Meiosis/Mitosis, Clinical Cytogenetics, Some syndromes, Bayes Flashcards
ploidy/n refers to
of alleles of different sources at a locus, OR number of chromosomes from different people
eg, 2n = 1 paternal, 1 maternal
(even if the two are duplicated in a cell)
ploidy/c refers to
number of chromosome copies of a single chromosome (maternal, and paternal combined)
2c = 1 maternal, 1 paternal
4c = 2 maternal, 2 paternal (at beginning of meiosis 1)
1c = 1 paternal OR maternal chromosome, inside each gamete
meiosis 1 begins with __n and __c
2n and 4c
the genetic content is already duplicated before meiosis 1 begins, so 4c, not 2c
end of meiosis 1, __n and __c
end of meiosis 1:
1n, 2c
–> only maternal or paternal chroms, half the # of chroms
Does DNA replication increase the number of chromosomes?
NO!
DNA replication itself increases the amount of DNA but does not increase the number of chromosomes. The two identical copies—each forming one half of the replicated chromosome—are called chromatids
what is on the p arm of the acrocentrics?
rRNA genes
Cell division
G1
S
G2
M
G1 –> cell does whatever it is programmed (e.g., liver cell does liver things)
S –> DNA is replicated (46 chrs -> 46 chrms, but with two sister chromatids for every paternal and maternal)
G2 –> resting, not all cells have this
M –> mitosis
the genetic map is longer in males or females? why?
Recombination map is longer in females because they have a higher rate of recombination than males
males have ~2.4 chiasmata per chromosome, and male recombination rate is HIGHER at telomeres
At what age do female eggs go through meiosis I?
At 3-4 months IN UTERO –> suspended in diplotene in Meiosis I (after doubling of DNA)
When is the first division (Meiosis I) complete in female eggs?
1st division of Meiosis completes at ovulation
When is second division of meiosis (meiosis II) complete in female eggs?
2nd division in eggs is complete at fertilization
Meiosis in males - when?
begins at puberty, takes 20 days
spermatogenesis takes longer
Three mechanisms that lead to aneuploidy
- non-disjunction –> trisomy and monosomy
- premature centromere division (in meiosis 1) –> trisomy and monosomy
- anaphase lag —> monosomy only
(anaphase lag = one chrom doesn’t attach to spindle at metaphase, and is lost outside of the cell and digested by enzymes. Results in MONOSOMY)
e.g. female has non-disjunction in Meiosis 1 vs Meiosis 2:
In which one, 1 or 2, is there a possibility of UPD?
non-disjunction in female meiosis 2 yields trisomy (in combination w other dad’s chrom), with two of the three chroms coming from the same chrom in mom (her paternal or her maternal, because the chromatids don’t separate properly during meiosis 2).
Any Trisomy can go through Trisomy rescue, and if dad’s chrom is lost in this case, the kid will be left with 2 of mom’s identical chromosomes (from the same grandparent)
gamete outcomes if
- non-disjunction in meiosis 1?
- non-disjunction in meiosis 2?
meiosis 1 - trisomy, monosomy
meiosis 2 - trisomy, monosomy, trisomy rescue (UPD poss), normal
leading known cause of pregnancy loss
aneuploidy
leading cause of intellectual disability
aneuploidy
100% of trisomy 16 is _____ (mat or pat) in origin
maternal - 100% of Tri 16
Klinefelter syndrome - source of aneuploidy - mom or dad?
55% mom
45% dad
mostly mom, but about even
Turner syndrome - source of aneuploidy - mom or dad? Source of X chrom, mom or dad?
Turner
aneuploidy mostly due to dad (80%)
X is maternal 80% of time
most aneuploidies are due to mom or dad? due to non-disjunction in meiosis 1 or 2?
most due to mom
most in meiosis 1 (75%)
what percent of Turner syndrome girls survive to term?
0.3%
what percent of XXX syndrome survive to term?
what is prevalence of XXX?
