Genetics

Front 1

what's normal human male/female KARYOTYPE?

Back 1

46 XY / 46 XX

Front 2

what are G-pos and G-neg bands in karyotyping?

Back 2

G-positive: dark bands
G-neg: light bands

Front 3

characteristics of G-negative bands in karyotyping?

Back 3

high in GC content
rich in SINE and Alu repeats,
housing-keeping genes,
early replication,
rich in transcribed sequences

Front 4

characteristics of G-positive bands in karyotyping?

Back 4

high in AT content
rich in LINE repeats
tissue-specific genes
late replication
sparse genes

Front 5

3 different chromosome structures

Back 5

Front 6

t/f
female recombination freq > male recomb

Back 6

true

Front 7

t/f
recombination decreases near telomeres

Back 7

false
Recombination increases near telomeres in both sexes

Front 8

when does meiosis of germ cells commence in males? females?

Back 8

male: at puberty
female: 3rd month prenatal (arrest in MI prophase until ovulation, arrest again in MII metaphase until fertilization)

Front 9

t/f
Parental origin of the extra chromosome in trisomy is most often maternal and most often a result of a MI error.

Back 9

true

Front 10

which one is the smallest chromosome?

Back 10

21

Front 11

what is polyploidy? is it euploid or aneuploid?

Back 11

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)

Front 12

what is least severe: trisomy 18, 13 or 21?

Back 12

21 (down's syndrome) 1/600 - 1/700 births (40% have heart defects)

Front 13

what are some characteristics of trisomy 18 and 13?

Back 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

Front 14

what is this type of chromosome abnormality called?

Back 14

isochromosome

Front 15

what is paracentric vs pericentric inversion?

Back 15

paracentric: centrosome not involved
peri: centrosome involved

Front 16

what is FISH in cytogenetics?

Back 16

fluorescent in-situ hybridization;

Labeled DNA Probe Hybridized To Metaphase Or Interphase Preparations

Identification And Characterization Of Structural Chromosome Abnormality

Front 17

what is DiGeorge syndrome? what causes the genetic abnormality?

Back 17

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)

Front 18

what is william's syndrome?

Back 18

deletion of ch 7 region;
Deletion of elastin gene + others
Mental Retardation w/ microcephaly
Supravalvar aortic stenosis

Front 19

what is miller dierker syndrome?

Back 19

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.

Front 20

what is prader willi and angelman syndrome? what is the genetic significance of these disorders?

Back 20

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

Front 21

t/f
gene encoding Insulin-like growth factor 2 (IGF2/Igf2) is only expressed from the allele inherited from the father

Back 21

true (maternal imprinting)
remember from endo: paternal genes want baby to grow, maternal genes want to suppress.
IGF2 for neonatal growth, not important postnatal.

Front 22

where is the pseudoautosomal region on Y chromosome in relation to SRY gene?

Back 22

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

Front 23

what are Barr bodies?

Back 23

inactive X chromosomes - associated with nuclear membrane

Front 24

when are X chromosomes inactivated?

Back 24

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")

Front 25

what are the characteristics of X chr inactivation?

Back 25

RANDOM - either paternal or maternal X, random cells (mosaic)
CLONAL
INCOMPLETE - some genes escape inactivation (most on short arm)

Front 26

how are X chromosomes inactivated?

Back 26

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

Front 27

what is turner's syndrome?

Back 27

45, x
amenorrhea
short webbed neck
short stature
congenital heart problems

Front 28

what is unfortunate lyonization?

Back 28

skewed X inactivation
5-10% females (inactivate X chr with wildtype alleles -> active X expresses abnormal alleles or carries unbalanced translocation)

Front 29

consequences of polysomy X in females?

Back 29

47 XXX : usually benign, mild mental retardation, sterility, menstrual irregularity
48 XXXX, 49 XXXXX: each additional X = inc. MR and physical abnormalities

Front 30

what is Klinefelter Syndrome?

Back 30

47 XXY, 48 XXXY, 49 XXXXY
MALE, each additional X = inc. MR and physical abnormalities;
-small testes
-infertile
-gynecomastia (incr. risk breast cancer)

Front 31

consequences of 47 XYY?

Back 31

(prev. thought to be involved in violent crimes, but not true)

taller than avg, 10-15 lower IQ pts, hyperactive, ADD, learning problems

Front 32

what are comparative genomic hybridization arrays?

