Download Chromosome Aberrations

Chromosome Aberrations
• Chapter 3 covered normal cell division and
chromosomal segregation
• Things don’t always go smoothly
• Nondisjunction is the process of failed
chromosome and sister chromatid
segregation, which can result in abnormal
chromosome numbers and abnormal
chromosome morphology
• The normal ‘complete set’ number of
chromosomes in any individual of a species
is the euploid number
• If that number is not accurate for a given
cell, it is considered an aneuploidy
• Aneuploid cells and organisms typically
have a reduced survival rate
Genomes and Genome Evolution
Course Announcement: Spring 2015
Listing: 4301 (CRN 49684); 6301 (CRN 49685)
Instructor: David A. Ray
Time: MWF 10 – 10:50 AM
Room: 021 Biology
A lecture and interactive course that aims to clarify what
genomes are, how they are investigated and what has
been and can be learned from them. Topics will include :
1. Basic genome structure
2. Concepts in genome analysis
3. Genome change over time
…there are people who have concerns
that are quite reasonable, and they are
frightened of things they don't understand.
--Thomas R. Cech (discussing the human
genome)
-----------------------------------------------What more powerful form of study of
mankind could there be than to read our
own instruction book? -- Francis S. Collins
Announcements
• Exam review sessions – TBA
– Sunday and Monday evening
• No homework this week – no
corresponding chapter in the
Sapling system
Chromosome Aberrations
Nondisjunction has different
effect depending on when
it takes place
Normal meiosis
Chromosome Aberrations
Nondisjunction in meiosis I
Meiosis I
Chromosome Aberrations
Nondisjunction in meiosis II
Meiosis II
Chromosome Aberrations
• Karyotype – the number and appearance of chromosomes
in the nucleus of a eukaryotic cell
• Nondisjunction generally results in abnormal karyotypes
Chromosome Aberrations
• Gene dosage is the main impact of aneuploidy
• Increased or decreased numbers of genes means increased or
decreased amounts of gene products – disrupting the chemical
balance of the cell
• Plants tend to handle gene dosage imbalances better than animals
• Datura stramonium is a weed with 2n=24
• 12 phenotypically distinct lineages were identified in 1913, one for
each chromosome that could be impacted
Chromosome Aberrations
• Gene dosage is the main impact of
aneuploidy
• a – trisomic (chromosomes 3 and 5)
Arabidopsis thaliana
• b – tetrasomic (chromosome 4) wings
from Drosophila melanogaster
• c – trisomic (chromosome 16) mouse
embryo
Chromosome Aberrations
• Humans are very sensitive to gene dosage changes and
aneuploidy is typically lethal
• Autosomal trisomy of 13, 18, and 21 are the only ones seen in
surviving infants
• No autosomal monosomies are seen
• Sex chromosome aneuploidy is more tolerated and several
forms of trisomy are observed along with one type of monosomy
• >50% of human conceptions are spontaneously aborted in the
first trimester
• >50% of those are the result of chromosomal aneuploidy
Chromosome Aberrations
Chromosome Aberrations
• Trisomics typically exhibit reduced fertility
because of problems in meiosis
• The extra chromosome results in improper
pairing and segregation
• Two synapsis scenarios are possible –
neither results in proper segregation at
anaphase I
• If fertilization occurs with the aneuploid
gamete, the offspring is usually inviable
• Semisterility, some significant proportion
of the progeny is inviable
Chromosome Aberrations
• Mitotic nondisjunction in somatic cells
results in daughter cells that are 2n+1
or 2n-1
• They usually do not survive and are
limited in number
• If they do survive and the
nondisjunction occurs early in
embryogenesis, mosaicism can result
• 25-30% of Turner syndrome cases are
mosaics – some cells are 2n=45, some
are 2n=46, some are 2n=47
Chromosome Aberrations
• Uniparental disomy - when both chromosomes of a pair in the
offspring were derived from a single parent
• Scenario 1 - rare
• Nondisjunction for the same chromosome occurs in sperm
and egg
• One gamete with neither copy unites with the other gamete
with both copies
• Scenario 2 – more common
