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Cytogenetics II
Structural chromosomal
aberrations
RNDr Z.Polívková
Lecture No 432 - course: Heredity
Causes of structural aberrations:
external mutagens (except Robertsonian translocations)
origin in: G1,S, G2, mitosis, meiosis
Structural CHA:
• unbalanced – loss or gain of chromosomal material
• balanced – abnormal rearrangement without loss or
gain of chromosomal material
Unbalanced
• Deletion (del) = partial monosomy – terminal
- interstitial
- break and loss of chromosomal segment in G1
- unequal crossing over in meiosis
- segregation of balanced aberration in meiosis →
unbalanced product
• Duplication (dup) = partial trisomy
- duplication in S phase,
- insertion of a segment of sister chromatid
- unequal crossing over in meiosis,
- segregation of balanced aberration in meiosis
• Ring chromosome (r) – partial monosomy of segments distal to
breaks on short and long arms
- reunion of broken chromosome to a ring formation
• Dicentric chromosome (dic) – abnormal chromosome with 2
centromeres
- 2 breaks of 2 chromosomes or 2 chromatids and
reunion of broken ends, in G1, G2
• Isochromosome – partial monosomy of one arm and partial
trisomy of other arm
- misdivision (transverse splitting) of centromere in MI,
MII, mitosis
• Additional marker chromosome (+mar)
small chromosome of unknown origin – supernumerrary
- if heterochromatic – mostly without clinical consequences
Detection of origin of marker chromosome – FISH method
Balanced CHA:
• Robertsonian translocation (Rob t)– fusion of 2
acrocentrics near centromere – origin in meiosis-by
nonhomologous pairing and exchange similar to
crossing over
• Reciprocal translocation (rcp t) – reciprocal exchange of
2 segments of 2 chromosomes – in G1,G2 – breaks
and exchanges
• Inversion (inv) - pericentric – 2 breaks on p (short arms)
and q (long arms) and reconstitutions of inverted
segment between breaks – in G1
- paracentric – 2 breaks on one arm and
reconstitutions of inverted segment between breaks – in G1
• Insertion – segment removed from 1 chromosome is inserted
into another chromosome – 3 breaks rearrangement
Deletions
terminal
interstitial
break, (2 breaks) and loss of terminal (interstitial) segment
in G1
Terminal deletion Xp – short stature
Terminal deletion Xq -steriliy
Origin of interstitial deletion and duplication
unequal crossing over between homologs or
unequal exchange between sister chromatids
Origin of interstitial deletion and duplication
insertion of a segment of sister chromatid in G2
Interstitial deletion 16q – congenital abnormalities + MR
Interstitial deletion 16q
Interstitial duplication 2q – congenital abnormalities + MR
dup2q
Ring chromosome
breaks on p and q and joining of broken ends
Ring chromosome X – patient with TS – mosaic with 45,X
Dicentric chromosome
S
translocation dicentric
+ acentric fragment
Breaks of 2 chromosomes and fusion
of centric (and acentric) fragmens
S
isodicentric
breaks on both chromatids and chromatid reunion
inactivation of 1 centromere = pseudodicentric
dicentric (pseudodicentric) chromosome X from 2 cells,
C-band
Isochromosome
missdivision of centromere – loss of one arm and
duplication of the second arm – i(q)
patient with clinical features of TS but fertile
Robertsonian translocation
break on 2 acrocentrics near centromere
and fusion of long arms (fused product of
short arms is lost) – origin usually in meiosis
balanced Robertsonian translocation
unbalanced Robertsonian translocation - DS
Origin of reciprocal translocation
chromatid exchange in G2
chromatid breaks on 2 chromosomes
and exchange
breaks and exchange in G1
t(4;6)
reciprocal translocation-balanced
der(6)t(4;6) derivative chromosome 6 – congenital abnormalities + MR
t(4;6)
der (6)
Origin of inversions
pericentric
2 breaks on p and q
paracentric
2 breaks on one arm
inversion and joining of inverted segment
pericentric inversion 6 - balanced
recombinant chromosome 6 – congenital abnormalities + MR
Inversion 6
recombinant
chromosome 6
paracentric
inversion 1q
balanced
Origin of insertion
insertion of interstitial segment of one chromosome to the
site of break on another chromosome - in G1
ins(10;14) - insertion of a part of 14q to 10q - balanced
ins(10;14)
CCR(1;6;14;18) - complex chromosomal rearrangement - balanced
Risk of balanced structural aberration:
Carrier of balanced structural aberration
usually without clinical signs
risk of unbalanced aberration in progeny
Nonhomologous Rob t
Carrier of
