Chromosome Structure

Chromosomal changes occur in three basic categories:

rearrangement, aneuploidy, and polyploidy.
Centromere Position
Arm length and centromere
position is sometimes used
to classify chromosomes.
- Metacentric: centromere in
middle with equal arms.
- Submetacentric: shifted
away from middle with
unequal arms.
- Acrocentric: shifted near
ends.
- Telocentric: centromeres
very near ends; adjacent to
telomeres.
Chromosome Structure
Humans normally have no
telocentric chromosomes.

We do have five
acrocentric, and mostly
sub- and metacentrics.

Centromere position varies

a lot among organisms.

Mice, for example, have all

telocentric chromosomes.
Rearrangements
Rearrangements
Deletions
DNA is lost from a chromosome during replication or
recombination.
- From 1 bp, potentially deactivating genes,
- To millions of bp, removing entire gene complexes.
- Large deletions visibly shorten chromosomes.
Deletions
Large deletions involving many genes are detected by
loop structures made when homologs pair in meiosis I.
Deletions
Consequences depend on which genes are located in a
deleted region.

Centromere deletions cause segregation failure in

mitosis meiosis, leading to aneuploidy.

Large homozygous deletions are often lethal because

all copies of essential genes are lost.

Heterozygous deletions may bot be fatal, but usually

have deleterious due to the loss of essential genes.
Gene Dosage
Gene products, whether
RNA or protein, are
balanced in meticulously
evolved proportions.

In eukaryotes, genes form

complex regulatory
networks.

For every gene, the

amount of product is
proportional to its copy
number.
 Gene Dosage
Increasing copies of a gene
with respect to the rest of the
genome alters the balance.

Altering gene dosage

throws off the stoichiometry
of gene products in a cell.

Development is altered in
some way, sometimes
fatally.
Cri-du-chat Syndrome
Early discovery of genetic
disease caused by
deletion.

Around 1 in 50,000 births.

Characteristics:
- Microcephaly
- Widely-spaced eyes.
- Mental retardation.
- Difficulty swallowing.
Cri-du-chat Syndrome
“Cry of the cat” because infants
make an unusual wailing cry
said to sound like a cat.

Caused by heterozygous
terminal deletion of ~10% of the
small arm of chromosome 5.

Effectively partial monosomy of

chromosome 5.
Deletion Mapping
Deletions are used to map the position of genes on
chromosomes via abnormal expression.

Pseudodominance is the expression of recessive

alleles when paired with a deleted region.

For example, red-green colorblindness is X-linked and

recessive.

Males are X-chromosome hemizygous, so inheritance of

an deficient red-green opsins will always be apparent.
Deletion Mapping
In classical deletion mapping, homozygous recessive individuals are
mated with heterozygous deletion individuals. Recessive phenotypes
will be expressed if the gene and deletion are co-located.
Duplications
DNA is added to a chromosome.
- Tandem duplications are immediately adjacent to the
original DNA: AB⦁CDEFEFG
- Displaced duplications are located some distance
away: AB⦁CDEFGEF
Duplications
Like with deletions, “looping
out” occurs with duplication
chromosomes.

Heterozygous chromosomes
align to maximize pairing of
homologous regions.

Visually, this is hard to

distinguish from deletion
loops.
Bar Mutations
Bar gene directly effects
eye development in fruit
flies.

Duplications increase the

expression of Bar.

Eye size is progressively

reduced as the number of
facets decreases.
Unequal Crossing-Over
The primary cause of large deletion and duplications.
Ideal homologous pairing aligns chromosomes perfectly
for recombination. This doesn’t always happen.
Unequal Crossing-Over
When two nearly identical sequences are adjacent to
each other, the chance of unequal crossing-over is
increased. These events simultaneously delete and
duplicate.
Globin Genes
Duplicated genes provide an opportunity for new gene
function to evolve via neofunctionalization.

With a single copy of any given gene, evolutionary

changes might lead to the expression of new
phenotypes, but the original function is lost.