Back 32

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 #)

Front 33

how can we categorize chromosomal abnormalities?
(3)

Back 33

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)

Front 34

identify the structural chromosome abnormality

Back 34

Front 35

Most balanced translocations have normal phenotype, unless what?
(3 things)

Back 35

-breakpoint disrupts a gene
-deletion occurs at breakpoint or -involves an X-autosome rearrangement

Front 36

draw it out...seriously!!
okay afshan, remember that they're different chromosomes!

Back 36

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

Front 37

explain imprinting

Back 37

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.

Front 38

phenotype of 17q deletion?

Back 38

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

Front 39

When you see written 2n2c, what does

n =


c =

Back 39

n=haploid chromosome #

c=DNA content

Front 40

when is DNA least condensed? most condensed?

Back 40

Front 41

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

Back 41

Front 42

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).

Back 42

dicytotene

Front 43

Monosomies of ALL chromosomes are not viable except those of __________

Trisomes of only 3 chromosomes are viable. which ones?

Back 43

sex chromosomes

13, 18, 21

Front 44

Draw out the outcomes

Back 44

(Trisomy and monosomy can originate from meiotic or mitotic nondisjunction)

Front 45

features of Down's syndrome?

Back 45

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.

Front 46

name the disorder

Back 46

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

Front 47

name the disorder

Back 47

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

Front 48

what are 2 causes of nondisjunction?

Back 48

Advanced maternal Age


Altered Recombination

Front 49

A Robertsonian translocation is a type of nonreciprocal translocation between two___________ ____________ chromosomes

Back 49

nonhomologous acrocentric

(chromosomes that are not members of the same pair and have centromeres near their ends)

Front 50

The more X’s you have, then the more risk of defects… why?

Back 50

Because there are some stuff on X’s that escape inactivation

Front 51

what are 2 potential outcomes of
a female carrier of an X-linked mutation or deletion on one of her two X chromosomes:

Back 51

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.

Front 52

Most Turner syndrome cases caused by

Back 52

meiotic error in the father (offspring receives X chromosome from mother, but no sex chromosome from the father).

Front 53

t/f
30-40% of individuals with Turner are mosaics:

Back 53

true

45,X/46,XX
45,X/46,XY – these individuals are at risk for developing malignancies in their streak gonads (gonadoblastomas)

Front 54

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???

Back 54

Explained by X-inactivation resulting in dosage compensation

Front 55

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?

Back 55

bc x-inactivation is incomplete

Front 56

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

Back 56

concordant

discordant

Front 57

what's the relative risk ratio?

Back 57

relative risk ratio =
(prevalence of the disease in the relatives of an affected person/prevalence of disease in general population)

Front 58

what's ascertainment bias?

Back 58

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

Front 59

recall bias?

Back 59

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.

Front 60

osteogenesis imperfecta: genetic defect?

Back 60

dominant negative COL1A1 or 2 (collagen triple helix formation -> mutation interrupt formation of normal collagen molecules)

Front 61

define:
homozygous
heterozygous
hemizygous

Back 61

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

Front 62

Phenotype results from only 1 copy of the mutated allele (heterozygotes)

Back 62

dominant

Front 63

achondroplasia is an example of a ________ mutation

Back 63

gain of function!
Mutation leads to increased function of receptor
so increased or too much restriction of bone growth.

Front 64

osteogenesis imperfecta is an example of _________ mutation

Back 64

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.

Front 65

how can only 1 copy of a
mutated allele cause a disorder/disease?

Back 65

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.

Front 66

what's locus heterogeneity?

Back 66

Mutations at two or more loci
may result in similar phenotype (genetic or locus
heterogeneity)


Deafness, tuberous sclerosis, muscular dystrophy

Front 67

what's this:
Different mutations in the same gene may result in the same disease.

Back 67

allelic heterogeneity

Front 68

More than one phenotype
may be caused by different mutations in the same gene

Back 68

phenotypic heterogeneity

Front 69

what kind of mutation is trasmitted in this pedigree?

Back 69

autosomal dominant

Front 70

this?

Back 70

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

Front 71

this?

