Download Cells, Development, Chromosomes

Chromosomes
Chromosome Structure
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DNA is long and thin and fragile: needs to
be packaged to avoid breaking.
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Lowest level is the nucleosome, 150 bp of
DNA wrapped 1 3/4 times around a core of
8 histone proteins (small and very
conserved in evolution). A string of beads.
– Modifications of the histones, such as adding
acetyl or phosphate groups, affects how
tightly condensed the chromatin is, which
affects whether it can be transcribed or not.
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The nucleosomes coil up into a 30 nm
chromatin fiber. This level of packaging
exists even during interphase.
During cell division, chromatin fibers are
attached in loops of variable size to a
protein scaffold. The DNA probably
attaches at specific AT-rich areas called
scaffold attachment regions.
The loops may be functional units: active vs.
inactive in transcription.
Further coiling gives the compact structures
we see in metaphase.
Centromeres
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The centromere is the attachment point
for the spindle.
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Acentric chromosomes, which don’t have a
centromere, don’t attach to the spindle and don’t
end up in either nucleus after mitosis.
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Sometimes called the “primary
constriction” on a chromosome, based on
microscopic appearance.
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The centromere is a region of DNA on
the chromosome. During cell division, a
large protein structure, the kinetochore,
that attaches to the centromere DNA
sequences. The spindle proteins then get
attached to the kinetochore.
The centromere is many repeats of a
about 170 bp element (very difficult to
clone in humans but well known in
yeast). Called alpha-satellite DNA.
The centromere can extend over several
million bases of DNA, and contain large
amounts of repeated sequence DNA and
transposable elements that are also
found in other non-centromere locations.
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Telomeres
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Telomeres are the DNA sequences at
the ends of chromosomes.
Chromosomes that lose their
telomeres often fuse with other
chromosomes or become degraded.
There are telomere-binding proteins
that protect the chromosome ends.
Telomeres are also needed to ensure
complete replication of the DNA: the
end-replication problem
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DNA polymerase must have a double
stranded primer region with a free 3’ –
OH to build on. The primer is made of
RNA, synthesized by primase. At the
3’ end of the chromosome, the RNA
primer gets degraded, leaving a single
stranded region of DNA that is about
150 bp long.
In the next round of replication, one
DNA molecule will be shorter than the
other.
Process repeats, gradually shortening
the chromosomes.
Thought to be a cause of cell mortality.
More Telomeres
• Chromosome shortening is
prevented by telomerase, an
RNA/protein hybrid enzyme.
• Telomerase has a short RNA that
is used as a template for a reverse
transcriptase: binds to 3’ end of
chromosome, then synthesizes
DNA extension. This extension
acts as a template for regular DNA
polymerase, keeping chromosome
length intact.
• Telomere sequences are multiple
repeats of a highly conserved 7
base sequence.
Origins of Replication
• During the S phase, the DNA in the
cell replicates. When S starts, each
chromosome has one chromatid, a
single DNA molecule and its
supporting proteins. After the S
phase, each chromosome has 2
identical sister chromatids, held
together at the centromere.
• DNA replication starts at many
different origins of replication
along the length of the chromosome.
The origins of replication are DNA
sequences that bind to DNA
polymerase.
Euchromatin and Heterochromatin
• Chromosomes are about 50% DNA and
50% protein. Together, this complex of
DNA and protein is called chromatin.
• Euchromatin is the location of active
genes (although many genes in
euchromatin are not active: depends on
cell type). During interphase euchromatin
is extended and spread out throughout the
cell.
• Heterochromatin is darkly staining,
condensed, and late replicating. Genes in
heterochromatin are usually inactive.
– Some heterochromatin is constitutive : always
heterochromatin: especially around centromeres.
Composed mostly of repeat sequence DNA.
– Other heterochromatin is facultative: can be
heterochromatin or euchromatin: e.g. inactive X
chromosome in females., the Barr body.
Chromosomes in the Microscope
• Cytogenetics is the study of
chromosomes, primarily by
microscopy.
• Studied in metaphase cells,
usually white blood cells or skin
cells.
• Technique:
– Grow cells in tissue culture for a few
generations.
– arrest cell division at metaphase
with colchicine or colcemid (blocks
spindle microtubules).
– hypotonic treatment swells them
and spreads out the chromosomes.