95% – most survive
1 in 1000
UPD (from isodisomy followed by trisomy rescue) is due to Meiosis __ error
meiosis II
heterodisomy – what is it?
from error in which meiosis?
inheritance of two different chromosomes from ONE parent
e.g., one grandma’s and one grandpa’s from mom, and one from dad
error in meiosis I
UPD mechanisms
- gamete complementation (disomic egg and nullosomic sperm)
- trisomy rescue
- monosomy rescue (duplication of monosomic chrom)
- somatic crossing over (segmental UPD) - heterodisomy from one parent, but only segmental due to crossing over BEFORE meiosis begins
Significance or random marker or ring chromosome
could mean UPD
Prader-Willi with less hypopigmentation – what is likely molecular mechanism of this syndrome?
matUPD15
Triploidy - what percent of
- chromosomally abnormal spontaneous abortions
- all spontaneous abortions
- 15-20% of chrom abn
2. ~6% of ALL
Triploidy mostly due to mom or dad?
dad (85%)
hydatiform mole - can be due to what? larger, cystic(hydropic vili) placenta… survive or do not survive to term?
diandric triploidy (extra dad set of chroms) –> usually do NOT survive to term
syndactyly of 3rd and 4th fingers, incomplete ossification of the skull;
signs of …?
triploidy
IUGR, small/fibrotic placenta, macrocephaly
digynic triploidy (extra mom set of chroms) –> can survive up to a year
complete vs partial mole: has fetus or no?
partial – may have fetus
complete - never has fetus
complete mole - typical karyotype and mechanism
46,XX (85%) –> because empty egg fuses with sperm; sperm DNA doubles.
complete vs partial mole – why necessary to karyotype?
if triploid, then partial, very very rare risk for choriocarcinoma.
if not triploid, then complete, then 15-20% chance choriocarcinoma.
what is a benign ovarian teratoma?
tumor with hair, teeth, etc.
from egg with two sets of chroms from non-disjunction.
teratoma due to female, mole due to male.
___% of couples with 2 or more SABs have a chromosomal abnormality (translocation or inversion)
6%
3% if you’re looking at an individual within a couple
__% liveborns with chromosomal abnormality
0.5%
__% SABs with chromosomal abnormality in 1st tri
40%
__% SABs with chromosomal abnormality in 2nd tri
15%
MCC rate in CVS
1.8%
confined placental mosaicism rate
1-2%
confined placental mosaicism: increased risk for which 3 things?
- chromosomal abnormality
- UPD
- IUGR, IUFD in 16-21%
if see confined placental mosaicism – what is the chance fetus actually has mosaicism?
10%
things like common trisomies, and mosaicism in cultured prep and/or involving marker chromosomes make it more likely
if ultrasound abnormality, chance of chrom abnormality?
16%
Robertsonian Down syndrome in baby – what is chance that a parent is a carrier of a Rob?
40-60%
Trisomy 21 is what percent of Down syndrome?
95% ; trisomy refers to non-disjunction type
female 14;21 translocation carrier is more/less likely to have a carrier vs “normal” child
more likely to have carrier (60%) than “normal” (40%) if child is phenotypically “normal”
Patau syndrome (tri 13) — what proportion is due to Rob 13;14?
46,XX,+13,der(13;14)(q10;q10)
if due to Rob, chance a parent is a carrier?
1 in 5 due to Rob
55% chance that parent is t(13;14) carrier
Rob 13/14 carrier parent: chance of child with tri 13?
prevalence of rob 13/14
1% because tri13 so lethal
1 in 1,100
most common autosomal trisomy
tri 16 (not in liveborn kids – pay attention to liveborn vs not)
if child has unbalanced translocation, __ of the time, the parent has a balanced one.
Inversions in kid = ___% it’s inherited
82% – majority of time inherited from balanced parent!
92% inversions inherited
if de novo inversion, __% chance serious congenital abnormality
9% –> but, ascertainment bias in this 1991 study.
most LARGE structural rearrangements (terminal deletions, interstitial deletions, unbalanced translocations, de novo non-recurring, balanced reciprocal translocations) —> maternal or paternal in origin?
paternal 62-84%
de novo non-homologous Robertsonian translocations (e.g., 14;21) — mostly maternal or paternal?
90% maternal
microdeletions – mostly maternal or paternal?
neither - no sex bias in these, only in LARGE structural rearrangements.
Most common Robertsonian translocation
13;14 (85% of total!!!)
