Chromosome rearrangements
Chromosome rearrangements
Chromosome rearrangements are caused by breakage of DNA double helices in
the genome at two different locations, followed by a rejoining of the broken
ends to produce a new chromosomal arrangement of genes, different from the
gene order of the chromosomes before they were broken.
Most common chromosome rearrangements are
(i) deletions
(ii) duplications
(iii) inversions
(iv) translocations
imbalanced - change the gene dosage of a part of the
affected chromosomes, similar to aneuploidy for whole
chromosomes (the loss of one copy or the addition of
an extra copy of a segment of a chromosome can
disrupt normal gene balance)
balanced - change the chromosomal gene order
but do not remove or duplicate any of the DNA of
the chromosomes
Chromosome rearrangements: points to remember
• each chromosome is a single double-stranded DNA molecule (DNA helix)
• the first event is the generation of two or more double-strand breaks (DSBs) in the
chromosomes
• DSBs are potentially lethal, unless they are repaired
• repair systems in the cell correct the DSBs by joining broken ends back together
• if the two ends of the same break are rejoined >> the original DNA order restored,
if ends of two different breaks are joined together (= mis-repair of DNA damage) >>
chromosome rearrangement
• segment of DNA lost or duplicated in the rearrangement cannot be “too large” (gene
balance); the larger the segment of a chromosome lost or duplicated, the more likely will
it cause phenotypic abnormalities
Chromosome rearrangements – the role of repeats
In organisms with repetitive DNA, homologous repetitive segments within one
chromosome or on different chromosomes can act as sites for illegitimate
crossing-over.
Deletions, duplications,
inversions, and translocations
can all be produced by such
crossing-over.
Chromosome rearrangements
Deletion formation by breakage and rejoining
Deletion formation by intra-chromosomal crossover
deletion
lost
lost
another example…
Sometimes during meiosis two chromatids from homologous
chromosomes (A) are misaligned during a cross-over event
(B) as a result, one chromatid gained a duplicated region
and the another lost a deleted region (C). The duplication
as well as the deletion are inherited by resulting gametes.
Deletion (and duplication) formation by unequal cross-over
misaligned homologous
chromosomes
polytene chromosomes
Drosophila deletion
heterozygote
How deletions can be identified
Duplications: polyploidy
autopolyploidy vs. allopolyploidy
Segmental duplications
Sometimes during meiosis two chromatids from homologous
chromosomes (A) are misaligned during a cross-over event
(B) as a result, one chromatid gained a duplicated region
and the another lost a deleted region (C). The duplication
as well as the deletion are inherited by resulting gametes.
Duplication (and deletion ) formation by unequal cross-over
misaligned homologous
chromosomes
• common mechanism of duplications
Consequences of duplications
• evolution of RNA genes
• in particular rRNA genes (rDNA)
• 5-10 copies/bacterial genome
• c. 130 copies/Drosophila genome
• Xenopus c. 400 copies/genome (but the
oocyte may have 1500 micronuclei, each
with an NOR, it is c. 600,000 copies of
rDNA)
1970 Susomo Ohno – “Evolution by Gene Duplication”
Gene duplication produces a reservoir of genes
from which to evolve new ones. Why reinvent the
wheel from scratch?
Inversions
Inversions as balanced rearrangements are generally viable and show no particular
abnormalities at the phenotypic level. Many inversions can be made homozygous.
Inversion heterozygote - cells that contain one normal haploid chromosome set plus
one set carrying the inversion. Microscopic observation of meioses in inversion
heterozygotes reveals an inversion loop.
meiotic inversion loop
Inversion formation by intra-chromosomal crossover
inverted repeats
inversion
Two types of inversions
mechanism of inversion formation: breakage and rejoining
How the chromosomes pair in an inversion heterozygote?
by forming an inversion loop…
(paracentric) inversion heterozygote
pericentric inversion
paracentric inversion
Inversion loops in para- and pericentric
inversion heterozygotes
When no recombination occurs, 50% of gametes have inversion. Next two slides
show what happen if a recombination event does occur in the inversion loop…
A crossover within the inversion loop of a
heterozygote for a pericentric inversion
(gametes/zygotes not viable)
(gametes/zygotes not viable)
Crossing-over within the inversion loop connects homologous
centromeres in a dicentric bridge while also producing an
acentric fragment - one without a centromere.
Anaphase I
- the acentric fragment cannot align itself and it is lost
- tension eventually breaks the dicentric bridge, forming two
chromosomes with terminal deletions
Gametes containing deleted chromosomes may be inviable,
but, even if viable, the zygotes that they eventually form will
probably be inviable. Crossing-over generates here lethal
products.
Inversions affect recombination in another way, too. Inversion
heterozygotes often have mechanical pairing problems in the
region of the inversion, which reduces the opportunity for
crossing-over in the region. Consequences for speciation.
two nonsister
chromatids cross
over within the loop
A crossover within the inversion loop of a
heterozygote for a paracentric inversion
Can be “adaptive” when it stabilizes a superior combination of
alleles on a chromosome (examples seen in Drosophila)
Inversions and recombination: evolutionary significance
Reciprocal translocations
Symmetric
Asymmetric
Translocations: „nonreciprocal“ and reciprocal
attachment of chromosome fragment to
a non-homologous chromosome (leading
to deletions and duplications in progeny)
exchange of chromosome fragments
between nonhomologous chromosomes
Nonreciprocal translocations were not proven
experimentally! Infact all translocations are reciprocal.
Reciprocal translocation: homozygotes
Two ways of segregation:
a) translocation chromosomes segregate
together (balanced translocation)
b) translocation chromosomes are separated
> > gametes with duplications and deletions
(imabalanced gametes) > > 50% of the
gametes are not viable (= semisterility)
Reciprocal translocations:
heterozygotes
Robertsonian translocations are the
most common recurrent structural
anomaly in humans, with about 1
in 1000 individuals carrying this
rearrangement. The carriers of
ROBs have 45 chromosomes
instead of the normal 46.
Robertsonian translocations - ROBs (centric „fusions“)
• type of a reciprocal translocation between two acrocentric chromosomes
• also called whole-arm translocations or centric-fusion translocations
• named after the American insect geneticist W. R. B. Robertson, who first described a
Robertsonian translocation in grasshoppers in 1916
• evolutionary significance >>> chromosome number reduction (from 2 acrocentric
chromosomes one metacentric chromosome)
lost lost
Dicentric ROB
(more frequent)
Monocentric ROB
Familial or translocation Down syndrome:
Robertsonian translocation and its consequences
„fusions“ of long arms of
two acrocentric
chromosomes (13, 14, 15,
21 and 22)
• Most of long arm from chromosome
21 translocated to 14 (14/21
translocation)
• „Fusion“ occurs at two rDNA regions
on the chromosomes
• about 20% rDNA copies lost
• carrier still normal (2n = 45)
• woman is usually a carrier of the
14/21 chromosome
Familial Down syndrome