Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
224 Cards in this Set
- Front
- Back
what's normal human male/female KARYOTYPE?
|
46 XY / 46 XX
|
|
what are G-pos and G-neg bands in karyotyping?
|
G-positive: dark bands
G-neg: light bands |
|
characteristics of G-negative bands in karyotyping?
|
high in GC content
rich in SINE and Alu repeats, housing-keeping genes, early replication, rich in transcribed sequences |
|
characteristics of G-positive bands in karyotyping?
|
high in AT content
rich in LINE repeats tissue-specific genes late replication sparse genes |
|
3 different chromosome structures
|
|
|
t/f
female recombination freq > male recomb |
true
|
|
t/f
recombination decreases near telomeres |
false
Recombination increases near telomeres in both sexes |
|
when does meiosis of germ cells commence in males? females?
|
male: at puberty
female: 3rd month prenatal (arrest in MI prophase until ovulation, arrest again in MII metaphase until fertilization) |
|
t/f
Parental origin of the extra chromosome in trisomy is most often maternal and most often a result of a MI error. |
true
|
|
which one is the smallest chromosome?
|
21
|
|
what is polyploidy? is it euploid or aneuploid?
|
euploid (exact multiples of haploid number)
polyploidy = complete sets of extra chromosomes e.g. 3N = 69 chromosomes Jump to: navigation, search Polyploidy occurs in cells and organisms when there are more than two homologous sets of chromosomes. (aneuploid e.g. 45, 47) |
|
what is least severe: trisomy 18, 13 or 21?
|
21 (down's syndrome) 1/600 - 1/700 births (40% have heart defects)
|
|
what are some characteristics of trisomy 18 and 13?
|
both 13 and 18: most die at first month
13 (Patau): polydactyly, cleft lip/palate, holoprosencephaly (midline anomalies) 18 (Edward): small low-set ears, clenched fist 2,5 over 3,4; club foot |
|
what is this type of chromosome abnormality called?
|
isochromosome
|
|
what is paracentric vs pericentric inversion?
|
paracentric: centrosome not involved
peri: centrosome involved |
|
what is FISH in cytogenetics?
|
fluorescent in-situ hybridization;
Labeled DNA Probe Hybridized To Metaphase Or Interphase Preparations Identification And Characterization Of Structural Chromosome Abnormality |
|
what is DiGeorge syndrome? what causes the genetic abnormality?
|
3 Mbp deletion on ch 22 due to recombination of low-copy repeat sequence flanking the 3 Mbp region. ~1:4000
Cleft lip (cheiloschisis) and cleft palate (palatoschisis) (colloquially known as harelip), which can also occur together as cleft lip and palate, are variations of a type of clefting congenital deformity caused by abnormal facial development during gestation. Note that harelip is now considered as a derogatory term. A cleft is a fissure or opening—a gap. It is the non-fusion of the body's natural structures that form before birth. CATCH 22: Cardiac defects (congenital) Abnormal facial expression Thymus aplasia Cleft palate (feeding problems) Hypocalcemia and chromosome 22 (also immune dysfunction -> recurrent infections; and psch problems) |
|
what is william's syndrome?
|
deletion of ch 7 region;
Deletion of elastin gene + others Mental Retardation w/ microcephaly Supravalvar aortic stenosis |
|
what is miller dierker syndrome?
|
deletion of ch 17 chunk.
LISSENPHALIC (loss of cortical surface folds) Vertical ridging of forehead Small nose with anteverted nostrils Upslanted palpebral fissures Low set posterior rotated ears Palpebral fissure is the anatomic name for the separation between the upper and lower eyelids. In the adult this measures about 10mm vertically and 30 mm horizontally. |
|
what is prader willi and angelman syndrome? what is the genetic significance of these disorders?
|
both: chr. 15 deletion of 7 genes
PW: milder (fat and short and small penis, mild MR), paternal imprinting Angelman: severe MR, paroxysms of laughter, maternal imprinting |
|
t/f
gene encoding Insulin-like growth factor 2 (IGF2/Igf2) is only expressed from the allele inherited from the father |
true (maternal imprinting)
remember from endo: paternal genes want baby to grow, maternal genes want to suppress. IGF2 for neonatal growth, not important postnatal. |
|
where is the pseudoautosomal region on Y chromosome in relation to SRY gene?
|
pseudo: short arm of Y, near top;
SRY gene right below it -> recombination can happen at pseudo region cos it's complimentary. if happen close to SRY, can give XX male or XY female |
|
what are Barr bodies?
|
inactive X chromosomes - associated with nuclear membrane
|
|
when are X chromosomes inactivated?
|
2nd week fertilization, at several hundred cell stage (blastocyst)
(note: inactive X must be reactivated in female germ line so that each egg can have one active X - "RESET") |
|
what are the characteristics of X chr inactivation?
|
RANDOM - either paternal or maternal X, random cells (mosaic)
CLONAL INCOMPLETE - some genes escape inactivation (most on short arm) |
|
how are X chromosomes inactivated?
|
XIST gene - in the X inactivation center of Xq13, transcribed only frominactive X
XIST mRNA coats Xi, affects replication (inactive chromosome is late replicating) and condensation. Silencing follows shortly. Methylation maintain stability of inactivation |
|
what is turner's syndrome?
|
45, x
amenorrhea short webbed neck short stature congenital heart problems |
|
what is unfortunate lyonization?
|
skewed X inactivation
5-10% females (inactivate X chr with wildtype alleles -> active X expresses abnormal alleles or carries unbalanced translocation) |
|
consequences of polysomy X in females?
|
47 XXX : usually benign, mild mental retardation, sterility, menstrual irregularity
48 XXXX, 49 XXXXX: each additional X = inc. MR and physical abnormalities |
|
what is Klinefelter Syndrome?
|
47 XXY, 48 XXXY, 49 XXXXY
MALE, each additional X = inc. MR and physical abnormalities; -small testes -infertile -gynecomastia (incr. risk breast cancer) |
|
consequences of 47 XYY?
|
(prev. thought to be involved in violent crimes, but not true)
taller than avg, 10-15 lower IQ pts, hyperactive, ADD, learning problems |
|
what are comparative genomic hybridization arrays?
|
to detect gain/loss in copy numbers in DNA content on chromosomes:
1. test DNA green; ctrl (normal) DNA red 2. hybridize to normal metaphase chromosomes 3. red/green ratio analyzed -> too much red: reduced DNA content (deletions) in test DNA; too much green: increased test DNA content (duplications) balanced translocations or inversions cannot be detected (does not change copy #) |
|
how can we categorize chromosomal abnormalities?