Homologous vs non-homologous Robertsonian translocations – risk of UPD
homologous»_space; non-homologous for risk of UPD
66-73% »_space; 0.6-0.8%
…if in phenotypically normal individuals
…if phenotypically abnormal, then
~100% if homologous»_space; 5% if non-homologous
When test for UPD?
The ACMG recommends that UPD testing be considered when a carrier fetus is identified with a Robertsonian involving chromosomes 14 or 15
Test patients with abnormal phenotypes and a balanced Robertsonian involving 14 or 15
Remember that carriers of both familial and de novo Robertsonian translocations have been identified with UPD
Reciprocal translocation - what percent are inherited?
70% inherited
Reciprocal translocation - estimating risk of abnormal birth:
if have “abnormal” liveborn children in family?
if do not?
if ascertained due to “high risk pregnancy” (eg AMA)?
other affected kids in fam - 20-25%
no affected kids - 3%
high risk 4-5%
Reciprocal translocation: size of imbalance
small –> risk of “abnormal” birth?
large –> risk of abnormal birth?
small –> high
large –> low, but high risk of miscarriage
in reciprocal translocations, in the cruciform:
difference between adjacent 1 and adjacent 2 segregation? which is more common? which is more likely to cause an unbalanced karyotype in a liveborn, along with 3:1 segregation?
adjacent 1 –> segregants have 1 of each “type” of centromere
adjacent 2 –> both centromeres are from the same “type” of chromosome (this is much more rare)
adjacent-1 is more likely to cause an unbalanced karyotype
alternate segregation of a reciprocal translocation can have which outcomes?
2 normal chromosomes, OR
2 abnormal, but balanced chromosomes
alternate = every other chromosome segregates together out of cruciform
3-1 segregation in the reciprocal translocation cruciform yields what
two of the same chromosome, and one extra of a different type
Common reciprocal translocation in human population, and what type of segregants are most likely for offspring of carriers?
what are risks of kids “affected” based on sex of parent?
t(11;22)(q23.3;q11.2) ; typically, with an extra chr 22
3:1 –> most likely mechanism of”abnormal” birth
dad carrier: 3%
mom carrier: 5-7%
Another common reciprocal translocation mimics Wolf-Hirschorn syndrome
46,XX or XY t(4;8)(p16;p23)
mimics W-H due to deletion of 4p being viable, partial trisomy 8p
breakpoints are clustered in the 2 olfactory receptor (OFR) gene clusters on 4p and one OFR gene cluster on 8p
de novos due to inversion in mom
pericentric inversions - if odd number of crossing-over, what kind of cytogenetic abnormality is likely in the kid?
deletion/duplication syndromes
the larger the inversion (the more distal the breakpoints) – the higher the risk of an abnormality in liveborn children.
- because larger inversion – more risk of crossing over in between
- larger inversion –> smaller distal section that can be deleted/duplicated –> higher risk of liveborn child with abnormality
paracentric / pericentric inversions –> if odd number of recombinants between them, more or less likely to have a cytogenetic imbalance?
odd # crossovers –> imbalanced recombinant chromosomes
risk of unbalanced karyotype if
- pericentric inversion
- paracentric inversion
peri 10-15%
para 0.1-0.5%
Ring chromosomes can lead to dynamic mosiaicism. what is it?
dynamic mosaicism due to ring chroms is:
when various things can happen to ring chroms: lose it, etc, over course of development.
Ring Chromosome Syndrome
severe growth retardation
mild-moderate mental retardation
due to either “dynamic mosaicism” and interrupted mitosis in developing tissues, OR due to microscopic deletions.
Ring chromosomes
% de novo?
if inherited, from whom?
99% de novo
inherited from mom
Ring chromosomes can be a symptom of…
UPD – if trisomy rescue, extra chromosome forms ring and peaces out
can you see supernumerary marker chromosomes on traditional karyotype? (SMCs)
no
Marker chromosomes
- prevalence
- which chroms preferentially derived from?
- what fraction de novo?
- any other associations?
marker chromosomes:
1 in 4,000
acrocentrics, esp chr 15 (40%)
80% de novo
maternal age effect
Pallister-Killian
- traits?
