Chromosome variation

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Chromosome variation Powered By Docstoc

Bridges - 1916 - examined inDrosophila the first case of a disturbance of chromosome
disjunction (i.e. separation) during meiosis and named it "nondisjunction". It is important
to note that this can happen in meiosis 1, meiosis 2, or in mitosis.
Chromosome aberrations are variations from the wild-type condition in either
chromosome number or chromosome structure. They can occur spontaneously or as
a result of some exposure to radiation, chemicals, viruses, etc.

Chromosome aberrations may involve either whole chromosomes or parts of

Chromosome aberrations may have genetic consequences. We will be
considering changes in phenotype due to a larger unit than a single gene.
Chromosome aberrations may greatly affect the phenotype of an organism,
depending on the aberration and the organism.


Most eukaryotic organisms are diploid, i.e. they have two sets of chromosomes in their
somatic cells, one set from each of their parents.

Changes in Complete Sets of Chromosomes (Ploidy)

These are variations from the normal diploid number of chromosomes by one or more

entire sets of chromosomes) monoploid - n = x diploid - 2n = 2x polyploid - more than

diploid number of sets triploid - 3x

tetraploid - 4x pentaploid - 5x hexaploid - 6x may be 2n (functionally diploid)
Monoploidy (haploidy) - loss of a complete set of chromosomes Rarely

survive in animals

.       •      Exception - in bees and wasps, males are haploid (n), developing from
unfertilized eggs
.       •      Humans, XX and XY, so males haploid for a part of the genome
  .•    Plants - more frequently can survive, especially in polyploids
.       •      In plants, haploids are most frequently produced by tissue culture of
microspores - anther culture
.       •      Can arise spontaneously
.       •      Can be used directly to give genetic information, e.g. recessive alleles not
.       •      Haploids can be doubled to produce homozygous lines
.       •      and in the "resynthesis" of natural polyploids

Polyploidy - occurs when cell or organism has more than the normal two sets of
3 sets - triploidy - 3n = 3x

4 sets - tetrasomy - tetraploid - 4n = 4x
Diploidy (2n) is the natural state of affairs in most eukaryotes and polyploidy is
rare in animals (some shrimp, frogs, fish?). However, polyploidy is fairly common
in plants; 30 to 50% of all angiosperms are thought to be polyploid.

Why the difference?

       Polyploidy in animals is greatly restricted, since the XY mechanism of sex
       determination can be easily upset when chromosome sets are duplicated,
 .e.g. XXY, XXXY individuals are quite abnormal. Thus, polyploidy in animals is usually
accompanied by some kind of asexual reproduction,
 .e.g. parthenogenesis.

How do higher ploidy levels arise?

.          •     multiple fertilization
  .•       unreduced gametes
a.         o     mitotic failure in the germinal cells giving rise to gametes
b.         o     meiotic failure
Triploids - 3x

.      •       Can arise from a cross between an autotetraploid (see below) and a
diploid or from a union of an unreduced gamete and a typical gamete from 2 diploids
(both 2n + n)
.      •       Usually are a dead end; sterile even if viable (All polyploids with odd
numbers of chromosome sets are generally sterile because of unbalanced pairing at
meiosis; you get some combination of trivalents, monovalents, and bivalents.)

Triploids have some utility in plants, particularly seedlessness, e.g. bananas,
watermelons, citrus

Perhaps also size - triploids vegetatively propagated

Triploidy is the only polyploidy "tolerated" in humans; 3n = 69; the only individuals that
survive are mosaics and they are typically quite abnormal

   •   somatic nondisjunction during mitotic cell division during early development may
       lead to mosaics or chimeras, organisms with mixtures of cells of different
       chromosome compositions

Tetraploids - 4x

Who cares about tetraploids? Actually they have some utility in plant breeding. They
may have an increased size of various organs of interest to man- roots, leaves,
flowers, fruits, seeds. For example, tetraploid sugar beets produce increased sugar per
hectare even though sugar decreases as rootsize increases because the root size
becomes large enough to compensate for the sugar loss.