Back 71

Don’t rule out autosomal dominant….it could be low penetrence

Front 72

Back 72

Don’t rule out autosomal dominant….it could be low penetrence

Front 73

For Autosomal Dominant mutation, what's the:
Transmission


Recurrence risk

Sex ratio

Status of parents

Back 73

Transmission
Vertical
Through both sexes
Male to male

Recurrence risk
1-in-2

Sex ratio
Males = females

Status of parents
Often affected

Front 74

Back 74

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

Front 75

Back 75

The parents are cousins!!! So recessive

Front 76

for autosomal recessive, what's the:

Status of parents

Disease alleles

Complicating factors

Back 76

Status of parents
Normal
Consanguineous


Disease alleles
Identity by descent
Compound heterozygosity

Complicating factors
Ethnic associations
Genetic heterogeneity

Front 77

what can complicate classifiying a mutation autosomal dominant?

Back 77

Complicating factors
Penetrance
Variable expressivity
New mutation
Pleiotropy
Homozygosity
Anticipation/Mosaicism

Front 78

Back 78

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

Front 79

Back 79

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)

Front 80

Back 80

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)

Front 81

x-linked activation:


Females may be either _________or _________
Males have only 1 X chromosome so __________

Back 81

Front 82

For X-linked, what's the

transmission
recurrence risk
carrier risk
sex ratio

Back 82

Front 83

Back 83

y-linked

Front 84

what type of mutation is described?

Back 84

Y-linked

Front 85

The transcriptional factors are _____-acting because they are synthesized on remotely located genes and are required to migrate to their sites of action.

Back 85

trans

Front 86

The promoter elements are ___-acting because their function is limited to the DNA duplex on which they reside.

Back 86

cis

Front 87

different types of transcriptional modification?

Back 87

Front 88

what's the difference between general transcription factors and upstream txn factors?

Back 88

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

Front 89

what are some types of DNA binding domains for txn factors?

Back 89

zinc finger
leucinezipper (hetero/homodimers)
helix-turn-helix domains

Front 90

what are insulator elements?

Back 90

- buffer genes from the repressing effects of heterochromatin
- block the action of enhancers
- divide genome into "independent domains" of gene regulation

Front 91

list common epigenetic control

Back 91

DNA methylation
histone modification (acetylation, methylation, phosphorylation)
RNA processing

Front 92

what mediates histone acetylation?

Back 92

histone acetyl transferases (acetylated -> active)
deacetyltransferases silence

Front 93

effect of histone methylation?

Back 93

of lysine 9 on the N terminus of histone H3 is a hallmark of silent DNA, of lysine 4 of histone H3 denotes activity

Front 94

effect of DNA methylation?

Back 94

C5 position of cytosine/guanine pairs (CpG) -> silencing, mediated by DNMT

CpG islands: txn activators bind

Front 95

how is H9 methylation-silencing mediated?

Back 95

MECP2 binds methylated promotor sites and recruits the mSinA/HDCA1,2 corepressor complex

Front 96

what is UPD?

Back 96

uniparental disomy: inheriting both chromosomes from same parent.

Front 97

what are microRNAs?

Back 97

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)

Front 98

marfan features?

Back 98

dislocated lenses
dilated aortic root
arachnodactyly (spider fingers...long and slender fingers)
flat feet
pectus excavatum
family history

Front 99

what mediates the phenotypic consequences of marfan?

Back 99

TGFb overexpression

Front 100

what are common environmental causes of neural tube defects?

Back 100

-Teratogens: aminopterin, thalidomide
-maternal insulin dependent diabetes

Front 101

what are common syndromes associated with neural tube defects?

Back 101

trisomy 13, 18
meckel's syndrome (single gene)

Front 102

what's a good treatment to prevent neural tube defects?

Back 102

maternal folate therapy

Front 103

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).

Back 103

10^6

Front 104

what factors affect recombination rate?

Back 104

sex (F>M), distance from centromere (dec recombination), distance from telomere (­inc recombination), and other chromatin structures

Front 105

what kind of newborn screening is detected by tandem mass spec?

Back 105

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

Front 106

what's PKU? symptoms?

Back 106

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

Front 107

what's the most common f.a. oxidation disorder?

Back 107

MCAD (medium chain acyl
CoA dehydrogenase deficiency)
fat accumulation in liver and mm.

Front 108

why are CG dinucleotides hotspots for mutations?

Back 108

C -> (meth) 5-methylcytosine -> deamination: thymine

Front 109

what's most common mutation for CF?

Back 109

deltaF508 (in frame deletion)

Front 110

what's the common genetic cause of b-thalassemia?