(3) |
Numerical vs. Structural
(different mechanisms of origin) Autosome vs. Sex chromosome (same mechanism, but different consequences) Germline (congenital) vs. Somatic (acquired) (meiotic vs. mitotic event) |
|
identify the structural chromosome abnormality
|
|
|
Most balanced translocations have normal phenotype, unless what?
(3 things) |
-breakpoint disrupts a gene
-deletion occurs at breakpoint or -involves an X-autosome rearrangement |
|
draw it out...seriously!!
okay afshan, remember that they're different chromosomes! |
The outcome for unbalanced offspring (liveborn vs. nonviable) depends on the chromosomes involved and the size of the piece of DNA duplicated or deleted.
As for the balanced outcome, that's definitely viable bc that's what the parents have |
|
explain imprinting
|
In diploid organisms somatic cells possess two copies of the genome. Each autosomal gene is therefore represented by two copies, or alleles, with one copy inherited from each parent at fertilization. For the vast majority of autosomal genes, expression occurs from both alleles simultaneously. In mammals however, a small proportion (<1%) of genes are imprinted, meaning that gene expression occurs from only one allele.
The expressed allele is dependent upon its parental origin. For example, the gene encoding Insulin-like growth factor 2 (IGF2/Igf2) is only expressed from the allele inherited from the father. |
|
phenotype of 17q deletion?
|
Mental retardation
Blonde hair Hypotonia Facial dysmorphology Protuberant tongue Skin Pigmenatation Seizures Tracheomalacia Feeding/sleeping problems Poor attention/ motor control Hypoplasis of the corpus callosum |
|
When you see written 2n2c, what does
n = c = |
n=haploid chromosome #
c=DNA content |
|
when is DNA least condensed? most condensed?
|
|
|
list 4 differences between female and male meiosis
in terms of 1) when it commences? 2) duration of meiosis? 3) how many gametes produced per meiosis 4) gamete production in general |
|
|
Female meiosis begins prenatally (3rd month) and is
arrested in the first meiotic prophase in a special stage called __________ (this stage never occurs in males). |
dicytotene
|
|
Monosomies of ALL chromosomes are not viable except those of __________
Trisomes of only 3 chromosomes are viable. which ones? |
sex chromosomes
13, 18, 21 |
|
Draw out the outcomes
|
(Trisomy and monosomy can originate from meiotic or mitotic nondisjunction)
|
|
features of Down's syndrome?
|
Common Features:
Hypotonia (low muscle tone, strength) Almond-shaped eyes upslanting palpebral fissures epicanthal folds depressed nasal bridge brachycephaly (round head shape w/ flattened occiput) excess nuchal skin Heart defect - 40% (most A-V canal) An epicanthic fold, epicanthal fold, or epicanthus is a skin fold of the upper eyelid (from the nose to the inner side of the eyebrow) covering the inner corner (medial canthus) of the eye. The trait arises because the eyelid muscles are weaker or lower compared with people who do not have this epicanthic fold, resulting in a lower fold in the eyelid, when the eyes are open. The fold gives the eyes of East Asians a characteristic shape which is narrower and almond-like in comparison to most Westerners, whose eyes appear rounder. |
|
name the disorder
|
trisomy 18
Weak, feeble activity and cry (hypoplastic muscles) Clenched hand position w/ 2 & 5 over 3 & 4; clubfoot or rocker-bottom feet; small, low set ears; omphalocele; severe MR Early lethality most die in first month; 5-10 % survive > 1 yr |
|
name the disorder
|
trisomy 13
IUGR, microcephaly, severe MR Midline anomalies cleft lip/palate, holoprosencephaly, scalp defect, CHD, omphalocele Polydactyly, postaxial Early lethality most die in first month; 5% survive > 6 months |
|
what are 2 causes of nondisjunction?
|
Advanced maternal Age
Altered Recombination |
|
A Robertsonian translocation is a type of nonreciprocal translocation between two___________ ____________ chromosomes
|
nonhomologous acrocentric
(chromosomes that are not members of the same pair and have centromeres near their ends) |
|
The more X’s you have, then the more risk of defects… why?
|
Because there are some stuff on X’s that escape inactivation
|
|
what are 2 potential outcomes of
a female carrier of an X-linked mutation or deletion on one of her two X chromosomes: |
May express an abnormal phenotype if most of her cells happen to have inactivated the X chromosome carrying the normal gene
OR May express a normal phenotype if most of her cells inactivated the X chromosome carrying the mutant gene. |
|
Most Turner syndrome cases caused by
|
meiotic error in the father (offspring receives X chromosome from mother, but no sex chromosome from the father).
|
|
t/f
30-40% of individuals with Turner are mosaics: |
true
45,X/46,XX 45,X/46,XY – these individuals are at risk for developing malignancies in their streak gonads (gonadoblastomas) |
|
There are many important genes on the X chromosome…
So, how can males, with only one X chromosome, and females, with two X chromosomes, not differ in the products encoded by most of these genes??? |
Explained by X-inactivation resulting in dosage compensation
|
|
If only one X remains active per cell, while the others are inactive, what happens in individuals with sex chromosome abnormalities, such as Turner syndrome (45,X) or Klinefelter syndrome (47,XXY)?