Two types of natural origins: 1) intraspecific - all sets of chromosomes are from the
same species - most likely arise from nonreduced gametes or failure in mitosis
(nondisjunction in mitosis or meiosis)-autoploidy

   •   Colchicine or nitrous oxide can encourage the production of polyploid plants

2) interspecific - the sets of chromosomes involved come from different,
although usually related species - alloploidy

   •   In plants, true allopolyploidy is rare, but segmental allopolyploids are common

How do allopolyploids arise? Two different species interbreed producing an organism in
which each cell has one haploid set of chromosomes from each parent. Then both
chromosome sets are doubled. How does this happen? A miracle occurs! Actually, we
don't know, but it has happened in nature in plants on a number of occasions. The only
man-made example is triticale (wheat x rye).

Thus, polyploids have wholesale gene duplication. When allopolyploids are created
from diploids with different alleles, heterozygosity is fixed. However, over time, since
there are two copies of each gene pair present, there is an opportunity to evolve
different functions for the two different gene pairs, finally creating a species that is
essentially diploidized.

Tobacco T -N. tomentosa (tomentosiformis)

2n = 4x = 48 S -N. sylvestris

Wheat A -T. monococum

2n = 3x = 42 B -A. speltoides

                          D -A. squarrosa

Segmented allopolyploids can occur, e.g. from the same population isolated in
different environments, become two populations favoring different chromosome
Allopolyploidy is rare in animals (besides the XY problems) because of the rarity of
interspecific cross-fertilization. Even when fully viable hybrid animals are formed, they
are unable to reproduce vegetatively and therefore cannot last long enough for the rare
chromosome doubling event which forms allopolyploids to occur.

Polyploidy, especially alloploidy, is fairly common in plants, and in fact has greatly
contributed to the evolution and speciation of plants. e.g. wheat, tobacco, maize

Genetic consequences of polyploids:

.      •       Autopolyploids - fertility is reduced unless there is some system to
enforce strict pairing at meiosis; otherwise, pairing at meiosis is irregular, as is
segregation at anaphase. Pollen formation or seed sterility can occur. Sterility is usually
less than in triploids.
.      •       Allopolyploids - meiotic pairing is typically regular so fertility is not
reduced - genetic analysis and breeding may be more complex

Changes in One or a Few Chromosomes
Aneuploidy vs Euploidy

Aneuploidy is the abnormal state where one or two or a few entire chromosomes
are lost from or added to the normal chromosome complement. Abnormal doesn't
sound good, does it?

In most cases, aneuploidy is lethal in animals, so it is detected mainly in aborted
fetuses. Aneuploidy is not lethal in some plants (more below).

How does aneuploidy occur?

.      •       loss of individual chromosomes in meiosis or mitosis - "anaphase lagging"
.      •       nondisjunction - most important - chromosomes that should normally be
separated during cell division remain together and are transported at anaphase to one
pole - may occur during mitosis but more common during meiosis I or II (see above).
Here is a question for you, that could be a test question (are you really reading these
notes?) What is the result of nondisjunction in each case, during meiosis I, meiosis II, or
mitosis, in terms of fertility and survival of individuals produced?

Main Types of Aneuploidy
disomy - usual somatic condition - disomic - 2n

nullisomy - involves loss of one homologous chromosome pair, producing a
nullisomic, 2n - 2. Usually occurs due to nondisjunction. Tolerated best by polyploid
species. In wheat, the whole nullisomic set is available; in tobacco, some
nullisomics have been produced

monosomy - loss of a single chromosome, producing a monosomic - 2n - 1. The whole
set is available in wheat , tobacco, some other crops.

trisomy - gain of an extra chromosome, so that the cell has 3 copies of a single
chromosome type (i.e. two copies of one homologous chromosome, one copy of the
other one) - trisomic - 2n + 1

tetrasomy - gain of 2 extra chromosomes of the same type, resulting in 4 copies
-tetrasomic - 2n + 2

            more complex aneuploids occur, e.g. double monosomics 2n - 1 -
       1; mosaicism is also possible, when nondisjunction happens during
       mitosis early in the development of an organism, which can lead to
       serious consequences
Trisomics are important genetic tools to understand dosage effects

.      • AAA, AAa, Aaa, aaa
.      • also for linkage analysis (see below)
.      • Down's syndrome - trisomic 21 - 1/2,000