Back 110

nonsense mutation in b-globin gene to make hemoglobin
(many other mutations reported)
-> a/b globin ratio imbalance,excess globins destroy rbc membrane -> anemia

Front 111

genetic cause of sickle cell?

Back 111

glu -> val mutation in b-globin gene -> sticky

Front 112

what is singlestrand conformational polymorphism?

Back 112

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

Front 113

what's Heteroduplex-based mutation scanning

Back 113

followed by separation by size (gel or HPLC)

Front 114

what's DHPLC?

Back 114

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

Front 115

wot's genetic cause of DMD?

Back 115

duchene muscular dystrophy (muscle wasting), X-linked rec, >60% b/c of intragenic deletions

Front 116

newborn test for PKU is mandated in the US. what's the common test for PKU?

Back 116

Guthrie test
(excess F in blood help bacterial growth in media with inhibitor)
or just tandem-repeat mass spec

Front 117

what are some PCR based genetic methods for detecting known mutations?

Back 117

single base extension
allele-specific PCR
FRET primers
real-time quantitative PCR

Front 118

how do you detect mutations with known genes but unknown common mutations?

Back 118

sequencing, heteroduplex-based mutation scanning, Single Stranded-Conformational Polymorphism, genetic marker (e.g. RFLPs, SNPs) linkage analysis

Front 119

genetic cause of achondroplasia?

Back 119

(dwarfism)
GOF mutation of FGFR3 (normally inhibitory for bone growth, mutation leads to const. activation)

Front 120

what is stickler' syndrome?

Back 120

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

Front 121

class 1 vs class 2 trinucleotide repeat disorders?

Back 121

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.

Front 122

some examples of trinucleotide repeat disorders?

Back 122

Myotonic dystrophy
huntington
Friedreich ataxia
fragile x (FMR1 gene)

Front 123

what's GJB2/Connexin 26 implicated in?

Back 123

Accounts for 50-80% of non-syndromic recessive deafness and 10-37% of sporadic deafness,
potassium recycling in cochlear endolymph

Front 124

how do you calculate allele frequency?

Back 124

Front 125

what are the assumptions of the Hardy-Weinsberg model?

Back 125

. 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

Front 126

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

Back 126

(p x p) = p2

(p x q) + (q x p) = 2pq

(q x q) = q2

Front 127

p2 + 2pq + q2 = ____

Back 127

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

Front 128

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

Back 128

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)

Front 129

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?

Back 129

2pq is the population carrer frequency….(prob that Jim is a carrier)

Front 130

What is the chance Sam’s brother is a carrier?

Back 130

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

Front 131

It is not uncommon to find _____ among parents of children with rare autosomal recessive conditions.

Back 131

consanguinity

Front 132

Alters genotype proportions in a population by increasing or decreasing fitness

Back 132

natural selection

Front 133

Sickle cell anemia is an exampleof ____selection

Back 133

balancing


Carriers of the sickle allele (and other hemoglobin mutations) are more resistant to malaria than either homozygous class (HbAA or HbSS)

Front 134

Males are ____for X-linked conditions

Back 134

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

Front 135

The frequency of an X-linked condition in males equals ______

Back 135

the recessive allele frequency = q


The frequency of carrier females equals 2pq

Front 136

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.

Back 136

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)

Front 137

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.

Back 137

Front 138

recurrence risk of chromosomal abnormalities?

Back 138

Front 139

indications for diagnosis of mendelian disorders?

Back 139

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

Front 140

what are some multifactorial disorders?

Back 140

Neural tube defects
Facial clefts
Cardiac defects
Abdominal wall defects

Front 141

indications for diagnosis of multifactorial disorder?

Back 141

Previous child, either parent or parental sibling with a multifactorial abnormality
Ultrasound examination suggesting presence of an isolated anomaly
Elevated maternal serum AFP

Front 142

what are the prenatal screens/tests?

Back 142

Maternal blood tests
Ultrasound
Amniocentesis
CVS (chorionic villus sampling)
PUBS (percutaneous umbilical blood sampling)

Front 143

indications for NTD diagnosis?

Back 143

Previous affected offspring
Affected parent
Affected sib of parent
Affected niece or nephew
Elevated maternal serum alpha-fetoprotein

Front 144

what's ALPHA-FETOPROTEIN?

Back 144

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

Front 145

what's the ALPHA-FETOPROTEIN prenatal testing protocol?

Back 145

Front 146

what would the uE3, AFP, hCG, inhibin profile look like for trisomy 21, 18?