balanc. Rob.t
normal
gametes
after MI
+
Zygotes
after S phase
transl.trisomy
1/3
carrier of balanc.t
1/3
normal
1/3
monosomy 21
letal
theoretic risk
Theoretic risk of translocation form of Down syndrome (DS)
in parent - carrier = 1/3
Actual risk: 10-15% for woman - carrier of t21/14
2% for man - carrier of t21/14
For other nonhomologous translocations lower risks (21/22, 13/14)
Mechanisms of selection against chromosomal anomaly:
• some types of segregation are less probable (influenced by
morphology of rearranged chromosomes)
• in ♀ meiosis= cell with CHA more probably become polar body
• in ♂ meiosis – irregularities in pairing of rearranged chromosomes
→ poor sperm development → oligospermia, azoospermia
• gamete with CHA – selectional disadvantage in fertilisation (in sperm)
• selection against abnormal zygote = spontaneous abortion
Homologous Rob t
21/21 (13/13)
45,XX
t21/21
Carrier of
balanced
Robt
22,X
-21
Normal
karyotype
46,XX
23,X
t21/21
23,X
23,X
de novo origin
23,X
t21/21
23,X
t21/21
+
23,Y
46,XY
t21/21
risk
100% (DS or abortion)
+
23,X
t21/21
22,X
-21
46,XY
t21/21
risk
0%
translocation form of DS (homologous fusion 21/21)
Reciprocal translocation
T2
N1
N1
T1
T2
N2
T2
N2
in M I prophase - kvadrivalent
Balanced reciprocal translocation
Segregation 2:2
Types of segregation:
T1,T2 - N1, N2 = alternate → balanced + normal gametes
T1, N2 - T2, N1 = adjacent 1
unbalanced gametes
T1, N1 - T2, N2 = adjacent 2
with duplication a deletion
Empiric risk: 10% for woman - carrier
2-5% for man - carrier
But risk is dependent on the type of translocation (length of translocated
segments)
Segregation 3:1 = tercial trisomy
One of the translocated chromosomes is small and its trisomy is
compatible with life
t(4;6)
der(6)
Pericentric inversion – mechanism of meiotic
recombination
a)
b)
crossing over inside meiotic loop→ a) duplication of p and
deletion of q or b) duplication of q and deletion of p
Risk of meiotic recombination in a carrier of
pericentric inversion
depends on the length of inverted segment
in average: for woman – carrier - 10%
for man - carrier - 5%
Paracentric inversion
Crossing over inside loop → dicentric chromosome and
acentric fragment
Origin of interstitial deletion and duplication
Unequal crossing over outside of meiotic loop
– in both inversions
Consequences of balanced aberrations
• Segregation of unbalanced genome (affected child,
abortion)
• Sterility (esp.in men)
• Effect on phenotype – MR, anomalies (rcp t, inv de novo)
Balanced CHA with phenotypic effect :
1. Small deletion
2. Small mosaic?
3. Inactivation of gene (site of break inside gene) →
manifestation of recessive alleles on homologous
chromosome (described in X/A translocations)
4. Posion effect: incorrect gene order, impairment of gene
regulation, neighbourhood of heterochromatine (spreading effect)
Consequences of unbalanced aberrations
• congenital malformations
• mental retardation
Partial trisomy – less severe than partial monosomy of
the same segment
Lack of chromosomal material = more severe
then excess
Degree of expression – depends of the length of trisomic
and monosomic segment and its gene content
Indications to chromosomal examination !!!
Postnatal (from peripheral blood – lymphocytes):
1. Specific phenotype (MD……)
2. Psychomotoric retardation (PMR), growth
retardation, dysmorpfic features, congenital
malformations, small stature in girls, oedema in
newborns (TS)
3. Dysfertility (repeated spontaneous abortions,
sterility – chromosomal examination in both
partners)
4. Amenorrhea, delayed puberty, genital
malformations
Indication of prenatal cytogenetic examination
From cells of amniotic fluid, chorionic villi, fetal blood
1. Increased maternal age (≥ 35 years)
2. Patological values of biochemical markers
3. Abnormality on ultrasound
4. One parent is a carrier of balanced chromosomal
aberration
Indication of prenatal cytogenetic examination
From cells of amniotic fluid, chorionic villi, fetal blood
1. Increased maternal age (≥ 35 years)
2. Patological values of biochemical markers
3. Abnormality on ultrasound
4. One parent is a carrier of balanced chromosomal
aberration
http://dl1.cuni.cz/course/view.php?id=324 presentation
http://dl1.cuni.cz/course/view.php?id=324 supplementary text
to cytogenetics
Thompson &Thompson: Genetics in medicine, 7th ed.
Chapter 5: Principles of clinical cytogenetics
Chapter 6: Clinical cytogenetics: Disorders of the autosomes
and the sex chromosomes
+ informations from presentation