Trisomics in humans Illustration from Dr. Jonathan Wolfe, The Galton Laboratory, London Other
autosomes 18, 13, 8, 9, 22 - very rare Others lethal Sex chromosomes - all lead to
serious morphological abnormalities and

frequently to early death XXY - Klinefelter's


                Illustration from Dr. Jonathan Wolfe, The Galton Laboratory, London
XO - Turner's syndrome


Detection of linkage groups with aneuploids

When complete sets (for all nonhomologous chromosomes of an organism) of an
aneuploid type are available, they are very valuable for gene mapping and other genetic

   •   Can use aneuploids to determine which chromosome (or linkage group) a gene
       is located on because in the critical family, unusual genetic ratios are obtained;
       these are compared with disomic ratios

.     • Done mostly in plants - trisomics used in true diploid plants because
monosomics, nullisomics are not viable; entire set of trisomics available in wheat, oats,
tomato, spinach, rice, sorghum, barley - often distinct morphology
.     • Monosomics and nullisomics used in polyploid plants; complete set of
monosomics available in wheat, oat, tobacco, nullisomics in wheat


The presence and arrangement of many genes on a single chromosome permit a
change in genetic information to occur not only through a change in chromosome
number but also through a change in chromosome structure; involves changes in parts
of chromosomes rather than whole chromosomes or sets of chromosomes.

Structural modifications of chromosomes are common in nature and have apparently
played a significant role in evolution. They occur spontaneously, but the frequency is
increased by ionizing radiation and chemical mutagens.

The formation of these abnormalities presupposes breakage in chromosomes or
chromatids. When breakage occurs, involved pieces can: 1) remain ununited, leading
to the eventual loss of the chromosome segment without a centromere; 2) reunite
(reunion, restitution), leading to reconstitution of the original arrangement; or, 3) ends
from different breaks can join, leading to an exchange, or a nonrestitutional union.
Chromosomal rearrangements, like gene mutations, can take place either in
somatic or in germinal tissue; the former is very important in cancer - many cancers
are associated with somatic chromosome changes.

Depending on the number of breaks, their locations, and the pattern in which broken
ends join together, a variety of structural changes are possible:

Four Major Types
deletions - loss of segment

duplications - duplication of segment these involve a change in the amount of DNA

inversions - change in orientation of a DNA segment within a chromosome without
loss of material

translocations - change in location of a DNA segment to another location in the
genome without the loss of material

Any of these changes in chromosome structure is a rare event - usually occurs only in
one of the pairs of homologous chromosomes, so in the individual where the alteration
occurs, there is one altered homologue and one normal homologue. This is called a
structural heterozygote or structural hybrid. Selfing, inbreeding, or interbreeding,
depending on the organism, can produce individuals homozygous for the alteration
-structural homozygote. Usually meiotic pairing is regular in the structural
homozygote, but linkage relationships may be changed from the original type and
viability may be affected.

Deletion - deficiency - chromosome aberration resulting in the loss of a segment of
DNA and the information contained on it (This can be one nucleotide to large segments
of chromosomes).

.     • May be located anywhere along a chromosome
.     •      Deletion of a chromosome end results in an unstable chromosome unless
the end gets capped by a telomere

Breaks in heterochromatin are more likely to heal than breaks in euchromatin

If the centromere is lost, an acrocentric chromosome is created which is usually lost
during meiosis (death of cell or loss of fertility)

Deletions in other places are referred to as intercalary or interstitial defiencies

Caused by breaks in chromosomes due to radiation, heat, viruses, chemicals, or errors
in recombination

Consequences depend on what is deleted

.      •      May not be serious because a homologous gene is present, but if that
gene is recessive and deleterious, and is no longer masked, the consequences are
.      •      Expression of a recessive allele due to deletion of the wild-type allele is
termed pseudodominance - in structural heterozygotes (many dominant characters in
Drosophila are associated with small deletions in heterozygous condition - Minute,
Delta, Notch)
.      •      Small deletions can be homozygous viable and produce recessive
phenotypes; however, larger deletions are often lethal in structural

.       •      No crossovers can be detected in a deleted region; this affects linkage
.       •      Deletions often cause pollen sterility in plants
.       •      In animals, they are lethal to males if they occur on the x chromosome

Often proof of deletions is genetic in nature

.       • look at segregation in surrounding markers
.       • no crossovers expected in deleted area
        • no back mutations (reversions) expected
        • only large deletions can be detected by karyotype analysis or in polytene
.    •    pairing in meiosis causes a loop