Why, if all of these individuals only have 1 active X chromosome, do they have different phenotypes? Why aren’t individuals with aneuploidy for the sex chromosomes phenotypically normal? |
bc x-inactivation is incomplete
|
|
when 2 related individuals in a family have the same disease, they are said to be ________ for the disorder
when only 1 member of the pair of realtives is affected and the other is not, the relatives are ________ for the disease |
concordant
discordant |
|
what's the relative risk ratio?
|
relative risk ratio =
(prevalence of the disease in the relatives of an affected person/prevalence of disease in general population) |
|
what's ascertainment bias?
|
people with disease will be more likely to report affected relatives to the epidemiologist (bc they know more about the disease, paid attention to it, can recognize it, etc)
as opposed to people who DON't have the disease |
|
recall bias?
|
when false results are produced by non-random sampling and conclusions made about an entire group are based on a distorted or nontypical sample. If this is not accounted for, results can be erroneously attributed to the phenomenon under study rather than to the method of sampling. It is one of the most common reasons that researchers in the medical, social, or biological sciences may discover an association or correlation that does not actually exist. Ascertainment bias may be easy to recognize or difficult to detect.
|
|
osteogenesis imperfecta: genetic defect?
|
dominant negative COL1A1 or 2 (collagen triple helix formation -> mutation interrupt formation of normal collagen molecules)
|
|
define:
homozygous heterozygous hemizygous |
If both alleles of a locus are the same
If both alleles of a locus are different Compound heterozygote: 2 different mutant alleles If only one locus is present |
|
Phenotype results from only 1 copy of the mutated allele (heterozygotes)
|
dominant
|
|
achondroplasia is an example of a ________ mutation
|
gain of function!
Mutation leads to increased function of receptor so increased or too much restriction of bone growth. |
|
osteogenesis imperfecta is an example of _________ mutation
|
dominant negative
COL1A1 or COL1A2: Mutations in the triple helical formation of the protein leads to disrupted formation of normal collagen although half the collagen molecules are normal. |
|
how can only 1 copy of a
mutated allele cause a disorder/disease? |
Haploinsufficiency
Dominant negative Gain of function Random loss of other allele (cancer) Definition of Haploinsufficiency Haploinsufficiency: A situation in which the total level of a gene product (a particular protein) produced by the cell is about half of the normal level and that is not sufficient to permit the cell to function normally. Another way to define haploinsufficiency is as a condition that arises when the normal phenotype requires the protein product of both alleles, and reduction of 50% of gene function results in an abnormal phenotype. |
|
what's locus heterogeneity?
|
Mutations at two or more loci
may result in similar phenotype (genetic or locus heterogeneity) Deafness, tuberous sclerosis, muscular dystrophy |
|
what's this:
Different mutations in the same gene may result in the same disease. |
allelic heterogeneity
|
|
More than one phenotype
may be caused by different mutations in the same gene |
phenotypic heterogeneity
|
|
what kind of mutation is trasmitted in this pedigree?
|
autosomal dominant
|
|
this?
|
Autosomal dominant + Incomplete penetrance
recessive? Hmm very low probability bc 2 people coming into the family would have to have the recessive gene….very unlikely |
|
this?
|
Don’t rule out autosomal dominant….it could be low penetrence
|
|
|
Don’t rule out autosomal dominant….it could be low penetrence
|
|
For Autosomal Dominant mutation, what's the:
Transmission Recurrence risk Sex ratio Status of parents |
Transmission
Vertical Through both sexes Male to male Recurrence risk 1-in-2 Sex ratio Males = females Status of parents Often affected |
|
|
autosomal recessive
Can’t rule out germline mutation of autosomal dominant…. Hmmm, but chances that it is autosomal dominant and none of the 8 kids have it……low |
|
|
The parents are cousins!!! So recessive
|
|
for autosomal recessive, what's the:
Status of parents Disease alleles Complicating factors |
Status of parents
Normal Consanguineous Disease alleles Identity by descent Compound heterozygosity Complicating factors Ethnic associations Genetic heterogeneity |
|
what can complicate classifiying a mutation autosomal dominant?
|
Complicating factors
Penetrance Variable expressivity New mutation Pleiotropy Homozygosity Anticipation/Mosaicism |
|
|
Males more affected
Females are not affected by y-linked…so could be x-linked or y-linked BUT the mothers seem to be passing it on |
|
|
Skewed X-inactivation
The liver can have only 1 particular X activated for example Also uniparental monosomy of the X chromosome is a possibility (the female affected gets both of her x’s from her mom) |
|
|
Skewed X-inactivation
The liver can have only 1 particular X activated for example Also uniparental monosomy of the X chromosome is a possibility (the female affected gets both of her x’s from her mom) |
|
x-linked activation:
Females may be either _________or _________ Males have only 1 X chromosome so __________ |
|
|
For X-linked, what's the
transmission recurrence risk carrier risk sex ratio |
|
|
|
y-linked
|
|
what type of mutation is described?
|
Y-linked
|
|
The transcriptional factors are _____-acting because they are synthesized on remotely located genes and are required to migrate to their sites of action.
|
trans
|
|
The promoter elements are ___-acting because their function is limited to the DNA duplex on which they reside.
|
cis
|
|
different types of transcriptional modification?
|
|
|
what's the difference between general transcription factors and upstream txn factors?
|
general: bind to RNA Pol II at TATA box, used for all/most DNA txn (regardless of genes)
upstream: far away from TATA box, gene-specific, may or maybe be inducible/repressible |
|
what are some types of DNA binding domains for txn factors?
|
zinc finger
leucinezipper (hetero/homodimers) helix-turn-helix domains |
|
what are insulator elements?