– Squash them into a single layer
– Stain them to see bands
• Before this technique, people
thought humans had 48
chromosomes, not 46.
• Picture is a karyotype:
chromosome pictures cut out
and sorted by hand, or by
computer.
In pre-molecular days, chromosomes were
stained with Giemsa stain (G bands)or
quinacrine stain (Q bands). Light and dark
bands are caused by a combination of
differences in DNA composition and chromatin
condensation state.
Karyotype Analysis
• Length varies: longest is chromosome 1,
shortest is 21 (should be 22, but mistakes
were made early on).
• The centromere appears as a constriction:
called the primary constriction.
– Other, secondary constrictions occur on some
chromosomes: areas where the chromosome
partially de-condenses. The region beyond the
secondary constriction is called a satellite.
• Centromere position: centromere index:
length of short arm divided by total length.
Used to define metacentric, submetacentric, acrocentric. (No human
telocentrics)
– Most human chromosomes are sub-metacentric.
– Only 2 metacentrics and 5 acrocentrics
• The short arms of the 5 acrocentric
chromosomes contain the ribosomal RNA
genes.
– The nucleolus, which assembles ribosomes, sits
on the ribosomal RNA genes. Thus the short
arms of these chromosomes are called the
nucleolus organizer region.
Nomenclature
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Short arm is p (petite)
and long arm is q.
cen is centromere, ter is
terminus (telomere): pter
and qter. tel is often
used instead.
“proximal” means closer
to the centromere, and
“distal” means father
away from the
centromere
Regions divided at major
bands: p1, p2, p3, etc.
Then each region is
divided into lesser
bands; p11, p12, etc (pone-one, not p-eleven).
Even smaller bands too:
p12.1, etc.
FISH
• Fluorescence in situ
hybridization.
• Hybridize a DNA probe labeled
with a fluorescent marker to
chromosomes, then visualize in
fluorescence microscope.
• See location of the gene: often
can see sister chromatids even.
Chromosomes are dyads in
mitosis before anaphase.
• Picture is translocational Down
syndrome. Two copies of 14-21
translocation, plus one copy of
normal 14 (green) and one copy of
normal 21 (red).
• Chromosome painting: use
many probes from a single
chromosome (there is lots of
unique DNA on each
chromosome). Good for seeing
rearrangements.
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An application of FISH: using
fluorescently tagged DNA sequences
that are specific to a single
chromosome.
– These are found by isolating individual
chromosomes and then amplifying their
DNA.
– Sequences that aren't unique to that
chromosome are removed by hybridizing
them to a mixture of the other
chromosomes.
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Used to see things like translocations, or
to detect human chromosomes in
human/mouse hybrid cells. Cancer cells
often have very badly rearranged
genomes: chromosome painting can
help determine which chromosomes are
present and how they are connected
together.
Also used to demonstrate that each
chromosome occupies a distinct region
of the interphase nucleus (and not all
jumbled together).
Chromosome
Painting
Chromosome Number Abnormalities
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polyploid: having more than 2 sets of
chromosomes.
aneuploid: having an extra copy or a missing
copy of a single chromosome. (equal numbers
of all chromosomes is euploid).
mixoploid: having cell lines with different
chromosomal constitutions.
– mosaics: derived from a single zygote. After
a few cell divisions, one cell (and all of its
descendants) loses a chromosome
– chimeras: derived from the fusion of 2
different embryos. A favorite of crime shows
on TV: a person might have blood cells of 2
different types.
There are also chromosome structure variations,
which we will discuss later.
Fate of 1 million conceptions
Data from K.
Sankaranarayanan,
1979 Mutation
research
Polyploids
• Triploids (69 chromosomes) are usually
caused by dispermy: fertilization of the egg
by 2 sperm simultaneously.
– Usually prevented by 2 things: change in
membrane potential when first sperm penetrates,
and cortical reaction: release of extracellular
matrix material (glycosaminoglycans) that push
other sperm away.
– Frequency: 2-3% of pregnancies, but most are
spontaneously aborted.
• Occasionally survive to birth, but die shortly
after.
– why is triploidy lethal, since all chromosomes
are present in equal numbers (euploid)? May
be due to X inactivation: only a single X is
active in the cell, so there is an imbalance
between gene products from the X and gene
products from the autosomes.
• Tetraploidy (4 sets of chromosomes). Very
rare and always lethal. Usually due to
failure of first mitotic division: chromosomes
replicate and divide, but all end up in the
same nucleus.
