Download Chromosomal mutations

Chromosomal mutations
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Content
• Chromosomes
• Chromosome mutations
– Chromosome number changes
– Chromosome structure changes
• Examples
– Trisomies
– Alterations in sex chromosomes
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Karyotype – a complete set of chromosomes
• The number and appearance of
chromosomes in the nucleus of a eukaryotic
cell
– Each organism have a specific karyotype
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•
•
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In humans: female 46, XX, male 46, XY
Somatic cell: diploid 2N
Gamete: haploid 1N
Some polyploid cells exist in humans
– megakaryocyte, hepatocytes, muscle and heart cells
– several nuclei
• 0.6% of the live-born have chromosomal
anomaly
•
• Numerical abnormalities
• Structural abnormalities
0.2 % of newborns have a
chromosomal anomaly with
symptoms
• 0.2% symptoms during
childhood or teenage 3
• 0.2% symptomless changes
Chromosomal abnormalities
• Chromosomes contain a person’s genes  alteration
usually causes a disease
– Not necessarily inherited
– Due to excess or loss of genetic material
• Chromosome abnormalities are due to an error in during
meiosis (gametes)
– If it occurs later  transmitted to progeny → mosaicism
• 50% to 80% of abortions during first trimester show
chromosomal abnormalities  aneuploidy  fetal wastage
• Female meiosis is long  prone to chromosomal
abnormalities
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Normal set of metaphase chromosomes
Diploid (2N)
Aneuploidy
Nullisomic
(2N-2)
• Aneuploidy= abnormal
number of chromosomes
Monosomic
(2N-1)
– extra or missing
chromosome(s)
 numerical abnormality
Doubly monosomic
(2N-1-1)
Trisomic
(2N+1)
Tetrasomic
(2N+2)
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Variations in number of complete chromosome sets
Normal chromosomes
Diplod (2N)
Monoploid  only one set of chromosomes (haploid)
Monoploid (N)
Polyploid  tree or more sets of chromosomes
Triploid (3N))
Tetraploid (4N)
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Structural abnormalities of chromosomes
• A break occuring during DNA replication
or recombination event may remain
unrepaired
– Balances and unbalanced
translocations, inversions
→ unbalanced gamete in meiosis
→ disease to progeny
• Can be inherited, 60-70 %
p
q
– Requires intact telomere and centromere
regions to be transmitted
• 30% are new alterations
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Balanced translocations
https://www.youtube.com/watch?v=MLDCJ2gUC84
• Translocations involve the
breakage and rejoining of two or
several chromosomes
• In balanced translocation there is
an equal exchange of chromosomal
material
 Reciprocal translocation: the
location of a gene changes, but the
amount of genetic material is
• Most often either normal or
unaltered
translocation carrier
chromosomes are inherited
• Doesn’t usually cause problems for
• Other distributions lead to
a carrier, but a progeny may be
non-balanced chromosomes
affected
 miscarriage
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t(9;22)  Philadelphia chromosome
BCR-ABL fusion gene,
 uncontrollable division of cells, leukemia
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Fused genes/proteins
Second
Translocation
Associated diseases
t(8;14)(q24;q32)
Burkitt's lymphoma
c-myc on chromosome 8,
IGH (immunoglobulin heavy locus) on chromosome
gives the fusion protein lymphocyte- 14,
proliferative ability
induces massive transcription of fusion protein
t(11;14)(q13;q32)
Mantle cell lymphoma
cyclin D1 on chromosome 11,
gives fusion protein cellproliferative ability
t(14;18)(q32;q21)
Follicular lymphoma (~90% of
cases)
IGH (immunoglobulin heavy locus)
on chromosome 14,
Bcl-2 on chromosome 18,
induces massive transcription of
gives fusion protein anti-apoptotic abilities
fusion protein
t(10;(various))(q11;(various))
Papillary thyroid cancer
RET proto-oncogene on
chromosome 10
PTC (Papillary Thyroid Cancer) - Placeholder for any
of several other genes/proteins
t(2;3)(q13;p25)
Follicular thyroid cancer
PAX8 - paired box gene 8 on
chromosome 2
PPARγ1 (peroxisome proliferator-activated receptor γ
1) on chromosome 3
t(8;21)(q22;q22)
Acute myeloblastic leukemia with
maturation
ETO on chromosome 8
AML1 on chromosome 21
found in ~7% of new cases of AML, carries a
favorable prognosis and predicts good response to
cytosine arabinoside therapy