|
- buffer genes from the repressing effects of heterochromatin
- block the action of enhancers - divide genome into "independent domains" of gene regulation |
|
list common epigenetic control
|
DNA methylation
histone modification (acetylation, methylation, phosphorylation) RNA processing |
|
what mediates histone acetylation?
|
histone acetyl transferases (acetylated -> active)
deacetyltransferases silence |
|
effect of histone methylation?
|
of lysine 9 on the N terminus of histone H3 is a hallmark of silent DNA, of lysine 4 of histone H3 denotes activity
|
|
effect of DNA methylation?
|
C5 position of cytosine/guanine pairs (CpG) -> silencing, mediated by DNMT
CpG islands: txn activators bind |
|
how is H9 methylation-silencing mediated?
|
MECP2 binds methylated promotor sites and recruits the mSinA/HDCA1,2 corepressor complex
|
|
what is UPD?
|
uniparental disomy: inheriting both chromosomes from same parent.
|
|
what are microRNAs?
|
highly conserved, RNAs regulate the expression of genes by binding to the 3'-untranslated regions (3'-UTR) of specific mRNAs.
Each miRNA is thought to regulate multiple genes (Drosha processing in nuc, Dicer processing in cytoplasm, association with RISC -> bind and silence gene) |
|
marfan features?
|
dislocated lenses
dilated aortic root arachnodactyly (spider fingers...long and slender fingers) flat feet pectus excavatum family history |
|
what mediates the phenotypic consequences of marfan?
|
TGFb overexpression
|
|
what are common environmental causes of neural tube defects?
|
-Teratogens: aminopterin, thalidomide
-maternal insulin dependent diabetes |
|
what are common syndromes associated with neural tube defects?
|
trisomy 13, 18
meckel's syndrome (single gene) |
|
what's a good treatment to prevent neural tube defects?
|
maternal folate therapy
|
|
1 centimorgan (cM) = ? bp DNA?
n genetics, a centimorgan (abbreviated cM) or map unit (m.u.) is a unit of recombinant frequency for measuring genetic linkage. It is often used to imply distance along a chromosome. The number of base-pairs it corresponds to varies widely across the genome (different regions of a chromosome have different propensities towards crossover). |
10^6
|
|
what factors affect recombination rate?
|
sex (F>M), distance from centromere (dec recombination), distance from telomere (inc recombination), and other chromatin structures
|
|
what kind of newborn screening is detected by tandem mass spec?
|
usually metab. disorders (e.g. a.a. disorders, urea cycle and f.a. oxidation disorders)
Tandem mass spectrometry, also known as MS/MS, involves multiple steps of mass spectrometry selection, with some form of fragmentation occurring in between the stages |
|
what's PKU? symptoms?
|
mutation in PAH gene (phenylalanin hydroxylase: F->Y), auto rec
accumulation of F: progressive developmental delay, microcephaly, severe mental retardation, seizures, autistic behavior. 95% have IQ < 50. BH4: tetrahydropterin qBH2: quinonoid dihydropterin DHPR: dihydropterin reductase |
|
what's the most common f.a. oxidation disorder?
|
MCAD (medium chain acyl
CoA dehydrogenase deficiency) fat accumulation in liver and mm. |
|
why are CG dinucleotides hotspots for mutations?
|
C -> (meth) 5-methylcytosine -> deamination: thymine
|
|
what's most common mutation for CF?
|
deltaF508 (in frame deletion)
|
|
what's the common genetic cause of b-thalassemia?
|
nonsense mutation in b-globin gene to make hemoglobin
(many other mutations reported) -> a/b globin ratio imbalance,excess globins destroy rbc membrane -> anemia |
|
genetic cause of sickle cell?
|
glu -> val mutation in b-globin gene -> sticky
|
|
what is singlestrand conformational polymorphism?
|
Single strand conformation polymorphism (SSCP), or single strand chain polymorphism, is defined as conformational difference of single stranded nucleotide sequences of identical length as induced by differences in the sequences under certain experimental conditions. This property allows to distinguish the sequences by means of gel electrophoresis, which separates the different conformations
|
|
what's Heteroduplex-based mutation scanning
|
followed by separation by size (gel or HPLC)
|
|
what's DHPLC?
|
denaturing DHPLC
(separates DNA by charge/size/conformation) 1. TEAA mediates the binding of DNA to the column 2. ACN gradient elutes DNA off the column |
|
wot's genetic cause of DMD?
|
duchene muscular dystrophy (muscle wasting), X-linked rec, >60% b/c of intragenic deletions
|
|
newborn test for PKU is mandated in the US. what's the common test for PKU?
|
Guthrie test
(excess F in blood help bacterial growth in media with inhibitor) or just tandem-repeat mass spec |
|
what are some PCR based genetic methods for detecting known mutations?
|
single base extension
allele-specific PCR FRET primers real-time quantitative PCR |
|
how do you detect mutations with known genes but unknown common mutations?
|
sequencing, heteroduplex-based mutation scanning, Single Stranded-Conformational Polymorphism, genetic marker (e.g. RFLPs, SNPs) linkage analysis
|
|
genetic cause of achondroplasia?
|
(dwarfism)
GOF mutation of FGFR3 (normally inhibitory for bone growth, mutation leads to const. activation) |
|
what is stickler' syndrome?
|
locus heterogeneity in collagen genes: COL2A1, COL11A1, COL11A2
High myopia Arthropathy/osteoarthritis Deafness Flat midface with prominent eyes Cleft palate Micrognathia (undersized jaw) Bifid uvula |
|
class 1 vs class 2 trinucleotide repeat disorders?
|
Class 1 untranslated: repeat motif is not translated, larger expansions, risk is higher with maternal transmission
Class 2 translated: Repeat motif is translated as a polyglutamine tract, expansions are small, risk is higher with paternal tranmission, and most are neurological disorders. |
|
some examples of trinucleotide repeat disorders?