– But diploid/tetraploid mosaics are known
The Moment of Fertilization
Aneuploidy
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Aneuploid: having an extra or
missing chromosome (47 or 45
chromosomes)
Two causes:
– non-disjunction: paired
chromosomes both go to the same
pole in meiosis instead of to opposite
poles.
– anaphase lag: a chromosome moves
to the pole so slowly that it doesn’t
get incorporated into the nucleus as it
forms in telophase.
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Effects: fairly well tolerated for the
sex chromosomes, but bad for
autosomes. All autosomal
monosomies and trisomies have
been seen, but most are
spontaneously aborted.
Maternal Age Effect on Aneuploidy
Sex Chromosome Aneuploidy
• The sex chromosomes are the most tolerant of
aneuploidy, due to X chromosome inactivation.
Only a few genes are active on extra X
chromosomes.
• The main possibilities:
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45,X (XO: Turner syndrome).
XXX, XXXX, etc
XXY (Klinefelter syndrome).
XYY.
YY without an X: Embryonic lethal: many essential genes are on
the X.
Klinefelter Syndrome
• Klinefelter syndrome: 47, XXY
– A normal human has 46 chromosomes,
which can be designated 46, XX or 46,
XY
• The Y chromosome makes these
people male, but the testes are
small and produce insufficient
testosterone after puberty
– This leads to infertility, delayed puberty,
a female pattern of body hair and breast
development.
– Also, tall stature
• In some people with Klinefelter’s,
the ability to learn language and
read is impaired.
• Treatment with testosterone
alleviates most symptoms.
• Klinefelter variants: even more sex
chromosomes, like 48, XXYY; 48,
XXXY; 49, XXXYY
Turner Syndrome
• Turner syndrome: 45, X. Often
written as “XO”. They have only
one sex chromosome, an X.
• No Y means they are female, but
they lack ovaries and are thus
sterile. Also, they don’t produce
the surge in estrogen that causes
body changes at puberty, although
this can be treated with hormones.
– Turner’s is often detected when a girl
reaches her late teens without
entering puberty.
• Also: short stature and folds of
skin at the neck.
• No intellectual impairment in most,
but difficulties in spatial perception
have also been noted in some
cases.
Other Sex Chromosome Abnormalities
• 47, XYY. Male (due to Y chromosome), tall stature,
sometimes slightly sub-normal in intelligence or
developmentally delayed.
– Once thought to confer “criminality”, but this has been
disproven.
– Sterility is common due to abnormal chorionic
gonadotrophin levels, but testosterone level is normal
– Most XYY people are never diagnosed
• 47, XXX. Female, with usually normal intelligence
and only occasional fertility problems. However,
early menopause (age 30 vs. normal age 50) is
common. Usually not detected except by accident.
Tall stature.
• Note the effect of sex chromosome dosage on
stature: 3 sex chromosomes = tall, 1 sex
chromosome = short.
– Seems to be due to the SHOX (short stature homeobox)
gene, found on both the X and Y, and not subject to X
chromosome inactivation.
Autosomal Aneuploidies
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Approximately 2% of sperm cells
are aneuploid, with all possible
extra and missing chromosomes
occurring in equal numbers.
However, only 3 trisomies (and no
monosomies) occur frequently
enough to have a named
syndrome:
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Trisomy 21: Down syndrome
Trisomy 18: Edwards syndrome
Trisomy 13: Patau syndrome
No monosomies routinely survive
to birth.
Down Syndrome
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47, trisomy-21, Down syndrome, is the most
common autosomal aneuploidy. Chromosome 21 is
the smallest chromosome.
Down syndrome was first described by Dr. John
Langdon Down in the 1860’s, long before its cause
was found (in 1959).
People with Down syndrome have significant
intellectual disabilities, along with characteristic facial
and body features.
– Babies with Down’s are usually identifiable at birth
– Heart defects used to kill many at an early age.
– Fertility is lower than normal.
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People with Down’s often develop Alzheimer Disease
at an early age. This fact led to the discovery of a
major gene associated with Alzheimer’s: APP,
amyloid precursor protein.
– The amyloid plaques characteristic of Alzheimer’s are
made of a piece of this protein.
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Other causes: translocational Down syndrome and
mosaic Down syndrome
Edwards syndrome
• Edwards syndrome, trisomy 18.