t(9;22)(q34;q11) Philadelphia chromosome
Chronic myelogenous leukemia
(CML), acute lymphoblastic
leukemia (ALL)
Abl1 gene on chromosome 9[15]
BCR ("breakpoint cluster region" on chromosome 22
t(15;17)(q22;q21)
Acute promyelocytic leukemia
PML protein on chromosome 15
RAR-α on chromosome 17
persistent laboratory detection of the PML-RARA
transcript is strong predictor of relapse
t(12;15)(p13;q25)
Acute myeloid leukemia, congenital
fibrosarcoma, secretory breast
carcinoma, mammary analogue
TEL on chromosome 12
secretory carcinoma of salivary
glands
t(9;12)(p24;p13)
t(12;21)(p12;q22)
t(11;18)(q21;q21)
t(1;11)(q42.1;q14.3)
t(2;5)(p23;q35)
t(11;22)(q24;q11.2-12)
CML, ALL
ALL
MALT lymphoma
Schizophrenia
Anaplastic large cell lymphoma
Ewing's sarcoma
JAK on chromosome 9
TEL on chromosome 12
API-2
TEL on chromosome 12
AML1 on chromosome 21
MLT
ALK
FLI1
NPM1
EWS
t(17;22)
dermatofibrosarcoma protuberans
Collagen I on chromosome 17
Platelet derived growth factor B on chromosome 22
First
IGH (immunoglobulin heavy locus) on chromosome
14,
induces massive transcription of fusion protein
TrkC receptor on chromosome 15
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t(4;11)(q21;p13): meiosis
• Translocation chromosomes have aligned with
homologous chromosome segments in the division plane
and a tetravalent is formed.
• What kind of segregation possibilities there are in the I
division?
Normal situation
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Jukka Moilanen (http://www.oppiportti.fi/op/ltg01005/do)
Robertsonian centric translocation
• Fusion of 2 acrocentric chromosomes very close to the
centromeres  rearranged chromosome includes the long
arms
• Balanced centric translocation between chr. 13, 14, 15, 21
and 22
• Short arm is lost (no phenotypic effect)  45 chr.
• t(13;14)(p10;q10)
– carriers 1:1500
– Predisposes to trisomy 13 ja
miscarriage, mild infertility
• t(14q;21q), most frequent
– In carrier pregnancies 20% risk for extra
copy of chr. 21 (Down syndrome)
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Meiosis in the carrier of Robertsonian transloction
t(14;21)
• Trivalent aligning
• (A) half of the gametes will
have normal and half
translocation
• (B,C) unbalanced
chromosomes
– (B) monosomia or trisomy 14:
miscarriage
– 3:0 : miscarriage
– (C) trisomy 21
normal
T carrier
extra 14
14 deficiency
extra 21
21 deficiency
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Unbalanced translocation
 Loss of genetic material or too much of it
 deletions and duplications
• Extra gene material (>4%) or missing material
(>2%): miscarriage
• Small alteration (microdeletion/ duplication):
chromosome disease
• Usually sproradic, with mild phenotype,
inheritable changes
–Deletions of short arm of chr. 4 and 5: intellectual
disability
–Prader-Will: 15q11-13 paternal deletion
• intellectual disability, over-weight, special features
–Angelman syndrome: 15q11-13, maternal deletion
• severe intellectual disability, epilepsy, anxiety,
special features
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Inversions
• If two breaks occur in one
chromosome
 the region between the
breaks may rotate 180
degrees before rejoining with
the two end fragments
 the overall amount of the
genetic material is not
changed
• inv9(p11;q13), most common
in general population, 1 -3%
– Often detected in infertility
studies
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Inversions
• Recombination doesn’t happen
in short inversions
• In long inversions, inversion
chromosome aligns with
homologous chromosome
 inversion loop
 crossing-over
 deletions or duplications
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Chromosome deletions and duplications
• Due non-disjunction
during meiosis
• Defect in I meiotic division:
– Chromosome pair in same
pool
 diploid ja nullisome
gametes
– Most common cytological
cause for trisomies
– The age of mother
correlates with defects in
meiosis I
gamete
trisomic
monosomic
Chromosome deletions and duplications
Defect in meiosis II:
• One extra
chromosome/one
chromosome lost
• Rarely cause aneuploidy
gamete
trisomic
monosomic
normal
Chromosome deletions and
duplications
• trisomy, 2N+1
– chr.21, 13, 18, (8), (9)  contain less
genes
• Almost all chr. 16 trisomies are due to
defect in maternal meiosis I
• 90% chr. 13 ja 21 trisomies: maternal,
generally defects in meiosis I
• 90% chr.18 trisomies maternal  2/3
defects in meiosis II
• monosomy, 2N-1
• 2q31q33 –syndrome (partial)
• Turneri syndrome (X-chr.)
