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Mechanisms of origin of numerical and structural basis of ch
Transcript of Mechanisms of origin of numerical and structural basis of ch
Chromosomal breakage and loss of fragments
Require a single break and capping of the broken end with a telomere
Cri du chat - terminal deletion of 5p
Numerical and structural basis of chromosome abnormalities - Mechanisms
not generally due to mutations in single genes,
the result of structural alterations that can be seen under the light microscope.
include the rearrangement of genetic material in a chromosome, or numerical abnormalities due to the gain or loss of a chromosome.
Polyploidy - abnormal # of chromosome sets
Aneuploidy - abnormal chromosome number
Centromeric fusions (Robertsonian translocations)
Polyploidy - Triploidy (3 sets)
Has been reported in humans
can survive to birth but die shortly after
: = 2:1
2-3% of normal pregnancies
The result of either
extra haploid set from mother - normal sperm, diploid oocyte
predominates in late pregnancy miscarriages and birth
characterised by marked asymmetric intrauterine growth restriction, marked adrenal hypoplasia, and a very small, placenta
extra haploid set from father - diploid sperm, haploid oocyte - or haploid oocyte, fertilised by two sperms (dispermy).
characterised by a normally sized or mildly symmetrically growth retarded fetus with normal adrenal glands, and an abnormally large, cystic placenta
Both can show a wide variety of congenital anomalies such as
complete syndactyly (webbing/fusion) of the third and fourth fingers and of the toes,
cardiac, urinary tract, and brain anomalies
Polyploidy - Tetraploidy (4 sets)
Rarely present in a live birth
Could be due to
double haploid, sperm fertilisation with a diploid oocyte or
two haploid oocytes, each fertilised with one haploid sperm that fuse into one cell.
Number of chromosomes is not an exact multiple of the monoploid number (humans = 23)
Caused by extra or missing chromosome
Present in around 4% of live births.
Incidence of autosomal aneuploidies is directly related to increasing maternal age.
Usually due to non-disjunction event during meiosis I or meiosis II
Non-disjunction - failure of homologous chromosomes to separate properly
1. Lack of tension, activates Mad2.
2. Activated Mad2 together with BubR1 and Cdc20 forms a complex with APC, inhibiting the laters ubiquitating function.
3. Securin is not ubiquinated and thus stabilised.
4. Securin binds tightly to separin.
5. Anaphase is arrested.
Estimated aneuploidy in sperm is 4.5%
Smoking, alcohol and caffeine have all been implicated
Aneuploidy rates in human oocytes can reach 60% or higher
Aneuploidy rates are correlated with maternal age.
If nondysjunction occurs at M1, gamete gets both a maternal and paternal chromosome
If at M2, the gamete has 2 maternal or 2 paternal chromosomes
Common aneuploidies - Trisomy 21
95% of Downs syndrome patients
Characteristic phenotype risk increases with maternal age (especially after 30)
Usually occurs as nondisjunction at Meiosis 1
Trisomy 21 - Signs and Symptoms
Webbed toes, widely paced
Broad flat face
Small and arched palate
Short, broad hands
Congenital heart disease
failure to thrive
severe malformations of the heart
rocker bottom feet (congenital vertical talus)
characteristic hand position
Rarely survive to birth (1/7500 births)
severe mental retardation,
growth retardation, severe
polydactyly - extra fingers or toes
cleft lip and palate,
most die within first days or weeks - few live past their first year
Aneuploidy for the X chromosome is among the most common of cytogenetic abnormalities
Tolerated because of X chromosome inactivation - occurs early in embryogenesis
Occurs randomly between maternal vs paternal - some genes escape inactivation.
Once an X chromosome is inactivated it will remain inactive throughout the lifetime of the cell and its descendants in the organism.
Inactive X is functionally inactive (therefore females are mosaics)
Presence of Y chromosome determines male gender
Klinefelter Syndrome XXY
Rudimentary testes and prostate glands
Long arms and large hands
May develop breast tissue
May be slow learners
1 Barr body - (1 inactivated X chromosome)
Most of symptoms due to extra gene copies that are not inactivated (mainly in the pseudautosomal region)
1/500 male births
Triple - X female XXX
Tallness and menstrual irregularities
Less intelligent than siblings on average
Usually fertile and at risk of having
children with extra X
2 Barr bodies
1/1000 female births
Turner Syndrome XO
Wide spaced nipples
Skin flaps on back of neck
1/2000 live female births
Only anuploid condition that seems unrelated to the age of the mother
Jacobs syndrome XYY
slight speech and reading problems
Structural Chromosomal Abnormalities
A structural chromosomal abnormality with a gain or loss of the normal complement of genetic material
Normal complement of genetic material is maintained
Usually no clinical significance for the patient, but may have consequence for offspring
Formed from two terminal deletions -a break in both arms, with fusion of the ends
Represent a form of terminal deletion
Added feature of being mitotically unstable
Have been found in nearly all human chromosomes
More likely to be caused by the deletion of genes in the telomeric regions
Three types of ring chromosome are relatively common:
large rings with minimal loss from the terminal segments
very small rings as extra chromosomes
formed from the X-chromosome, generally found in females with features of Turner syndrome.