• Nondisjunction occurs in one parent, gamete is n+1
• Union with normal gamete produces trisomic zygote
• In trisomy rescue, one copy of the trisomic chromosome is
ejected during mitosis of early development
• If the two retained copies are from the same parent 
uniparental disomy
Chromosome Aberrations
• Polyploidy – the presence of three or more complete sets of
chromosomes in an organism’s nucleus
• Autopolyploidy – duplication of chromosome sets within a
species
• Allopolyploidy – combining chromosome sets from different
species
• Tolerated much more readily in plants
• Commercial cotton is the result of allopolyploidy
Chromosome Aberrations
• Commercial cotton is the result of allopolyploidy
Chromosome Aberrations
• Three mechanisms of
autopolyploidization
• Multiple fertilization of one egg by
multiple pollen grains
• Meiotic nondisjunction leading to
diploid rather than haploid gametes
• Mitotic nondisjunction in sex stem
cells
Chromosome Aberrations
• Allopolyploid hybrids are often
viable but infertile
• Chromosome pairs sets are not
homologous and cannot synapse
properly in meiosis
• Chromosome nondisjunction can
resolve this problem, the doubled
chromosomes have homologs for
pairing during synapsis  hybrid is
fertile
Chromosome Aberrations
• Allopolyploid hybrids can occur naturally or via human manipulation
• Hybrid vigor – more rapid growth, increased productivity, improved
resistance to disease is typical of allopolyploids
• Fruit and flowers sizes are typically increased in polyploids
• Fertility is often decreased, particularly in odd-numbered polyploids
• >50% of flowering plants are derived from polyploid ancestors
• Allopolyploids are reproductively isolated from parent species
•  ‘overnight’ speciation
• Reduced natural selection on duplicated copies of genes
Chromosome Aberrations
• Mutations may cause the loss or gain of chromosome segments,
yielding severe abnormalities via gene dosage
• Broken chromosomes can adhere to the broken ends or termini of
other chromosomes
• Acentric (lacking a centromere) chromosomes are lost during cell
division
• Partial chromosome deletions are sometimes large enough to be
seen through a microscope
• Terminal deletion  results from single break point
Cri-du-chat syndrome – 5p deletion
• high-pitched cat-like cry
• mental retardation
• delayed development
• distinctive facial features
• small head size (microcephaly)
• widely-spaced eyes (hypertelorism)
• low birth weight and weak muscle
tone (hypotonia) in infancy
Chromosome Aberrations
• Interstitial deletion  results from two break points on a single
chromosome
• WAGR syndrome  severity depends on the extent of the deleted
region
Chromosome 11p13 deletion
• Increased incidence (45-60%) of
Wilms’ tumor
• Aniridia
• Genitourinary problems
• Mental retardation
Chromosome Aberrations
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Unequal crossover or nonhomologous recombination
Most often occurs in repetitive regions of a genome
Caused by misalignment during recombination
Results in partial duplication on one homolog and partial deletion
on the other
• Individuals with these conditions are partial duplication
heterozygotes and partial deletion heterozygotes
Chromosome Aberrations
• Williams-Beuren syndrome
• Normal presence of duplicated PMS
gene on chromosome 7
• Partial deletion products have 17
missing genes
• Partial duplication products have 17
extra genes
• Hemizygotes for partial deletion exhibit
Williams-Beuren syndrome
• ‘elfin’ featurs
• Developmental delays
• Cardiovascular problems,
particularly aortic stenosis
• Increase socialbility but a tendency
toward phobias and anxiety
Chromosome Aberrations
• Microdeletions and microduplications
are smaller and not easily detected
• FISH (fluorescent in situ hybridization)
•
http://highered.mheducation.com/sites/dl/free/0072
835125/126997/animation41.html
Chromosome Aberrations
• Chromosome breakage can be repaired but may lead to:
• Inversions – repair in the wrong orientation
• Translocations – reattachement to the wrong chromosome or place
on the right chromosome
• Depending on conditions, there may be no phenotypic