(in the second trimester!)

Back 146

Front 147

what's the hCG, PAPP-A profile look like for trisomies?

**in the first semester!

Back 147

Front 148

what can you see in a fetal sonograph?

Back 148

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

Front 149

what's amniocentesis?

Back 149

Front 150

what's CVS?

Back 150

http://en.wikipedia.org/wiki/Chorion

Front 151

what's the "integrated" screening for Down Syndrome

Back 151

combination of first and second trimester screening

--first trimester: PAPP A, nuchal translucency
--second trimester: MSAFP, uE3, hCG

Front 152

etiology of congenital malformations?

Back 152

chromosome abnormalities
mendelian disorders (single gene disorders)
polygenic/multifactorial conditions
environmentally induced abnormalities

Front 153

indications for prenatal cytogenetic diagnosis?

Back 153

Advanced maternal age
Previous trisomic offspring
Parental chromosome rearrangement
Abnormal maternal serum screen
Abnormal ultrasound finding
Parental anxiety
Other tests being performed concurrently

Front 154

recurrence risk after birth of child with chromosome abnormality

Trisomy 21
Trisomy 18
Trisomy 13
Other autosomal abn.
Sex chromosome abn.
Total

Back 154

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%)

Front 155

with the following parental rearrangements, what's the risk of an unbalanced fetus?

Robertsonian
Translocation

Reciprocal
Translocation

Inversion

Back 155

Robertsonian
Translocation 1-15%

Reciprocal
Translocation 11%

Inversion 2%


these are empirical...not theoretical!
(how do you get an unbalanced fetus with an inversion...?

Front 156

what are the detection rates of anencephaly and spina bifida for AFP screening and amniotic fluid AFP

Back 156

screening:
ANENCEPHALY 90%

SPINA BIFIDA 80%

amniotic fluid AFP:
DETECTION RATE
ANENCEPHALY 100%

SPINA BIFIDA 90%

Front 157

when you do the second trimester maternal serum screening (checking the levels of hCG, inhibin, ue3, AFP)....what's the detection rate?

Back 157

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

Front 158

what about first trimester maternal serum screening (ie when you check hCG, PAPP-a)...what's the detection rate?

Back 158

83% detection rate for trisomy 21(5% false positive rate)

90% detection of other chromosome abnormalities (1% false positive rate)

Front 159

complications of amniocentesis?

Back 159

MATERNAL
Cramping Common
Fluid leakage,
infection,spotting Rare
FETAL
Abortion < 0.5%
Injury Very rare

Front 160

complications of CVS?

Back 160

MATERNAL
bleeding 1-30%
Amnionitis Rare
FETAL
Abortion 0.5%-1
Injury Very rare

Front 161

what's the rationale for preimplantation diagnosis?

Back 161

RATIONALE
Diagnosis before pregnancy begins
Reduces burden on family of multiple affected pregnancies
Treatment possible before irreversible damage

Front 162

what are the approaches of preimplantation diagnosis?

Back 162

Trophectoderm biopsy at 5-6 days

Zygote biopsy at 6-10 cell stage

Polar body analysis prior to fertilization

Front 163

rationale for testing fetal cells in the maternal circulation?

Back 163

Noninvasive

Applicable to the entire pregnant population

Front 164

fetal cells in maternal circulation?

Back 164

Lymphocytes
Trophoblasts
Erythroblasts (nucleated red blood cells)
Free DNA

Front 165

how do you test fetal cells in maternal circulation?

Back 165

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

Front 166

defect in ______ occurs in all tumors

Back 166

Front 167

tumors are clones of _____

Back 167

aberrant cells

Front 168

what's the 2-hit hypothesis?

Back 168

Front 169

only ____ % of all cancers are inherited

Back 169

5-10%

Front 170

what are the 3 classes of "cancer genes"

Back 170

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

Front 171

how is cell growth like in normal cells? cancer cells?

Back 171

Front 172

one/both alleles of tumor suppressor genes need to be inactivated for cancer

Back 172

both!

Front 173

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?

Back 173

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

Front 174

how do you lose heterozygosity?

Back 174

Front 175

what does RB do in the cell cycle?

Back 175

Front 176

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

Back 176

dominant

APC

Front 177

clinical features of Familial Adenomatous Polyposis (FAP)

Back 177

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

Front 178

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)

Back 178

dominant

Front 179

what are the 2 genes that account for 20-40% and 10-30% of inherited breast cancer?