A number of human disorders are caused by deletions; many are found in heterozygous
individuals because the deletions are lethal in homozygotes. Thus, they act as dominant

    •   cri-du-chat syndrome - results from observable deletion of part of the short arm of
        chromosome 5 - severe retardation, physical abnormalities, mewing, cat-like cry
        during infancy, early death
Philadelphia chromosome - part of long arm of c. 22 - chronic granulocytic

Chromosome aberration that results in the doubling or duplication of a segment of a

.     •     May or may not be lethal
.     •     Size varies considerably
.     •     Generally better tolerated than deletions
.     •     Thought to be caused by unequal crossing over due to inaccurate pairing
of homologous chromosomes or multiple replication of a looped region of DNA by DNA

Duplications may be classified in several ways

Reverse tandem

Displaced - same chromosome - homobrachial

      Extrachromosome - exists individually with its own centromere
Pairing at meiosis in a heterozygote results cytogenetically in a loop as in a
deletion in heterozygous individuals, and therefore in a reduction in fertility,
especially in pollen.

Further, unequal numbers of sequence repeats may lead to mispairing; i.e. there is an
intrinsic instability built into the process of meiosis. This "slippage": means that there is
a tendency for duplications to build up or decline in number. This is now known to be a
very important force in mutation.

Effects and uses of duplications

     •   May produce distinctive phenotype in heterozygotes

         Bar mutation in Drosophila - functions as incomplete dominant
         gene - duplication of segment (1 band, 16A) on the X chromosome
         The mutation reduces the number of facets in the eye.

Female                                                    Male

++                 wild type x-16a


+B reduced kidney x-16a x-16a-16a

BB more           bar                  x-16a-16a        bar                x-16a-16a
                                       x-16a-16a                           x-16a-16a

                  double bar          x-16a-16a-16a


Crossing experiments can lead to an odd result. When two Bar flies are crossed, all of
their offspring are expected to be Bar; and usually they are. Sometimes, though, the
cross produces a mixture of flies with tiny eyes (double-bar) and flies with normal eyes.
In the aberrant cross, there has been mispairing: and unequal crossing over in the
tandem duplication. We now know that this is an important mechanism of mutation;
many human diseases are due to increase in the number of short repeats within a gene
(dosage effect), as we will see later. This is also an example of gene position effect;
gene expression is stronger when genes are in tandem rather than on separate
   • Probably   have occurred often in nature and have evolutionary significance

Duplications have played an important role in the evolution of multigene families,
e.g. a-globin and ß-globin are each arranged in an array. Sequences of genes within a
family are similar and are thought to have evolved from an ancestral gene by duplication
and divergence. They are expressed at different times during development, so perhaps
due to unequal crossing over, mutations in the ancestral gene have given rise to new
functions (or pseudogenes).


Inversions are chromosome aberrations resulting when a segment of chromosome is
excised and then reintegrated in an orientation 180 degrees from the original
orientation, i.e. in reverse order

   • breaking   and rejoining during meiosis

Two types:
paracentric -(beside the centromere) when the inverted segment occurs on one
chromosome arm and does not include the centromere
pericentric - (around the centromere) when the inverted segment includes parts of both
chromosome arms and therefore the centromere

       • pericentric inversions less common In general, genetic material is not lost when
an inversion takes place, although there can be phenotypic consequences depending
on locations of break points
(e.g. within a gene) and changes in gene order (affecting gene regulation).

Pericentric inversions can produce morphological changes in the appearance of a
chromosome if the breaks extend unevenly along chromosome arms due to changes in
centromere position and arm lengths

    • Peromycus  - deer mouse - all species 2n = 48, but some species have entirely
               metacentric chromosomes, others mostly acrocentric ones

Meiotic consequences:

.     • None in homozygotes
.     • Heterozygotes:

      Small inversions can inhibit crossing over due to lack of pairing
      within the inverted region
      With larger inversions, inversion loops are formed at pachytene of
      Cross-overs within paracentric inversion loops result in - normal
      chromatid, inversion product, acentric fragment, dicentric chromatid
(bridge - breakage - fusion) Cross-overs in pericentric inversions result in -
normal, inversion, 2 products with duplications and deficiencies
Genetically - recombination is reduced or suppressed (not really, but it appears so
because gametes derived from recombined chromotids are not usually nonviable;
crossing over in or around the inversion loop may be suppressed by lack of pairing

This is the most common type of chromosomal aberration in plants or animals. Inversion
heterozygotes (intrachromosomal?) are not particularly rare in human populations.
About one person in 50 has a visible chromosome inversion. This cytological
abnormality usually have no visible effect on phenotype.