• A variety of defects: small head,
malformations of the kidney and the
heart, clenched hands with overlapping
fingers.
• Severe intellectual disability
• Most die before birth. About 8% survive
to age 1. A small percentage survive to
adulthood.
• As with Down and Patau syndromes,
translocational and mosaic forms of
Edwards syndrome exist.
Patau Syndrome
• Patau syndrome, trisomy 13.
• Most fetuses with this condition die
before birth or are spontaneously
aborted. Only 5% of those born alive
survive for 1 year.
• The most characteristic defect is
“holoprosencephaly”, which means the
brain doesn’t divide into 2 halves. This
leads to defects around the midline of
the head:
– Severe cleft palate and lip
– Eyes close together, or even in one orbit,
sometimes with only a single eyeball
(cyclops).
– Severe intellectual disability
– Abnormalities of other organ systems: heart,
digestive, urogenital, hands and feet
Mosaics
• A mosaic is an organism which is derived
from a single fertilization but which contains
cells with two or more different chromosome
compositions.
• Caused by problems in mitosis in the embryo:
non-disjunction, anaphase lag, abnormal
replication of a chromosome.
– Can occur at any stage in development, but will
probably be recognized only if there are a large
number of cells of each type.
• Most commonly, mosaics involve some
trisomic cells, such as mosaic Down
syndrome or mosaic Klinefelter syndrome
(46/47, XY/XXY)
– About 2% of people with Down syndrome are mosaic
– Leads to a wide range of phenotypes, depending on
which cells are affected.
Chimeras
• A chimera is an organism which is composed of
two genetically different organisms, which have
fused together.
– Fertilized eggs implant next to each other in the mother’s
uterus, and the growing embryos fuse.
– Less dramatically, non-identical twins often share blood
vessels before birth, and some of their hematopoetic
(blood cell forming) cells migrate into the other twin.
– Very rarely, an person can be born with both male and
female sex organs (ovaries and testes).
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A recent case of chimerism: Lydia Fairchild was asked
to provide DNA evidence that her children were actually
fathered by her ex-husband. The tests showed that he
was indeed the father, but that she wasn’t the mother.
Further tests showed that the children matched her
mother to the extent expected of a grandparent.
Finally, DNA tests from Lydia’s cervical smear matched
the children, even though DNA from her skin and hair
didn’t. The conclusion was that she was a chimera: her
reproductive system was formed from a fraternal twin.
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http://guardianlv.com/2014/01/pregnancy-no-proof-of-motherhoodwoman-was-her-own-twin-and-the-twin-was-the-mother-of-herchildren/
A geep: a sheep/goat
chimera, derived from
fused embryos of the 2
species.
Chromosome Structure Changes
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Caused by chromosome breaks. Two or more
breaks often means the wrong ends are
attached by the enzymes that repair double
stranded DNA breaks.
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Two main effects:
1. Sometimes rejoining the wrong ends can result
in a broken, non-functional gene at the
breakpoint.
2. No effect on the parent, but meiosis produces
aneuploid gametes
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A version of possibility 1 above: two genes
might be fused to give an abnormal phenotype.
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The Philadelphia chromosome is a
translocation between specific parts of
chromosomes 9 and 22, t(9;22)(q34;q11)
The result is a fusion of the ABL oncogene on
chromosome 9 with the BCR gene on
chromosome 22.
This produces chronic myleogenous leukemia,a
form of cancer.
Balanced vs. Unbalanced Translocations
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Most translocations are reciprocal
translocations: pieces of 2 different
chromosomes break off and switch
partners.
A balanced translocation has all of the
normal diploid number of genes: no gain or
loss of genetic material.
– Such people are normal in phenotype if
none of the above problems pertains.
– Abnormal segregation in meiosis will
produce aneuploid gametes, leading to
sterility or abnormal offspring.
Unbalanced translocations have extra or
missing genes.
– A common result of a balanced
translocation going through meiosis
– Many genes need to be present in
exactly 2 copies, and having 1 or 3
copies leads to abnormality.
– The deletion of several of these genes
can lead to a syndrome: a group of
symptoms or diseases that consistently
occur together.
Robertsonian Translocations and
Isochromosomes
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Robertsonian translocation. Also called a
centric fusion or a whole arm translocation.
– Chromosome breaks near the centromeres in
the short arms of 2 acrocentric chromosomes
gives one translocation chromosome with
both long arms and one with both short arms.