Duplicating a gene allows one copy to be maintained,

while the original or duplicate amass mutations that alter
the original function.
Globin Genes
Different globin genes are expressed at different
development stages. γ-globin genes are expressed as a
fetus, and give way to β-globin genes after birth.
Globin Genes
Globin genes with related function cluster closely on
chromosomes.

Best explanation for their origin is a series of

duplications.
Inversions
Two forms of inversion, distinguished form each other by
whether a centromere is included in the inverted region.
Inversions
Paracentric inversions involve chromosome Arms.

Pericentric inversions involve cEntromeres.

Recombination is suppressed within an inverted

chromosomal region.
- Not because recombination frequency is reduced.
Recombination events remain as likely.
- Because a proportion of recombinant gametes
become nonviable.
Inversions
Caused when double-
stranded breaks occur at
two chromosome loci.

Eukaryotes can repair

DSBs, but the wrong ends
may get joined.

Chromosomes are very

long, but distant loci might Chromosomes are relaxed and
be in close proximity when tangled most of the time.
chromatin is relaxed.
Paracentric Inversions
Inversion homozygotes can function normally,
assuming genes remain intact.

Inversion heterozygotes form inversion loops during

prophase I homologous pairing, which causes problems
during anaphase I.

Recombination within these loops generate severe

chromosomal deletion gametes.
- Dicentric bridge forms after crossing-over.
- Creates a chromatid with two centromeres.
Paracentric Inversions
During prophase I,
homologous
chromosomes align.

To maximize pairing,
one homolog contorts.

A synaptonemal
complex forms, and
crossing-over takes
place.
Paracentric Inversions
Crossing-over in the
inversion loop causes
a dicentric bridge.

One chromatid has

two centromeres.

One chromatid has no

centromere.
Paracentric Inversions
Homologs separate in
anaphase I.

The acentric chromatid

without centromere is
lost entirely.

Already, many genes

have been lost from
future daughter cells.
Paracentric Inversions
Microtubules continue to
pull homologs toward
opposite spindle poles.

The dicentric bridge

breaks at some point
between centromeres.

At the end of meiosis I,

each daughter cell has a
deficient chromatid.
Paracentric Inversions
Microtubules continue to
pull homologs toward
opposite spindle poles.

The dicentric bridge

breaks at some point
between centromeres.

At the end of meiosis I,

each daughter cell has a
deficient chromatid.
Paracentric Inversions
The results are three
gamete types:
- 1 normal chromosome.
- 2 recombinant chromosomes
missing genes.
- 1 inversion chromosome.

50% of gametes created

via inversion recombination
are very unlikely to
produce living offspring.
Pericentric Inversions
Again, inversion homozygotes can function normally,
assuming genes remain intact.

Inversion heterozygotes form inversion loops during

prophase I homologous pairing, which causes problems
during anaphase I.

All chromatids end with a single centromere, but 50% will

gain too many copies of some genes and lose others.
Pericentric Inversions
An inversion loop forms
during in prophase I.

An inversion loop
maximizes homologous
pairing.

The centromere is in the

loop.
Pericentric Inversions
The structure resolves itself during anaphase I, but
crossing over in the loop caused genes to be transferred.
Pericentric Inversions
Each homolog separates with a normal and an abnormal
chromatid.
Pericentric Inversions
When meiosis II is
completed, there are
three gamete types:
- 1 normal chromosome.
- 2 nonviable
recombinants.
- 1 inversion
chromosome.

50% of gametes are

nonviable.
Inversions
With peri- and paracentric inversions cases,
recombination is suppressed because recombinant
chromosomes are nonviable.

This means alleles within inversions will never

recombine with heterozygous DNA.
- Allele combinations favored by natural selection and
the environment will not be separated.
- Hybrids organisms with opposing inversions will not
mix alleles between parental chromosomes.
- Reinforces divergence of related species.
Inversions
Broad-scale, four human and chimpanzee chromosomes
differ by only a pericentric inversion.