- mechanism?
- testing limitations?
- MR
- hyper- and hypo- pigmented streaks
- heart, intestinal issues, skeletal issues
- less hair on temples
- coarse facies
isochromosome 12p
- iso12p not present in dividing cells of blood used for cytogenetic prep, but IS present in blood when doing array
- usually can see iso12p in fibroblasts
- “tissue-limited mosaicism”
marker chromosomes; risk of abnormal phenotype if
- acrocentric?
- non-acrocentric?
acrocentric 7-11%
non-acro 28%
UPD possible
what is Phytohemagluttinin added for?
To stimulate cell division of T cells
(limitation: DiGeorge patients don’t have many T cells, so need “pokeweed” added that stimulates both T and B cells).
purpose of adding colchicine to cell culture
stops cells division
purpose of hypotonic solution
water rushes into cells to swell cells – helps chroms get ddisentangled
What kind of cancer do these people have increased risk for? Tri8 Down syndrome Turner 47, XXY
Tri8 - myeloid neoplasia
Down Syndrome - acute leukemia
Turner (can be phenotypic female)- gonadoblastoma (due to Y chrom) -
Klinefelter - breast cancer ~ female br ca risk
Wilms Tumor predisposition area
11p13, 11p15
barr body - what is it
silenced X chromosome
barr body - how many in 47, XXY? How many in 47, XXX?
47,XXY - 1 barr body
47, XXX - 2 barr bodies
(total # of X minus 1)
cytogenetic location of XIC
Xq13 (XIST spreads from here up and down)
Y chromosome: tested determining factor (TDF)
- location?
- role?
- contains which genes?
next to pseudoautosomal region (35 Kb long)
determines gonad–> testes transformation
contains SRY - sex determining region (differentiation of testes)
deletion of Yq11.2 (AZF) –> responsible for ___
male infertility
sex chromosome abnormality - prevalence
1 in 500
postnatal sign of Turner syndrome
lymphoedema in feet (Swelling)
Turner syndrome:
- chance of having Y mosaicism
- chance of gonadoblastoma if Y mosaicism
- chance of having isoXq
- 25% or 1 in 4 of having Y mosaicism
- 12% of gonadoblastoma if have Y (phenotype of genitals doesn’t make a difference - externalmale genitals or phenotypic female).
Turner syndrome:
- chance of having isoXq
- 18% chance of isoXq (46,X, isoXq);
- iso and abnormal Xs are preferentially inactivated
Turner syndrome:
- risk of ring chromosome
- what factors make ring X phenotype more severe (e.g., MR)
- 6%
- ring chrom with euchromatin and NO XIST gene to turn it off
- ring chrom with faulty XIST silencing mechanism
X chromosome critical region - what are cytogenetic issues associated with if in this region?
Xq13-Xq26
gonadal dysgenesis
skewed x inactivation is related to which phenomenon
trisomy rescue
kid has lethal X-linked condition. Chance his mom is a carrier.
e.g., Hunter syndrome, or DMD
2/3
kid has lethal X-linked condition. Chance his aunt is a carrier.
e.g., Hunter syndrome, or DMD
1/6
b/c chance mom is 2/3, chance grandma is 1/3, and chance aunt is 1/6
prior probability of non-paternity
50%
prior probability of dizygotic vs monozygotic twins
di 70%
mono 30%
CF on one side of family - how to set up Bayes table?
P(both parents are carriers)
VS
P(NOT both parents are carriers)
eg., 1 minus both parents are carriers
e.g., one or both are NOT carriersp^2 + 2pq + q^2 = 1
p^2 = ?
percent of individuals with PP genotype
if ABO blood group has 3 alleles, what does hardy-weinberg equation look like?
(p + q + r)^2 = 1
or
p^2 + 2pq + 2pr + 2qr + q^2 + r^2 = 1
sum of :all individual factors squared, plus all combinations of two factors, multiplied by two
if four alleles at locus, what is fast way of calculating heterozygote frequency?
calculate homozygote frequency, and subtract from 1.
e.g., 1 - (p^2 + q^2 + r^2 + s^2)
For rare recessive traits (incidence
very close to one and the carrier frequency equals 2q.
recessive disease carrier frequency - in Hardy-Weinberg terms? p’s/q’s, etc?