|
Myotonic dystrophy
huntington Friedreich ataxia fragile x (FMR1 gene) |
|
what's GJB2/Connexin 26 implicated in?
|
Accounts for 50-80% of non-syndromic recessive deafness and 10-37% of sporadic deafness,
potassium recycling in cochlear endolymph |
|
how do you calculate allele frequency?
|
|
|
what are the assumptions of the Hardy-Weinsberg model?
|
. The population is infinitely large and the effects of random genetic drift are negligible
2. Mating is random with respect to genotypes (i.e., no consanguinity or assortative mating) 3. No new mutations introduce variability into population 4. Natural selection does not affect genotype frequencies |
|
Let p= probability of A
q= prob of a The probability of sampling an A allele from one parent and an A allele from the second parent = The probability of genotype AA = The probability of sampling an A allele from one parent and a B allele from the other The probability of genotype AB = (p x q) + (q x p) = 2pq The probability of sampling a B allele from one parent and a B allele from the second parent = The probability of genotype BB =(q x q) = q2 |
(p x p) = p2
(p x q) + (q x p) = 2pq (q x q) = q2 |
|
p2 + 2pq + q2 = ____
|
1
(this is for the simple case, where there's 2 alleles) For loci with n alleles, the relative frequencies of the genotypes = (p + q + r + s + ..... + n)2 = 1 |
|
Cystic fibrosis (CF) affects approximately1 in 2,500 U.S. Caucasians. The frequency of homozygotes for the recessive allele =1/2,500 = 0.0004 = q2
|
1/2,500 = 0.0004 = q2
The frequency of the recessive allele = q = disease frequency = q = 0.0004 = 0.02 = q p = (1-q) = 0.98 2pq = (2) x (0.02) x (0.98) = 0.04 = 1 in 25 For rare recessive conditions, p approximates 1 and the carrier frequency is approximately 2q or 2 x square root (disease frequency) |
|
Sue has 2 sibs with an autosomal recessive condition. Jim has a negative family history. What is the probability that they will have a child with the condition?
|
2pq is the population carrer frequency….(prob that Jim is a carrier)
|
|
What is the chance Sam’s brother is a carrier?
|
Assume that sam’s parents don’t have a disease….
At least one of the parent have to be a carrier So his change of being a carrier is a half Now if the other parent is a carrier: 1/25 (population carrier frequency) * (2/3) = 2/75…it’s not adding too much to the ½ |
|
It is not uncommon to find _____ among parents of children with rare autosomal recessive conditions.
|
consanguinity
|
|
Alters genotype proportions in a population by increasing or decreasing fitness
|
natural selection
|
|
Sickle cell anemia is an exampleof ____selection
|
balancing
Carriers of the sickle allele (and other hemoglobin mutations) are more resistant to malaria than either homozygous class (HbAA or HbSS) |
|
Males are ____for X-linked conditions
|
hemizygous
Describes an individual who has only one member of a chromosome pair or chromosome segment rather than the usual two; refers in particular to X-linked genes in males who under usual circumstances have only one X chromosome |
|
The frequency of an X-linked condition in males equals ______
|
the recessive allele frequency = q
The frequency of carrier females equals 2pq |
|
Ed and Jane’s fourth son was born with a lethal X-linked recessive condition for which there is no carrier testing. Jane reports a negative family history for this condition. What is their risk for having another affected child.
|
check it out....
(For XLR conditions with fitness = 0 and equal male and female mutation rates, 1/3 of sporadic cases are due to new mutations) |
|
Calculates overall relative probability of an event taking into account both anterior and posterior information
Anterior information provides the prior probability, which can be modified, or conditioned, by posterior information to give a joint probability. The posterior or relative probability is obtained by dividing the joint probability of event C by the sum of the joint probabilities of C occurring and C not occurring. |
|
|
recurrence risk of chromosomal abnormalities?
|
|
|
indications for diagnosis of mendelian disorders?
|
Previous child with autosomal dominant, recessive or X-linked recessive disorder
Either parent has autosomal dominant mutation Mother has X-linked recessive mutation Both parents are carriers of mutation for same autosomal recessive disorder |
|
what are some multifactorial disorders?
|
Neural tube defects
Facial clefts Cardiac defects Abdominal wall defects |
|
indications for diagnosis of multifactorial disorder?
|
Previous child, either parent or parental sibling with a multifactorial abnormality
Ultrasound examination suggesting presence of an isolated anomaly Elevated maternal serum AFP |
|
what are the prenatal screens/tests?
|
Maternal blood tests
Ultrasound Amniocentesis CVS (chorionic villus sampling) PUBS (percutaneous umbilical blood sampling) |
|
indications for NTD diagnosis?
|
Previous affected offspring
Affected parent Affected sib of parent Affected niece or nephew Elevated maternal serum alpha-fetoprotein |
|
what's ALPHA-FETOPROTEIN?
|
Produced by yolk sac and fetal liver
Levels very high in fetal blood, lower in amniotic fluid and still lower in maternal serum (MS) MSAFP levels are elevated in most pregnancies with NTD Elevated MSAFP may be due to incorrect gestational age, multiple gestation, placental abnormality, fetal anomaly |
|
what's the ALPHA-FETOPROTEIN prenatal testing protocol?
|
|
|
what would the uE3, AFP, hCG, inhibin profile look like for trisomy 21, 18?
(in the second trimester!) |
|
|
what's the hCG, PAPP-A profile look like for trisomies?