Inversions, especially pericentric inversions, have played a major role in the
phylogeny of higher primates, i.e. speciation.

Translocation - transposition - interchanges - chromosome aberration in which
there is a change in position of chromosome segments and the gene sequences they

Simple translocations may be classified as

.    • intrachomosomal - change in position occurs within a chromosome
.    •       interchromosomal - change in position between nonhomologous
        nonreciprocal - involves 3 breaks

        reciprocal - involves 2 breaks
Meiotic consequences - depends on the particular translocation

Robertsonian translocations (shifting around of different chromosome arms) in mice are
fixed in some populations; but these are nearly always isolated - eg groups on different
Orkney Islands or in different isolated Alpine valleys. All of the individuals in the group
carry the translocation, so no problems are created in heterozygotes.

However, translocation often results in duplications and deletions in
heterozygotes and therefore inviable gametes or zygotes

Reciprocal translocations - most frequent and genetically important

.      •      homozygotes - meiosis normal, but linkage relationships may be altered
.      •      heterozygotes - what is often formed is a connected group of 4
chromosomes tied together by the translocated sections at pachytene (referred to as a
quadrivalent or quadrangle) - cross-like metaphase configurations; if only homologous
sections pair, the position of the "cross" can indicate the breakage points of the
translocation. There are three segregation patterns:

Illustration from Dr. Jonathan Wolfe, The Galton Laboratory, London

.     •     alternate - only these viable - opposite or alternate nonhomologous
centromeres go to the same pole in a zig-zag fashion so that the nontranslocated and
translocated chromosomes are in separate gametes. Each gamete thus has a complete
balanced complement of genes without duplications and deficiencies
.      •      adjacent 1 - nonhomologous adjacent centromeres (chromosomes) go to
the same pole but each gamete contains both a nontranslocated and translocated
chromosome, thus duplications and deficiencies and an unbalanced genetic
.      •      adjacent 2 - adjacent centromeres again go to the same pole but these
are now homologous as well as containing both translocated and nontranslocated
chromosomes - not common - this occurs only when homologous chromosomes don't
separate at Anaphase I

           Therefore the result is about 50% sterility - semisterility in pollen

Translocation and the resulting shifting of genes around the genome gave the first
insight into an important aspect of modern genetics - that the effect of a gene can be
modified by its place in the genome -position effect. For example, the gene for the
Drosophila white eye mutation is normally on the X chromosome, very near the tip.
Usually a heterozygous female with one mutant (recessive) allele has red, wildtype,
eyes. However, when the locus is translocated to chromosome 4, next to a block of
heterochromatin, in heterozygous females where the wildtype red-eyed allele w+ is next
to the heterochromatin and the white eyed w allele is on euchromatin, then the normal
allele loses part of its dominance; and instead of the eye being red, there are patches of
white and red eye facets. This effect disappears if the wildtype allele is shifted out of the
place next to heterochromatin; i.e. it is not a change in the allele itself, but the way it is
expressed. Now we know that this is because the gene is not expressed properly in or
very close to heterochromatin. Discovery that the expression and effects of a gene
depends on its position on a chromosome are now central to the study of cancer. Many
cancers involve translocations; which in fact can be used as diagnostic tool. Now it is
known that cancer may be induced because a gene controlling normal cell division (a
proto-oncogene) has moved to a new place in the genome, next to other genes that
cause it to greatly increase its activity.

Bottom line: what has been learned over many years with what is now a very
traditional science, cytogenetics, particularly as it has been coupled with molecular
biology findings, has made important contributions to what has been learned or can
be accomplished in other fields such as cancer research, plant breeding, gene
mapping, and taxonomic and evolutionary studies.

This is especially true in speciation. "Evolution is a cytogenetic process". 1)
amount of DNA per genome; 2) evolution of individual chromosomes; 3)
karyotype changes within duplicated taxa