require two breaks with loss of the interstitial segment
partial monosomies can produce severe abnormalities and death of the embryo
only embryos with small deletions are likely to survive.
Extensive studies on
two distinct and clinically very different syndromes:
poor muscle tone,
hypoplastic genitalia and
moderate intellectual impairment
severe intellectual impairment,
delayed or absent speech,
spontaneous outbursts of laughter
characteristic facial features.
Both due to the same deletion
Difference due to genetic imprinting
SNRPN is a gene that is imprinted by the mother,
UBE3A - closely linked - is imprinted by the father.
Paternal chromosome - PWS
Maternal chromosome - AS
Unbalanced rearrangements that result in partial trisomy.
Milder than deletions but with similar clinical features
Unequal crossing over - so one chromosome has a duplication, the other an interstitial deletion
Duplications can be
- retain the same order of gene loci or
complete reversal of loci
Chromosomes with terminal deletions on both ends (thus lacking identifiable
telomeric sequences) are likely to form ring chromosomes
Quite rare but have been detected for every human chromosome.
When the centromere is within the ring, a ring chromosome is expected to be mitotically stable.
Sometimes the two sister chromatids become tangled in their attempt to disjoin at anaphase.
Result in breakage followed by fusion - forming larger and smaller rings.
One arm is missing and the other duplicated in a mirror-image fashion.
A person with 46 chromosomes carrying an isochromosome, has a single copy of the genetic material of one arm (partial monosomy) and three copies of the genetic material of the other arm (partial trisomy).
The most common isochromosome - isochromosome of the long arm of the X chromosome, i(Xq) (Turner syndrome)
Others include isochromosomes for the short arm of chromosome 18, i(18p), and for the short arm of chromosome 12, i(12p).
Commonly seen in malignant solid and haematological tumours
Chromosomal rearrangements called balanced when all chromosomal material is present even though it is packaged differently.
Though no phenotypical effect in the person, can pose a threat to the subsequent generations - likely to produce a high frequency of unbalanced gametes
The risk can range from 1% to as high as 20%.
Balanced Rearrangements - Inversions
Occurs when a single chromosome undergoes two breaks and is reconstituted with the segment between the breaks inverted.
- not including the centromere -
both breaks occur in one arm
does not change arm ratio
can only be identified by banding or FISH
gametes are either normal, inverted like parent or else non viable
- including the centromere -
a break in each arm
changes arm ratio - easier to identify
can give rise to similar gametes like parent or else to unbalanced gametes
higher chance of abnormalities in offsprings - estimated to be 5 to 10%
Involves the exchange of chromosome segments between two, usually nonhomologous,
Two main types:
Results from breakage of nonhomologous chromosomes followed by reciprocal exchange of the broken-off segments.
Usually only two (rarely more) chromosomes are involved
As exchange is reciprocal, the total chromosome
number is unchanged
Relatively common - 1 in 600 newborns.
Such translocations are usually harmless, but can give rise to unbalanced gametes
Combines the long arms of two acrocentric chromosomes: the tiny short arms are lost, and the result is a reduced number of chromosomes
The karyotype 'loses' two acrocentric chromosomes and 'gains' a single metacentric chromosome.
The human genome includes five acrocentric chromosomes: 13, 14, 15, 21, 22
Two (13q14q and 14q21q) are relatively common.
13q14q - 1 person in 1300 - the single most common chromosome rearrangement in humans
14q21q particularly important as unbalanced gametes can give rise to Down's syndrome
The risk of unbalanced offspring varies according to the particular Robertsonian translocation and the sex of the carrier parent; carrier females in general have a higher risk of transmitting the translocation to an affected child.
Monosomy 14, trisomy 14 and monosomy 21 are lethal
Observed figures for Robertsonian translocation carriers bearing an offspriong Down syndrome
10% if the mother is the translocation carrier
2.5% if the father is the translocation carrier.