**in the first semester! |
|
|
what can you see in a fetal sonograph?
|
Choroid plexus cysts
Thickened nuchal fold Echogenic bowel Renal pyelectasis Polyhydramnios Fetal echogenic bowel refers to increased echogenicity or brightness of the fetal bowel noted on second trimester sonographic examination Enlargement of the the renal pelvis is called fetal pyelectasis or “renal pelvic dilatation polyhydramnios: excess of amniotic fluid |
|
what's amniocentesis?
|
|
|
what's CVS?
|
http://en.wikipedia.org/wiki/Chorion
|
|
what's the "integrated" screening for Down Syndrome
|
combination of first and second trimester screening
--first trimester: PAPP A, nuchal translucency --second trimester: MSAFP, uE3, hCG |
|
etiology of congenital malformations?
|
chromosome abnormalities
mendelian disorders (single gene disorders) polygenic/multifactorial conditions environmentally induced abnormalities |
|
indications for prenatal cytogenetic diagnosis?
|
Advanced maternal age
Previous trisomic offspring Parental chromosome rearrangement Abnormal maternal serum screen Abnormal ultrasound finding Parental anxiety Other tests being performed concurrently |
|
recurrence risk after birth of child with chromosome abnormality
Trisomy 21 Trisomy 18 Trisomy 13 Other autosomal abn. Sex chromosome abn. Total |
Abnormals/Total
35/2353 (1.5%) 20/1132 (1.8%) 4/596 (0.7%) 4/256 (1.6%) 3/142 (2.1%) 66/4479 (1.5%) |
|
with the following parental rearrangements, what's the risk of an unbalanced fetus?
Robertsonian Translocation Reciprocal Translocation Inversion |
Robertsonian
Translocation 1-15% Reciprocal Translocation 11% Inversion 2% these are empirical...not theoretical! (how do you get an unbalanced fetus with an inversion...? |
|
what are the detection rates of anencephaly and spina bifida for AFP screening and amniotic fluid AFP
|
screening:
ANENCEPHALY 90% SPINA BIFIDA 80% amniotic fluid AFP: DETECTION RATE ANENCEPHALY 100% SPINA BIFIDA 90% |
|
when you do the second trimester maternal serum screening (checking the levels of hCG, inhibin, ue3, AFP)....what's the detection rate?
|
Screen positive for Down syndrome: risk > 1:270
Test raises or lowers a priori risk Not diagnostic Detection rate is 77% for women < 35 years old, and 92% of women > 35 |
|
what about first trimester maternal serum screening (ie when you check hCG, PAPP-a)...what's the detection rate?
|
83% detection rate for trisomy 21(5% false positive rate)
90% detection of other chromosome abnormalities (1% false positive rate) |
|
complications of amniocentesis?
|
MATERNAL
Cramping Common Fluid leakage, infection,spotting Rare FETAL Abortion < 0.5% Injury Very rare |
|
complications of CVS?
|
MATERNAL
bleeding 1-30% Amnionitis Rare FETAL Abortion 0.5%-1 Injury Very rare |
|
what's the rationale for preimplantation diagnosis?
|
RATIONALE
Diagnosis before pregnancy begins Reduces burden on family of multiple affected pregnancies Treatment possible before irreversible damage |
|
what are the approaches of preimplantation diagnosis?
|
Trophectoderm biopsy at 5-6 days
Zygote biopsy at 6-10 cell stage Polar body analysis prior to fertilization |
|
rationale for testing fetal cells in the maternal circulation?
|
Noninvasive
Applicable to the entire pregnant population |
|
fetal cells in maternal circulation?
|
Lymphocytes
Trophoblasts Erythroblasts (nucleated red blood cells) Free DNA |
|
how do you test fetal cells in maternal circulation?
|
Prerequisites:
1. Separate and enrich fetal cells Monoclonal antibodies Cell characteristics 2. Identify fetal cells 3. Perform genetic analysis In situ hybridization PCR and DNA probes |
|
defect in ______ occurs in all tumors
|
|
|
tumors are clones of _____
|
aberrant cells
|
|
what's the 2-hit hypothesis?
|
|
|
only ____ % of all cancers are inherited
|
5-10%
|
|
what are the 3 classes of "cancer genes"
|
Tumor suppressor genes (recessive oncogenes)
---Inhibits cell proliferation Oncogenes (dominant oncogenes) Activates proliferation Mutator genes (DNA repair genes) Maintains accurate replication and repair of DNA |
|
how is cell growth like in normal cells? cancer cells?
|
|
|
one/both alleles of tumor suppressor genes need to be inactivated for cancer
|
both!
|
|
retinoblastoma:
Sixth most common childhood cancer World wide incidence 1/13,500 to 1/25,000 Unilateral Ave age diagnosis 18 mo. Bilateral Ave age diagnosis 12 mo. Multifocal That's weird...why is bilateral RB more early onset than unilateral? |
An individual can inherit an Rb gene mutation from a parent; but for the disease to be present it must be
--Recessive at the level of the cell Both copies of the gene must be nonfunctional |
|
how do you lose heterozygosity?
|
|
|
what does RB do in the cell cycle?
|
|
|
Example of cancer caused by mutations in tumor suppressor genes (recessive oncogenes)
FAP! Autosomal ____ inheritance Caused by mutations in___ ---tumor suppressor gene on chromosome 5q Up to 30% of patients have de novo germline mutations Most families have unique mutations Most mutations are protein truncating Genotype/phenotype relationships emerging |
dominant
APC |
|
clinical features of Familial Adenomatous Polyposis (FAP)
|
Estimated penetrance for adenomas >90%
Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other) Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) may be present Untreated polyposis leads to 100% risk of cancer Desmoid tumors are histologically benign fibrous neoplasms originating from the musculoaponeurotic structures throughout the body. An osteoma (plural: "osteomata") is a new piece of bone usually growing on another piece of bone |
|
Example of cancer caused by mutation in tumor repressor genes:
Breast Cancer!! genetics of familial breast cancer: Approximately 5-10% of cases due to an inherited predisposition If inherited – 20-40% - BRCA1; 10-30% BRCA2 Autosomal ____ transmission Female carriers have an 85% risk of developing breast or ovarian cancer Early onset of cancer (75% < 50 years of age) |
dominant
|
|
what are the 2 genes that account for 20-40% and 10-30% of inherited breast cancer?
|
BRCA1 and BRCA2
|
|
oncogenes...how many mutated alleles need to be mutated for cancer?