consequences
• Disrupted genes
Chromosome Aberrations
• Inversions – repair in the wrong
orientation
• Paracentric inversions – the
centromere is not involved
• https://www.youtube.com/watch
?v=THAjvn1cdDM
• Pericentric inversions – the
centromere is part of the inversion
• https://www.youtube.com/watch
?v=QXU7XojaEOs
• Inversion heterozygotes –
individuals with one normal and one
inverted homolog
Chromosome Aberrations
• Meiotic consequences of inversions vary
• Synapsis b/t inverted and normal homolog
results in an inversion loop
• Problems arise when a crossover occurs
within the loop
• Paracentric inversion crossover results in
dicentric and acentric chromosomes
• Two normal and two abnormal gametes
• Dicentric chromosome is pulled in opposite
directions and parts are lost
• Acentric chromosome is lost
Chromosome Aberrations
• Meiotic consequences of inversions vary
• Synapsis b/t inverted and normal homolog
results in an inversion loop
• Pericentric inversion crossover results in
deletion and duplication products
• Two normal and two abnormal gametes
• The probability of crossover is proportional to
the size of the loop/inversion
• Fertility is impacted if inversions are very
large
Announcements
• Exam review sessions – Sunday and Monday 5pm – 6 pm – here
• Exam material will include –
– Everything from when I started to what I get through today
Chromosome Aberrations
• Translocation heterozygotes harbor one normal and one
translocated copy
• Like inversions, phenotype may be unaffected if no genes are
disrupted
• Also like inversions, fertility problems if there are segregation
abnormalities
Chromosome Aberrations
• Translocation types
• Unbalanced – an unreciprocated
translocation
• Reciprocal balanced – two nonhomologs
switch places
• Robertsonian – aka chromosome fusion
Chromosome Aberrations
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Meiotic consequences
Reciprocal balanced
No chromosome has a fully homologous partner
Cross-like structure forms at synapsis  two outcomes are possible
https://www.youtube.com/watch?v=MLDCJ2gUC84
Chromosome Aberrations
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Meiotic consequences
Robertsonian translocation
Occurs with acrocentric chromosomes (13,14, 15, 21, 22)
Carriers have one chromosome fusion while the other homologs
remain separate
• Carriers are normal but have an increased risk of trisomic offspring
• Robertsonian fusion of 14 and 21 increases risk of Down syndrome
offspring
Chromosome Aberrations
• Meiotic consequences
• Multiple patterns are possible
• https://www.youtube.com/watch?v=vb
Gw4VanNjk
Chromosome Aberrations
• Robertsonian translocations are a mechanism of
chromosomal evolution
• Muntjac chromosomes
Muntiacus reevesi
2n=46
~4.5 my
Muntiacus gongshanensis
2n=8F,9M
Chromosome Aberrations
• A Robertsonian translocation in the human lineage
– African apes – n=24
– Humans – n=23
– Where did the extra chromosome go?
Chromosome Aberrations
• A Robertsonian translocation in the
human lineage
– Human chromosome 2 = ancestral ape
chromosomes 12+13
– Predictions, if this is true, then…
Chromosome Aberrations
– Predictions, if this is true, then…
– Telomeric DNA?
• Ijdo JW, Baldini A, Ward DC, Reeders ST, Wells RA,
Origin of human chromosome 2: an ancestral
telomere-telomere fusion. Proc Natl Acad Sci U S A
1991 Oct 15;88(20):9051-5
– Centromeric DNA?
• Avarello R, Pedicini A, Caiulo A, Zuffardi O, Fraccaro
M, Evidence for an ancestral alphoid domain on the
long arm of human chromosome 2. Hum Genet 1992
May;89(2):247-9
– https://www.youtube.com/watch?v=8FGYzZOZxM
w
Chromosome Aberrations
• Chromosome diversity and organism complexity
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A misunderstanding of what evolutionary theory predicts
http://www.drdino.com/possum-redwood-tree-and-kidney-beanour-ancestors/
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What’s wrong with this argument?
Chromosome Aberrations
• Chromosome diversity and organism complexity
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1. “The theory of evolution teaches that living things are
becoming more complex as time progresses.”