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21-trisomy, Down syndrome
• incidence 1:600
• often defect in I division of meiosis, in 80% cases
maternal
– The age of mother correlates with the risk of
trisomy-21
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• Critical genes for the syndrome locate in
region 21q22
– 21q22.1-q22.3: 289 genes
• DSCR1 (Down Syndrome Critical Region
gene1): causes intellectual disability and
heart defects
– Overexpressed in brains of Down fetuses
• DSCR4: affects development of
morphologic features, hypotonia and
intellectual disability
– Expressed mainly in placenta
• Severity of symptoms vary, life time about
40 years (~ 50%)
– Intellectual disability, fastened aging
– Infections, heart problems (not all), dysfunction
of intestinal tract
– Females are fertile, men not
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http://www.answers.com/topic/down-syndrome
Function of DSCR1
• Protein affects the transcription of genes by inhibiting
the calsineurin dependent signaling pathway and
thus possibly disturbs the development of central
nervous system
Normal
Nature 441, 582-583(1 June 2006)
Down syndrome
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 DSCR1 and also DYRK1A 
Trisomy 18/ Edwards syndrome
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•
•
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More common that trisomy 13, 1: 5000
~ 95 % clear trisomies and 5 % mosaic cases
Partial trisomy 18 due to translocation (~2%)
Smallest extra region of chr.18 that causes the
syndrome is q21-22
Brain anomalies , Microcephaly
 severe developmental disbility
Heart defects (~90%)
clenched hands
“rocker bottom feet”
lifetime1-2 months, death latest at 1year of age
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Sex chromosome alterations
SRY
• Sex chromosomes, X and Y, determine the genetic
characteristics of sex-linked traits
• X and Y share sequence homology segments,
pseudoautosomal regions (PAR1, 2, 3)
– inherited in the same manner as autosomes
– in males, pairing and recombination are restricted to the PARs
– Reduced recombination in PAR1 can lead to aneuploid
sperm, which can cause X-chromosome monosomy (Turner European Journal of
Human Genetics
syndrome) or XXY (Kleinfelter syndrome) in the offspring
(2008) 16, 771–779
•  recombination is necessary in males
• SRY-part (pter-q11.2) of Y contains genes that direct
the development of the masculine features  without
femine phenotype
• Deletion or duplication of X/Y chr. is less harmful than
changes in the number of other chromosomes
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Turner syndrome
• 45, X, mosaicism
– mosaicism allow the survival in utero: placental rescue cell line 46, XX
– loss of genes in PAR1 affect development of placenta  lethality
• Incidence 1: 2500 newborn girls, more common in miscarriages (8.6%
vs 0.04%)
• Poorly developed fibrotic gonads  lack of germ cells and ovarian
follicles  no oocytes
– Activity of two active X chrs are needed to maintain the germ cells and later ovaries
• No estrogen synthesis  lack of female features
– No puberty without hormone therapy (estrogen and progesterone)
• Somatic abnormalities due to abnormal dosage of PAR genes
– Short stature (<150 cm)  SHOX important for bone development and growth
– Lymphedema of the hands and feet
– Heart defect
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Klinefelter syndrome
• Most common sex chromosome alteration in males
• 47, XXY 1: 500-1000 newborn males
– 48, XXXY, or 49, XXXXY: variant formsmore severe signs and
symptoms
– Extra copies of X chromosome are inactivated
• Extra copies of genes on the X chr. interfere with male
sexual development  often prevent testes to function
normally  reduce the levels of testosterone
• Affects male physical and cognitive development
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–
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Infertile, small testes
Slightly feminized physique (breast development, wide hip)
Poor muscle tone
Tall stature
Some have learning and psychological problems
• Testosterone treatment to improve musculine phenotype,
concentration and strenght
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• Not inherited
47, XYY
• 1:1000 newborn males
• Affected usually very tall
• Fertility and sexual development are
normal  normal physical appearance
• May include learning disabilities and
behavioral problems such as impulsivity
• Not inherited
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