1 or 2? |
1 is sufficient
|
|
oncogenes:
Originate from _____ ---Genes involved in the four basic regulators of normal cell growth Mutation in proto-oncogenes ---Becomes an oncogene Dominant at cellular level Activated - _____ mutations ---Most lead to the deregulation of cell cycle control |
proto-oncogenes
gain-of-function |
|
protooncogenes:
Highly conserved in evolution Products are important regulators of ____ and differentiation Localized throughout cell Regulate cascade of events that maintain ordered progression through the ____and ____ |
normal cell growth
cell cycle and cell division |
|
what are some mechanisms by which protooncogenes are activated?
|
Point mutations
Chromosomal rearrangements or translocations Gene amplifications |
|
example of cancer caused by mutation in protooncogenes (need only 1 allele to be mutated)
multiple endocrine neoplasia Type 2A? |
|
|
RET proto-oncogene:
--activating mutations (gain of function) results in..... --inactivating mutations (loss of function) results in |
--activating mutations (gain of function) results in.....MTC (medullary thyroid carcinoma) & MEN2A (multiple endocrine neoplasia 2A)
--inactivating mutations (loss of function) results in Hirshsprung disease |
|
name me cancers that are caused by mutations in the 3 types of "cancer genes"
1) TUMOR SUPPRESSOR GENES (need 2 mutated alleles...name 3) 2) ONCOGENES (need just 1...name 1) 3) DNA REPAIR genes (need 2 alleles...name 1) |
1) TUMOR SUPPRESSOR GENES --FAP, breast cancer, Rb
2) ONCOGENES -Multiple endocrine neoplasia 2A 3) DNA REPAIR genes --HNPCC (hereditary non-polyposis colon cancer) -HNPCC ( |
|
how common is colon cancer
|
1/12 people will get it!
very common |
|
types of colon cancer?
|
Colorectal cancer
Malignancy of the epithelium - colon and rectum ~15% of all cancer Familial polyposis coli Hereditary nonpolyposis colon cancer |
|
risk of colon cancer inc with
|
age and family hx
|
|
distribution of colon cancer (in terms of sporadic, familial)
|
|
|
____genes are altered in colon carcinogenesis
|
multiple
|
|
3) DNA REPAIR GENES:
Normal function is to repair DNA sequence errors acquired during replication mismatch repair double-strand break repair excision repair Mutations are inactivating/activating mutations (loss/gain of function) ? Mutations lead to unrepaired DNA replication errors and genomic instability Usually require____ to be mutated |
inactivating (loss of function)
both alleles |
|
t/f
mutations of DNA repair genes directly cause cancer |
it is not mutations of the repair genes that causes cancer, rather it is the inability to repair errors which may occur in other genes critical to cell cycle regulation, proliferation, differentiation or apoptosis which result in cancer
|
|
recessive syndromes of DNA repair:
-rare true autosomal recessive syndromes (requiring two inactivating mutations be inherited) Require two inactivating mutations be inherited _____ is one characteristic among many phenotypic abnormalities Cellular deficiency in various aspects of DNA repair |
Malignancy
|
|
Dominant syndromes of
DNA repair Hereditary Non-Polyposis Colon Cancer (HNPCC) frequency 1/200 autosomal dominant colon cancer, endometrial, ovarian age of onset <50years old inactivating mutations in one of the DNA mismatch repair genes (genetic heterogeneity) requires that both copies of the gene involved be mutated one event is___ the second event is ___ |
inherited
somatic |
|
purpose of cancer cytogenetic studies?
|
Diagnosis - recurring chromosomal abnormalities correlate with distinct types and subtypes of cancer
Prognosis - cytogenetic abnormalities are independent predictors of outcome Disease Status - cytogenetic analysis is used to monitor disease status, remission, residual disease, relapse, evolution Treatment - drug therapies can target specifically the abnormal protein resulting from the cytogenetic rearrangement (ATRA, Gleevec) Research - identification of genes involved in cytogenetic rearrangements aids in the understanding of cancer and the development of more effective treatments |
|
types of chromosome rearrangments in cancer
|
translocation
amplification deletion |
|
cytogenetics of leukemia and lymphoma:
Cancers of the blood and blood forming tissues Most studied due to ease of tissue acquisition and cell culture Leukemia and lymphoma are genetic diseases, however, they are not____diseases Chromosome abnormalities are ____ events |
inherited
somatic |
|
which disease is caused by this?
|
CML (Chronic Myelogenous
Leukemia) t(9;22) results in fusion of BCR on chr. 22 and ABL on chr. 9 100% of patients with CML have a fusion of BCR/ABL results in a fusion gene |
|
what's the Philidelphia chromosome?
|
|
|
what's being pointed at?
|
Philidelphia chromsome
|
|
how does Gleevec work?