Fine-scale, there are around 1500 small inversions

between humans and chimps.
 Translocations
Non-homologous chromosomes may exchange DNA when
double-stranded breaks occur and chromosomes fuse.
Translocations
Three major types.
1. Robertsonian translocation: fusion of two
acrocentric chromosomes into one metacentric
chromosome.
2. Nonreciprocal: DNA moves from one chromosome
to another. AB•CDEFG and ST•VWXYZ → AB•CDG
and ST•VWEFXYZ
3. Reciprocal: two-way exchange of DNA between
chromosomes. More common than nonreciprocal.
AB•CDEFG and ST•VWXYZ → AB•CDXYG and
ST•VWEFZ
Robertsonian Translocation
Breakage occurs on long
arm of an acrocentric
chromosome.

And the short arm of

another chromosome,
usually acrocentric.

Arms fuse, in some cases

along with a smaller
fragment that may fails to
segregate in meiosis.
Robertsonian Translocation
Somewhat common in humans and always involves the
five acrocentric chromosomes.

Recall that these have the shortest arms (we don’t have
telocentric chromosomes).
- Our acrocentric chromosomes, (13, 14, 15, 21, and
22), contain double-stranded break hotspots.
- DNA content, not arm length, biases these
chromosomes toward breakage and translocation.
- DSB hotspots might be the reason they’re acrocentric
in the first place.
Familial Down Syndrome
Less common than primary Down syndrome, caused by
trisomy 21.

Familial Down patients have 2 copies of chromosome

21.

But, individuals also have a translocation of chromosome

21 long arm to another chromosome.

It’s recessive, so it may goes undetected in families.

Translocation carriers have a normal complement of
genes (and gene dosage) for the most part.
Familial Down Syndrome

Translocation of 21 to chromosome 15 (45, XX, t15q21q). Individual is

normal, but a carrier for familial Down syndrome.
Familial Down Syndrome
Robertsonian Translocation
Further responsible for
barriers between species.

Our closest ape relatives all

have 48 chromosomes.
- Chimpanzee.
- Bonobo.
- Gorilla.

Humans have 46 due to the

fusion of two chromosomes.
Reciprocal Translocation
Occurs when two non-homologous chromosomes
exchange DNA.

This can cause problems when new gene combinations

are created on a chromosome.

N: normal non-homologous N1
chromosomes. N2
T1
T: translocated versions. T2
 Philadelphia Chromosome
Translocations can alter gene
expression and cause cancer.

A Philadelphia chromosome is
very common in leukemia
patients.

A reciprocal translocation
between the long arms of
chromosome 22 and 9.

The result is a shortened

chromosome 22.
 Philadelphia Chromosome
BCR is an always-on gene
promoter involved in white blood
cell production.

Philadelphia chromosomes
combine BCR with c-ABL.

c-ABL is normally involved in

regular cell division.

Combination of the BCR and c-

ABL genes stimulates unregulated
cell division.
Reciprocal Translocation
Problems occur also during meiosis when homologs pair.
Reciprocal Translocation
Four chromosomes share N1 T2
homologous regions with
two others in the set.

Cruciform pairing
structures are the most
common result.

Recombination is not T1 N2
affected. Segregation can
lead to deficient gametes.
Reciprocal Translocation
Anaphase I can resolve itself in three ways. The most likely
two mean each cell gets one chromosome from the red circle
and one from the blue.
Reciprocal Translocation
Reciprocal Translocation
If we assume that adjacent-2 segregation is very rare.

Most instances of reciprocal translocation will resolve via

the alternate or adjacent-1. These are about equally
likely.

An individual has a 50% chance of producing all viable

gametes with all genes accounted for.

And a 50% chance of producing all nonviable gametes

with some genes present in two copies and some
missing entirely.
Chromosome Structure
1. Four different rearrangements: deletion, duplication,
inversions, and translocations.
2. Basic causes of each rearrangement.
3. Examples of rearrangement consequences.
4. Pericentric versus pericentric.
5. Inversion loops.
6. Problems with inversion recombination.
7. Cruciform structures.
8. Problems with translocation meiosis.