Chromosomal aberrations; changes in the number of chromosomes, Aneuploidy and Euploidy
Written Assignment for first twenty students: Rolls numbers 01 to 20.
Topic: Chromosomal aberrations; Changes in the number of chromosomes, Aneuploidy and
EuploidyChromosomal aberrations; changes in the number of chromosomes, Aneuploidy and Euploidy
Written Assignment for first twenty students: Rolls numbers 01 to 20.
Topic: Chromosomal aberrations; Changes in the number of chromosomes, Aneuploidy and
EuploidyChromosomal aberrations; changes in the number of chromosomes, Aneuploidy and Euploidy
Written Assignment for first twenty students: Rolls numbers 01 to 20.
Topic: C
hromosomal aberrations; Changes in the number of chromosomes, Aneuploidy and Euploidy
he chromosome set of a species remains relatively stable over
long periods of time. However, within populations there can
be found abnormalities involving the structure or number of
chromosomes. These alterations arise spontaneously from
errors in the normal processes of the cell. Their consequences
are usually deleterious, giving rise to individuals who are
unhealthy or sterile, though in rare cases alterations provide
new adaptive opportunities that allow evolutionary change to
occur. In fact, the discovery of visible chromosomal
differences between species has given rise to the belief that
radical restructuring of chromosome architecture has been an
important force in evolution.
Changes in chromosome structure
Two important principles dictate the properties of a large
proportion of structural chromosomal changes. The first
principle is that any deviation from the normal ratio of genetic
material in the genome results in genetic imbalance and
abnormal function. In the normal nuclei of both diploid and
haploid cells, the ratio of the individual chromosomes to one
another is 1:1. Any deviation from this ratio by addition or
subtraction of either whole chromosomes or parts of
chromosomes results in genomic imbalance. The second
principle is that homologous chromosomes go to great lengths
to pair at meiosis. The tightly paired homologous regions are
joined by a ladderlike longitudinal structure called the
synaptonemal complex. Homologous regions seem to be able
to find each other and form a synaptonemal complex whether
or not they are part of normal chromosomes. Therefore, when
structural changes occur, not only are the resulting pairing
formations highly characteristic of that type of structural
change but they also dictate the packaging of normal and
abnormal chromosomes into the gametes and subsequently
into the progeny.
Deletions
The simplest, but perhaps most damaging, structural change
is a deletion—the complete loss of a part of one chromosome.
In a haploid cell this is lethal, because part of the essential
genome is lost. However, even in diploid cells deletions are
generally lethal or have other serious consequences. In a
diploid a heterozygous deletion results in a cell that has one
normal chromosome set and another set that contains a
truncated chromosome. Such cells show genomic imbalance,
which increases in severity with the size of the deletion.
Another potential source of damage is that any recessive,
deleterious, or lethal alleles that are in the normal counterpart
of the deleted region will be expressed in the phenotype. In
humans, cri-du-chat syndrome is caused by a heterozygous
deletion at the tip of the short arm of chromosome 5. Infants
are born with this condition as the result of a deletion arising
in parental germinal tissues or even in sex cells.
The manifestations of this deletion, in addition to the “cat cry”
that gives the syndrome its name, include severe intellectual
disability and an abnormally small head.
Duplications
A heterozygous duplication (an extra copy of some
chromosome region) also results in a genomic imbalance with
deleterious consequences. Small duplications within
a gene can arise spontaneously. Larger duplications can be
caused by crossovers following asymmetrical chromosome
pairing or by meiotic irregularities resulting from other types
of altered chromosome structures. If a duplication becomes
homozygous, it can provide the organism with an opportunity
to acquire new genetic functions through mutations within the
duplicate copy.
Inversions
An inversion occurs when a chromosome breaks in two places
and the region between the break rotates 180° before
rejoining with the two end fragments. If the inverted segment
contains the centromere (i.e., the point where the two
chromatids are joined), the inversion is said to be pericentric;
if not, it is called paracentric. Inversions do not result in a
gain or loss of genetic material, and they have deleterious
effects only if one of the chromosomal breaks occurs within an
essential gene or if the function of a gene is altered by its
relocation to a new chromosomal neighbourhood (called the
position effect). However, individuals who are heterozygous
for inversions produce aberrant meiotic products along with
normal products. The only way uninverted and inverted
segments can pair is by forming an inversion loop. If no
crossovers occur in the loop, half of the gametes will be
normal and the other half will contain an inverted
chromosome. If a crossover does occur within the loop of a
paracentric inversion, a chromosome bridge and an acentric
chromosome (i.e., a chromosome without a centromere) will
be formed, and this will give rise to abnormal meiotic
products carrying deletions, which are inviable. In a
pericentric inversion, a crossover within the loop does not
result in a bridge or an acentric chromosome, but inviable
products are produced carrying a duplication and a deletion.