|
found to be selective for ABL tyrosine kinases including BCR/ABL
|
|
cytogenetics of solid tumors:
Neuroblastoma Most common tumor in ___ Peripheral nervous system tumor arising in the ____ or postganglionic sympathetic neurons 70-80% have deletions or rearrangements of chromosome 1p dmins and hsrs present in ~50% of cytogenetically abnormal cases N-MYC is the critical gene within the amplification unit Cytogenetics has clear correlation to prognosis Homogeneously staining region (also HSR) is one type of change in a chromosome's structure which is frequently observed in the nucleus of human cancer cells. In the region of a chromosome where an HSR occurs, a segment of the chromosome, which presumably contains a gene or genes that give selective advantage to the progression of the cancer, is amplified or duplicated many times. As a result of the duplication this chromosomal segment is greatly lengthened and expanded such that when it is stained with a fluorescent probe specific to the region (Fluorescent in situ hybridization), rather than causing a focal fluorescent signal as in a normal chromosome, the probe "paints" a broad fluorescent signal over the whole of the amplified region. It is because of the appearance of this broadly staining region that this chromosomal abnormality was named a homogeneously staining region. |
children
adrenal medulla |
|
Common pediatric malignancy
~7/1,000,000 children Under age of 15 Most cases are lymphoid 75-80% Both ALL and AML A number of distinct entities --Unique prognosis --Clinical behavior --Response to therapy |
acute leukemia
|
|
Treatment for genetic diseases
|
Infusion therapy
Pharmacogenetics Genomics Gene Therapy |
|
treatment of PKU
|
Treatment: Protein restriction and low phenylalanine diet.
Treated patients show marked reduction in mental impairment if a rigorous diet is maintained. Recent evidence suggests that diet should be continued for life which is contrary to previous treatment regimens |
|
Expression cloning to obtain medically valuable reagents.
As an alternative to purifying an animal product (insulin from cows or pigs) a human gene can be expressed in different cell types so that large amounts of the gene product may be purified and used as recombinant pharmaceuticals. Examples include ____ |
Insulin, growth hormone,
granulocyte colony-stimulating |
|
Enzymes within _______catalyze the degradation of:
sphingolipids, glycosaminoglycans (mucopolysaccharides), glycoproteins and glycolipids Accumulation “storage” of undegraded macromolecules results in cell tissue and organ dysfunction |
lysosomes
|
|
Pompe disease---the enzyme that is deficient does what?
|
converts some glycogen--> gluocose
|
|
Myofibrils replaced by ____ with eventual muscle tissue destruction
|
glycogen
|
|
how can we use infusion technology for lysosomal storage disorders?
|
Lysosomal storage disorders:
DNA recombinant technology is used to artificially produce a protein outside the human body. Protein is isolated and infused intravenously into the patient on a regular basis. Reconstitutes normal activity in the cells and decreases accumulation of the substance. Drawback is protein is short lived, needs repeated infusions. |
|
Pharmacogenetics is the study of how an individual’s
_____ inheritance affects the body’s response to ___ |
genetic
drugs Genetic variability can affect: absorption metabolism transport to the target molecule structure of the intended and/or unintended target molecules degradation of the drug excretion of the degradation products |
|
Mechanisms of pharmacogenetic actions:
|
Drugs cleared by 50% or more by an enzyme exhibiting
functionally relevant polymorphism. Drugs with a steep dose-response curve and a narrow therapeutic window. Drugs whose activity depends upon a metabolite formed by a polymorphic enzyme. Polymorphisms in receptors affecting drug responses. |
|
Goals of gene therapy are to ___,____or ultimately
____ disease by altering the expression of a person’s genes. Genes can be targeted to somatic cells or germ cells. There are currently no clinical studies of germ line gene therapy being conducted. |
treat, cure, prevent
|
|
Tools of gene therapy?
|
Vectors are altered so that harmful genes that make the
viruses disease producing have been removed and the genes of interest have been added in. The genetic machinery that allows viruses to invade cells and incorporate genes into the host chromosome are left intact --Retroviruses: murine leukemia viruses, incorporate DNA into host genome but into dividing cells only. ---Adenoviruses: Viruses that cause the common cold. Higher rate of gene transfer, not incorporated into the genome, quickly rejected by host immune system. Lentiviruses: HIV viruses, incorporate genes into non-dividing cells, provide long term expression but raise concerns of safety despite their genetic engineering. Nonviral vectors: Liposomes are small vesicles made from lipids. Very small vector that can deliver large pieces of genetic material and do not invoke a large immune response but have a poor rate of gene transfer and usually only transiently express gene products. |
|
obstacles of gene therapy
|
Gene expression: Difficult to recapitulate physiological
expression. Altering of host genome. Immune response: Immune system often rejects vector delivery machinery and gene expression is transient. Most promising only altar 20% of target population. Incomplete understanding of pathogenesis and genes involved in disease processes. |
|
let's get the tandem repeats straight:
Tandem repeats occur in DNA when a pattern of two or more nucleotides is repeated and the repetitions are directly adjacent to each other. repeats of 10 and 60 nucleotides: MINISATELLITE or VARIABLE NUMBER TANDEM REPEAT (VNTR) fewer than that (like dinucleotides, trinucleotides) MICROSATELLITES or short tandem repeats (STR) When exactly two nucleotides are repeated, it is called a "dinucleotide repeat"; when three are repeated, it is called a "trinucleotide repeat" |
|
|
genetic polymorphism
|
occurrence of multiple alleles at a locus, where at least 2 alleles appear with frequencies greater than 1%
|
|
importance of DNA polymorphism in medical genetics
|
for gene mapping and linkage analysis--useful for the identification of disease genes. DNA polymorphisms can be used as markers for disease
for the detection of uniparental disomy (UPD) in disease involving imprinted genese |
|
missense mutations
|
point mutation-->results in change in aa
sickle cell anemia-beta-globin gene hemoglobin C (HbC) disease: beta-globin gene hemoglobin constant spring: alpha-globin |
|
nonsense mutation
|
mutation that causes a stop codon-->early termination
stop early?? nonsense! keep going! |
|
RNA splicing mutations
|
nucleotide changes that affect the splice donor/acceptor sites at intron/exon boundaries of genes
|
|
large deletions and insertions usually arise due to
|
recombination bw highly homologous DNA sequences
|
|
dominant mutations are usually
recessive mutations are usually |
gain-of-function or dominant negative
loss of function |