2 * q * (1-q) = recessive disease carrier frequency
if RARE recessive (
X-linked trait with incidence in males of M. What is incidence of carrier females?
M * (1-M) * 2 = 2pq,
because for x-linked traits, males have carrier frequency = incidence = q
and females have carrier frequency of 2pq
p + q = 1 males
p^2 + 2pq + q^2 = 1 females
Hardy Weinberg assumptions
- Random mating
2. No selection3. No new mutations 4. Population is infinitely large 5. No migration
Coefficient of Inbreeding (F)
the probability that a person who is homozygous at a particular locus inherited both alleles from a single ancestor,
or
the proportion of loci at which a person is homozygous by descent.
or
R * 1/2 = amount of DNA shared between parents * chance that mom passes it on (1/2)
Coefficient of relationship (R)
of first cousins?
In consanguineous couple:
For any allele that the father passes on to his child,
the likelihood that the mother inherited the same allele
from their common ancestors
aka, what fraction of genes do first cousins share in common?
1/2 ^ (degree of relatedness)
first cousins: 3 degrees of relatedness =
(1/2)^3 = 1/8 = R
Inbreeding Coefficient (F) of
1st cousins
brother/sister
first cousins once removed
brother/sister 1/4 = F
half brother/half sister 1/8 = F
1st cousins 1/16 = F
1st ocusins, once removed 1/32 = F
Coefficient of Selection (S)
loss of fitness s = 1-f, or selection against
f = fitness = probability of transmitting genes to next generation, relative to average
e.g., HD ; f=1 ; almost all mutations are inherited
if death by age 3, f = 0 ; almost all mutations are new
selection/fitness of DOMINANT conditions:
If the fitness of an individual improves through medical
improvements, etc., then selection against the mutant allele will
_____ and the frequency of the mutant allele will _____
If the fitness of an individual improves through medical
improvements, etc., then selection against the mutant allele will DECREASE and the frequency of the mutant allele will INCREASE
–> medical advances that improve fitness INCREASE dominant mutations in population
selection/fitness of RECESSIVE conditions:
increasing fitness by improved medical
treatment of individuals affected by AR conditions like
cystic fibrosis ___ frequency of the mutant CF gene.
increasing fitness by improved medical
treatment of individuals affected by AR conditions like
cystic fibrosis DOES NOT INCREASE frequency of the mutant CF gene.
–> medicine that improves RECESSIVE condition fitness does NOT increase recessive mutations in populations
X-linked recessive, lethal condition.
proportion of mutations in males/females, and how this impacts risk of mom being carrier if kid has XL - “lethal” condition
(“lethal” is f = 0)
males 1/3
females 2/3
For XR conditions in which f = 0 (e.g., DMD), 1/3 of mutant
alleles are lost with each generation through selection and
therefore must be replaced through new mutation.
Therefore, 1/3 of isolated males (i.e., no family history) with
a genetically lethal (f = 0) X-linked disorder are the result of a new mutation, while for 2/3 of isolated affected males, their mothers
are unaffected carriers.
u = ?
u = population mutation rate
u = s * q
miu = population mutation rate s = selection q = proportion of alleles that are selected against
rate of new mutations for autosomal dominant conditions
For achondroplasia, fitness (f) equals 0.2, therefore, s = 0.8
(i. e., 80% of all mutant alleles (q) are the result of new mutations) Incidence = 1/10,000 = 2pq; therefore, q (the frequency of the mutant allele) is 1/20,000. µ = 0.8 x 1/20,000 = 4 x 10-5 for achondroplasia.
calculate rate of new mutation in dominant condition if 8 of 10 kids born with the condition (out of 100k kids) is de novo
Example: 10 children with achondroplasia are born of 100,000 births. Of the 10 children, 8 of them were born to unaffected parents (i.e., due to new mutations)
µ = 8/(2*x100,000) = 4 x 10-5
multiply # births by two!!! since, two alleles possible to inherit
rate of new recessive mutation, for purposes of Bayes problems
assumed to be negligible - both parents of affected child are assumed to be OBLIGATE CARRIERS