Translocations
If a chromosome break occurs in each of two nonhomologous
chromosomes and the two breaks rejoin in a new
arrangement, the new segment is called a translocation. A cell
bearing a heterozygous translocation has a full set of genes
and will be viable unless one of the breaks causes damage
within a gene or if there is a position effect on gene function.
However, once again the pairing properties of the
chromosomes at meiosis result in aberrant meiotic products.
Specifically, half of the products are deleted for one of the
chromosome regions that changed positions and half of the
products are duplicated for the other. These duplications and
deletions usually result in inviability, so translocation
heterozygotes are generally semisterile (“half-sterile”).
Changes in chromosome number
Two types of changes in chromosome numbers can be
distinguished: a change in the number of whole chromosome
sets (polyploidy) and a change in chromosomes within a set
(aneuploidy).
Polyploids
An individual with additional chromosome sets is called
a polyploid. Individuals with three sets of chromosomes
(triploids, 3n) or four sets of chromosomes (tetraploids, 4n)
are polyploid derivatives of the basic diploid (2n) constitution.
Polyploids with odd numbers of sets (e.g., triploids) are
sterile, because homologous chromosomes pair only two by
two, and the extra chromosome moves randomly to a cell pole,
resulting in highly unbalanced, nonfunctional meiotic
products. It is for this reason that triploid watermelons are
seedless. However, polyploids with even numbers of
chromosome sets can be fertile if orderly two-by-two
chromosome pairing occurs.
Though two organisms from closely related species frequently
hybridize, the chromosomes of the fusing partners are
different enough that the two sets do not pair at meiosis,
resulting in sterile offspring. However, if by chance the
number of chromosome sets in the hybrid accidentally
duplicates, a pairing partner for each chromosome will be
produced, and the hybrid will be fertile. These chromosomally
doubled hybrids are called allotetraploids. Bread wheat, which
is hexaploid (6n) due to several natural spontaneous
hybridizations, is an example of an allotetraploid. Some
polyploid plants are able to produce seeds through an asexual
type of reproduction called apomixis; in such cases, all
progeny are identical to the parent. Polyploidy does arise
spontaneously in humans, but all polyploids either abort in
utero or die shortly after birth.
Aneuploids
Some cells have an abnormal number of chromosomes that is
not a whole multiple of the haploid number. This condition is
called aneuploidy. Most aneuploids arise by nondisjunction, a
failure of homologous chromosomes to separate at meiosis.
When a gamete of this type is fertilized by a normal gamete,
the zygotes formed will have an unequal distribution of
chromosomes. Such genomic imbalance results in severe
abnormalities or death. Only aneuploids involving small
chromosomes tend to survive and even then only with an
aberrant phenotype.
The most common form of aneuploidy in humans results
in Down syndrome, a suite of specific disorders in individuals
possessing an extra chromosome 21 (trisomy 21). The
symptoms of Down syndrome include intellectual disability,
severe disorders of internal organs such as the heart and
kidneys, up-slanted eyes, an enlarged tongue, and abnormal
dermal ridge patterns on the fingers, palms, and soles. Other
forms of aneuploidy in humans result from abnormal
numbers of sex chromosomes. Turner syndrome is a condition
in which females have only one X chromosome. Symptoms
may include short stature, webbed neck, kidney or heart
malformations, underdeveloped sex characteristics, or
sterility. Klinefelter syndrome is a condition in which males
have one extra female sex chromosome, resulting in an XXY
pattern. (Other, less frequent, chromosomal patterns include
XXXY, XXXXY, XXYY, and XXXYY.) Symptoms of Klinefelter
syndrome may include sterility, a tall physique, lack of
secondary sex characteristics, breast development,
and learning disabilities.
Molecular genetics
The data accumulated by scientists of the early 20th century
provided compelling evidence that chromosomes are the
carriers of genes. But the nature of the genes themselves
remained a mystery, as did the mechanism by which they
exert their influence. Molecular genetics—the study of the
structure and function of genes at the molecular level—
provided answers to these fundamental questions.