• No, it predicts that organisms will adapt over time to become
more effective at reproducing. If becoming less complex
accomplishes that task, so be it.
2. “… it would seem logical … that organisms with least number of
chromosomes were the first ones to evolve and those with the
most chromosomes are the end result of millions of years of
evolution experimenting to increase complexity in living
organisms.”
• No. Chromosome number has no relationship to organisms
complexity.
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Split your textbook into 50 individual books. Does it change the
amount of information?
Two examples to illustrate this point
Chromosome Aberrations
• Chromosome diversity and
organism complexity
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Two examples:
1.
http://genetics.thetech.org/original_news/ne
ws124 - “The 44 Chromosome Man And What
He Reveals About Our Genetic Past”.
A balanced translocation of chromosomes 14
and 15 yields a chromosome number of 44,
not 46.
According to Kent’s argument, he should now
be flying around and echolocating to catch
insects.
What happens to the information in 20 books
if you decide to combine them into a single
volume?
Chromosome Aberrations
• Chromosome diversity and organism complexity
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Two examples:
2. Which bat?
The lesser horseshoe bat (Rhinolophus hipposideros) has 56
chromosomes but the short-tailed fruit bat (Carollia perspicillata)
only has 20.
Does that mean that the fruit bat is actually an ear of corn or that
the horseshoe bat is really a silkworm in disguise?
Is one bat “more complex” than the other?
Transposition
• Transposable Genetic Elements are DNA sequences that the ability to
move and/or copy themselves in a genome
• Mobilize via processes called transposition or retrotransposition
• Powerful agents of genomic change and instability
“A substantial proportion of … eutherian-specific CNEs arose from
sequence inserted by transposable elements, pointing to
transposons as a major creative force in the evolution of
mammalian gene regulation.” - Mikkelson et al., 2007.
Transposition
• Transposable Genetic Elements are DNA sequences that the ability to
move and/or copy themselves in a genome
• Mobilize via processes called transposition or retrotransposition
• Powerful agents of genomic change and instability
• Vary in length, sequence composition, copy number and mechanism of
mobilization
Transposition
• Transposable Elements
• Two major classes of TEs
• Class II – DNA transposons
– Replicative (copy-and-paste) and non-replicative (cut-and-paste) transposition
– Encode a gene for transposase, the enzyme responsible for transposition
Target
Donor
Transposon w/ transposase gene
Pol II transcription
Translation
Transposase
Transposition
• Transposable Elements
• Two major classes of TEs
• Class I – retrotransposons
– Replicative (copy-and-paste)
– Mobilize via an RNA intermediate and that RNA intermediate is reverse transcribed
back to DNA as part of the mobilization mechanism
Reverse transcription
and insertion
Pol III transcription
Transposition
Transposition
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Transposable Elements
LINE and SINE elements in humans
>50% of the human genome is derived from TEs.
Most of this mass is from Long INterspersed Elements and Short
INterspersed Elements
• LINEs are autonomous – encode many of the enzymes required for their
mobilization
• ~850,000 copies
Transposition
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Transposable Elements
LINE and SINE elements in humans
>50% of the human genome is derived from TEs.
Most of this mass is from Long INterspersed Elements and Short
INterspersed Elements
• SINEs are nonautonomous – rely on other TEs (LINEs) for the enzymes
required to mobilize
• ~1 million copies
Transposition
• Transposable Elements
• LINE-1 and Alu are the most common LINEs and SINEs, respectively in
the human genome
• Both are associated with a variety of human structural variants and
functional mutations
– A LINE-1 insertion into the factor VIII gene is responsible for some
cases of hemophilia
– Some cases of Duchenne muscular distrophy
– Alu insertions are confirmed to be the cause of at least 25 human
diseases
Transposition
• Transposable Elements
• Exon shuffling
exon 1
SINE
exon 2
intron
DNA copy of transcript
SINE
exon 2
SINE transcription can extend past the normal stop signal
Reverse transcription creates DNA copies of both the SINE and exon 2
Reinsertion occurs elsewhere in the genome