Centromeres fuse together.
– The short arms of acrocentrics
(chromosomes 13, 14,15,21, and 22) often
have no vital genes and so can be lost.
Mostly they contain multiple copies of the
ribosomal RNA genes, so losing a few copies
has very little effect.
– balanced, but offspring are often aneuploid
– cause of translocational Down syndrome, a
t(14;21) –long arms of chromosomes 14 and
21.
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isochromosomes. Both arms of a
chromosome are identical. Caused by
unusual crossover event between sister
chromatids.
Chromosome Structural
Variations
• --Types: Consider a normal chromosome
with genes in alphabetical order: abcdefghi
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--deletion: part of the chromosome
has been removed: abcghi
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--duplication: part of the chromosome
is duplicated: abcdefdefghi.
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--inversion: part of the chromosome
has been re-inserted in reverse order:
abcfedghi
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--ring: the ends of the chromosome
are joined together to make a ring
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--translocation: parts of two nonhomologous chromosomes are joined: if
one normal chromosome is abcdefghi and
the other chromosome is uvwxyz, then a
translocation between them would be
abcdefxyz and uvwghi.
Deletion
Duplication
Inversion
Translocation
Deletion Syndromes
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Many human genes are sensitive to dosage: they need to be present in
2 copies, and having only 1 copy leads to a syndrome of diseases.
– Haploinsufficiency: when having only 1 copy pf a gene leads to a disease
phenotype
– Most deletion syndromes are the result of haploinsufficiency at several
different genes.
– However, many genes in the deleted region function quite normally with
only 1 copy.
• Having a deletion on one chromosome makes all the genes in
the deleted region present in only 1 copy.
• Deletion breakpoints are usually not the same in different
individuals. This leads to slightly different sets of genes being
deleted, and consequently slightly different phenotypes.
• Most deletion syndromes are new mutations, but some come
from parents who had a balanced translocation.
• There is also the (rarer) phenomenon of triplosensitivity:
having 3 copies of a gene produces a disease condition.
Cri du chat Syndrome
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Cri-du-chat syndrome (cry of the cat) is a
deletion of part of the short arm of
chromosome 5 (designated 5p-).
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Hear the sound at:
https://www.youtube.com/watch?v=TYQrzFABQHQ
Babies with this syndrome cry in a characteristic way,
which sounds like the meowing of a cat.
Small head, intellectual impairment, behavioral
problems
Distinctive facial features: wide apart eyes, low set
ears, small round face
Chromosome breakpoints vary, from p13 to
p15.2. Also, some are not terminal deletions
At least 2 different regions are involved in the
syndrome: 5p15.3 for the cry, and 5p15.2 for
the facial features and intellectual disability.
So far, 2 genes are known to be involved:
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CTNND2 (located at 5p15.2), whose protein product
is associated with neuron development
TERT (located at 5p15.3), a gene involved with
telomerase activity
WAGR Syndrome
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WAGR syndrome: (WILMS TUMOR--ANIRIDIA-GENITOURINARY ANOMALIES--MENTAL
RETARDATION) is caused by a deletion of 11p13.
– A subtype is WAGRO syndrome, with the O standing for
Obseity.
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Wilms tumor affects the kidneys, usually in young
children
Aniridia: absence of an iris (pigmented region) of the
eye
Genitourinary anomalies includes malformed sex
organs (both male and female) as well as a high risk for
gonadoblasatoma, a cancer that affects the testes and
ovaries.
Genes showing haploinsufficiency:
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PAX6: affects development of the eye
WT1: a transcription factor involved in urogenital development
Translocational Down Syndrome
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Most cases of Down syndrome, trisomy-21, are spontaneous: caused by
non-disjunction. However, about 5% of Down’s cases are caused by a
translocation between chromosome 21 and another chromosome, often
chromosome 14.
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Both chromosome 14 and chromosome 21 are acrocentric, and the short
arms contain no essential genes. (just copies of ribosomal RNA genes)
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A translocation between 21 and 14 is a Robertsonian translocation
Sometimes translocational Down’s is caused by an isochromosome: 2 long arms of
chromosome 21 joined together.
The reciprocal part of the translocation, the 2 short arms joined, is usually lost.
Usually, the carrier parent has a balanced translocation: a normal
chromosome 14, a normal chromosome 21, and a translocation
chromosome, called t(14;21). No symptoms.