Back 179

BRCA1 and BRCA2

Front 180

oncogenes...how many mutated alleles need to be mutated for cancer?

1 or 2?

Back 180

1 is sufficient

Front 181

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

Back 181

proto-oncogenes

gain-of-function

Front 182

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 ____

Back 182

normal cell growth

cell cycle and cell division

Front 183

what are some mechanisms by which protooncogenes are activated?

Back 183

Point mutations
Chromosomal rearrangements or translocations
Gene amplifications

Front 184

example of cancer caused by mutation in protooncogenes (need only 1 allele to be mutated)

multiple endocrine neoplasia Type 2A?

Back 184

Front 185

RET proto-oncogene:

--activating mutations (gain of function) results in.....

--inactivating mutations (loss of function) results in

Back 185

--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

Front 186

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)

Back 186

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 (

Front 187

how common is colon cancer

Back 187

1/12 people will get it!
very common

Front 188

types of colon cancer?

Back 188

Colorectal cancer
Malignancy of the epithelium - colon and rectum
~15% of all cancer

Familial polyposis coli

Hereditary nonpolyposis colon cancer

Front 189

risk of colon cancer inc with

Back 189

age and family hx

Front 190

distribution of colon cancer (in terms of sporadic, familial)

Back 190

Front 191

____genes are altered in colon carcinogenesis

Back 191

multiple

Front 192

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

Back 192

inactivating (loss of function)


both alleles

Front 193

t/f
mutations of DNA repair genes directly cause cancer

Back 193

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

Front 194

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

Back 194

Malignancy

Front 195

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 ___

Back 195

inherited

somatic

Front 196

purpose of cancer cytogenetic studies?

Back 196

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

Front 197

types of chromosome rearrangments in cancer

Back 197

translocation
amplification
deletion

Front 198

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

Back 198

inherited

somatic

Front 199

which disease is caused by this?

Back 199

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

Front 200

what's the Philidelphia chromosome?

Back 200

Front 201

what's being pointed at?

Back 201

Philidelphia chromsome

Front 202

how does Gleevec work?

Back 202

found to be selective for ABL tyrosine kinases including BCR/ABL

Front 203

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.

Back 203

children

adrenal medulla

Front 204

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

Back 204

acute leukemia

Front 205

Treatment for genetic diseases

Back 205

Infusion therapy

Pharmacogenetics

Genomics

Gene Therapy

Front 206

treatment of PKU

Back 206

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

Front 207

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 ____

Back 207

Insulin, growth hormone,
granulocyte colony-stimulating

Front 208

Enzymes within _______catalyze the degradation of:
sphingolipids, glycosaminoglycans (mucopolysaccharides), glycoproteins and glycolipids
Accumulation “storage” of undegraded macromolecules results in cell tissue and organ dysfunction

Back 208

lysosomes

Front 209

Pompe disease---the enzyme that is deficient does what?

Back 209

converts some glycogen--> gluocose

Front 210

Myofibrils replaced by ____ with eventual muscle tissue destruction

Back 210

glycogen

Front 211

how can we use infusion technology for lysosomal storage disorders?

Back 211

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.

Front 212

Pharmacogenetics is the study of how an individual’s
_____ inheritance affects the body’s response to ___

Back 212

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

Front 213

Mechanisms of pharmacogenetic actions:

Back 213

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.

Front 214

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.

Back 214

treat, cure, prevent

Front 215

Tools of gene therapy?

Back 215

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.

Front 216

obstacles of gene therapy

Back 216

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.

Front 217

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"

Back 217

Front 218

genetic polymorphism

Back 218

occurrence of multiple alleles at a locus, where at least 2 alleles appear with frequencies greater than 1%

Front 219

importance of DNA polymorphism in medical genetics

Back 219

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

Front 220

missense mutations

Back 220

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

Front 221

nonsense mutation

Back 221

mutation that causes a stop codon-->early termination

stop early?? nonsense! keep going!

Front 222

RNA splicing mutations

Back 222

nucleotide changes that affect the splice donor/acceptor sites at intron/exon boundaries of genes

Front 223

large deletions and insertions usually arise due to

Back 223

recombination bw highly homologous DNA sequences

Front 224

dominant mutations are usually


recessive mutations are usually

Back 224

gain-of-function or dominant negative


loss of function