
DNA methylation
|
2 clinical manifestations of imprinting |
Prader-Willi syndrome
Angelman syndrome
|
chromosome involved in Prader-Willi and Angelman syndromes |
Chromosome 15
(q11-q13)
|
Symptoms of Prader-Willi |
neonatal hypotonia (similar to Trisomy 21)
poor feeding, FTT to age 2
at age 2, hyperphagia
short stature, small hands/feet, micropenis, hypogonadism
mod to severe microencephaly
obesity
|
Symptoms of Angelman syndrome |
usu. normal at birth, then manifest:
progressive microcephaly
severe MR, lack of speech onset
gait ataxia
abnormal EEF, seizures
|
Deletions in Chr 15q11 inherited from MOTHER results in ____ |
Angelman syndrome
|
Uniparental disomy - probable mechanism |
initially trisomic zygote subsequently loses chromosome
|
Equation for ALLELE frequencies |
p + q = 1
|
Equaltion for GENOTYPE frequencies |
p^2 + 2pq + q^2 = 1
|
Hardy-Weinberg Equilibrium Principle |
Allele and phenotype frequencies remain constant in subsequent generations
|
4 assumptions of H-W Equil. |
Two allels
random mating
large population
no migration, new mutations, natural selection
|
Do H-W practice problems, p. 268 |
do them!
|
2 types of enzymes required for recombinant DNA technology |
Restriction endonucleases
DNA ligases
|
Biological function for restriction enzymes |
bacterial defense mechanisms - cut up foreign DNA
|
recombinant DNA |
DNA molecule consisteing of components from different "parent" molecules
|
cloning |
making many copies of the recombinant DNA using a host organism
|
vector |
DNA molecule that can be replicated (i.e.: has an ORI specific to a particular host organism - bac, yeast, etc.)
|
Insert |
DNA fragment from organism/individual of interest, which will be joined to a vector
|
host |
organism that will replicate the recombinant DNA
|
transformation |
process by which teh recombinant DNA is put into the host
|
2 essential features of vectors |
insertion site
origin of replication
|
plasmid vectors |
small, circular DNA vectors
|
cDNA |
capture just one protein coding region per ONE fragment (one insert) for cloning
|
how to make cDNA |
synthesize from mRNAs using reverse transcriptases
|
what will cDNA not have? |
introns
promoters
enhancers
spacer DNA
|
expression clones |
special case of cDNA inserts
get host cell to synthesize protein encoded by cDNA
require expression vectors
use bacterial RNA polymerase and bacteral ribosome to make eukaryotic protein
|
clone libraries |
collection of clones, made simultaneously, from a given sample
|
How do you differentiate between autosomal dominant and x-linked dominant? |
Can males lead to affected males?
AD = Yes
XD = No
|