During meiosis, one possible gamete that occurs has both the normal 21 and
the t(14;21) in it. When fertilized, the resulting zygote has 2 copies of the
important parts of chromosome 14, but 3 copies of chromosome 21: 2
normal copies plus the long arm on the translocation. This zygote develops
into a person with Down syndrome.
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Since this can happen in every meiosis, there is a good chance of having more than one child
with Down syndrome in the family: the condition is heritable.
Translocational Down’s Punnett Square
1p36 Deletion Syndrome
• This syndrome is caused by the deletion of the
terminal band of the short arm of chromosome 1.
• These deletions are usually too small to be seen in
a standard karyotype. For this reason, the 1p36
deletion syndrome wasn’t described until the
1980’s.
– Nevertheless, the deletions involve 1.5 to 10 million base
pairs of DNA
• Characteristic facial features, including a small
head, deep set eyes, flat nose, small mouth,
pointed chin.
• Intellectual disability, prone to seizures, behavioral
problems, and developmental delays.
Chromosomes from the Wrong Parent
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It is possible to be euploid but still
abnormal, because it is necessary to have
one set of chromosomes from the father
and one set from the mother.
The DNA of some genes is modified by
adding methyl groups to some C bases.
This is called imprinting.
– For some genes imprinting is different for
male and female gametes, and the gene
from the father doesn’t work the same as
the gene from the mother, at least in the
embryo.
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Uniparental diploids: both sets of
chromosomes from the same parent. All
are very non-viable:
– paternal uniparental diploid. Egg loses its
nucleus, gets fertilized by an X-bearing
sperm, with first mitosis resulting in one
diploid nucleus. Result is a hydatidiform
mole, has external membranes and
structures of an embryo, but no actual
embryo. Can become cancerous.
– maternal uniparental diploids. Unfertilized
egg gets activated. Results in an ovarian
teratoma, a disorganized mass of tissues
often including hair, bones and teeth, but no
external embryonic membranes.
Uniparental Disomy
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Uniparental disomy: a single chromosome with
both copies from one parent.
– Results from a trisomic cell losing a chromosome
(by non-disjunction in mitosis or anaphase lag)
and thus becoming viable.
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Best known case is PRADER-WILLI
SYNDROME/ANGELMAN SYNDROME, where
inheriting 2 copies of the mother’s chromosome
15q gives Prader-Willi and 2 copies of the
father’s 15q gives Angelman.
– Prader-Willi: "low muscle tone, short stature,
incomplete sexual development, cognitive disabilities,
problem behaviors, and a chronic feeling of hunger that
can lead to excessive eating and life-threatening
obesity."
– Angelman Syndrome ("Happy Puppet"): "The gait
is jerky and puppet-like and behavior is marked by
frequent spells of inappropriate laughter. Severe
intellectual disability and speech impairment are usually
present."
Paintings by
Juan Carreno de Miranda
(above) and Giovanni
Francesco Caroto (below)
Balanced Translocations and Fertility
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Balanced translocations are euploid: 2 copies of every gene.
During meiosis (prophase of Meiosis 1), the translocated chromosomes pair
up with the normal set of chromosomes, forming a quadrivalent, a structure
with 4 chromosomes interacting.
When anaphase of M1 occurs, the centromeres in the quadrivalent are
pulled to opposite poles.
There are 2 main possibilities for segregation:
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Alternate segregation: leads to euploid gametes: half the gametes get both normal
chromosomes and the other half of the gametes get both translocation chromosomes
Adjacent segregation: leads to aneuploid gametes: each gamete gets one normal
chromosome and one translocated chromosome.
Adjacent and alternate segregation occur at about equal frequencies, so
about 1/2 of the gametes are aneuploid.
This leads to reduced fertility and recurrent miscarriages.
Translocation Segregation
Inversions
• Large inversions lead to aneuploid
gametes, if there is a crossover
between the inverted region and the
normal homologue.
– People with newly originated large inversions
are likely to be sterile
• There are only a few polymorphic
inversions (that is, present in at least
1% of the population) known, and the
longest of these is about 4.5 Mbp,
about 1/20 of the length of the
chromosome.
• Bioinformatic methods are detecting
many smaller inversions, and they may
prove to be more important than
currently believed.
– The methods are still imperfect, and only a
small number have been experimentally
validated.