Chromosomal Aberrations
Chromosomal aberrations are abnormalities in the
structure or number of chromosomes and are often
responsible for genetic disorders. For more than a
century, scientists have been fascinated by the study of
human chromosomes. It was not until 1956, however,
that it was determined that the actual diploid number of
chromosomes in a human cell was forty-six (22 pairs
of autosomes and two sex chromosomes make up the
human genome). In 1959 two discoveries opened a new
era of genetics. Jerome Lejeune, Marthe Gautier, and M.
Raymond Turpin discovered the presence of an extra
chromosome in Down syndrome patients. And C. E. Ford
and his colleagues, P. A. Jacobs and J. A. Strong first
observed sex chromosome anomalies in patients with
sexual development disorders.
Advances in Chromosomal Analysis
Identification of individual chromosomes remained
difficult until advances in staining techniques such as Q-
banding revealed the structural organization of
chromosomes. The patterns of bands were found to be
specific for individual chromosomes and hence allowed
scientists to distinguish the different chromosomes. Also,
such banding patterns made it possible to recognize that
structural abnormalities or aberrations were associated
with specific genetic syndromes. Chromosome disorders,
or abnormalities of even a minute segment (or band) are
now known to be the basis for a large number of genetic
diseases.
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Chromosomal disorders and their relationship to health
and disease are studied using the methods
of cytogenetics . Cytogenetic analysis is now an integral
diagnostic procedure in prenatal diagnosis. It is also
utilized in the evaluation of patients with mental
retardation, multiple birth defects, and abnormal sexual
development, and in some cases of infertility or multiple
miscarriages. Cytogenetic analysis is also useful in the
study and treatment of cancer patients and individuals
with hematologic disorders. The types of chromosomal
abnormalities that can be detected by cytogenetics are
numerical aberrations, translocations, duplications,
deletions, and inversions.
Chromosomal Aberrations
Chromosomal abnormalities can result from either a
variation in the chromosome number or from structural
changes. These events may occur spontaneously or can
be induced by environmental agents such as chemicals,
radiation, and ultraviolet light. However, mutations are
most likely due to mistakes that occur when the genes
are copied as the cells are dividing to produce new cells.
These abnormalities may involve the autosomes, sex
chromosomes, or both. The disruption of the DNA
sequence or an excess or deficiency of the genes carried
on the affected chromosomes results in a mutation. Such
a change may or may not alter the protein coded by a
gene. Often, however, a mutation results in the
disruption of gene functionality. The resulting altered or
missing protein can disrupt the way a gene is meant to
function and can lead to clinical disease. Only mutations
occurring to the DNA in the gametes will potentially pass
on to the offspring.
Mutations appear in gametes in one of two ways. A
mutation may be inherited from one of an individual's
parents. However, a mutation may also occur for the first
time in a single gamete, or during the process of
fertilization between an egg cell and a sperm cell. In this
case the mutation or change is often called a de novo
mutation. The parents are not affected by the condition
and are not "carriers" of the mutation. The affected
individual will have this mutation in all of his or her cells
and may be able to pass the mutation on to any
offspring. Some common abnormalities and their
resulting phenotypes are discussed below.
Aneuploidy
Aneuploidy is the gain or loss of individual chromosomes
from the normal diploid set of forty-six chromosomes. As
in structural anomalies, the error may be present in all
cells of a person or in a percentage of cells. Changes in
chromosome number generally have an even greater
effect upon survival than changes in chromosome
structure. Considered the most common type of clinically
significant chromosome abnormality, it is always
associated with physical and/or mental developmental
problems. Most aneuploid patients have a trisomy of a
particular chromosome. Monosomy , or the loss of a
chromosome, is rarely seen in live births. The vast
majority of monosomic embryos and fetuses are
probably lost to spontaneous abortion during the very
early stages of pregnancy. An exception is the loss of
an X chromosome, which produces Turner's syndrome.
Trisomy may exist for any chromosome, but is rarely
compatible with life.
Aneuploidy is believed to arise from a process called
nondisjunction. Nondisjunction occurs when
chromosomes do not separate correctly during meiosis.
The direct result is that one gamete will have an extra
chromosome and the other will be lacking a
chromosome. When these gametes are fertilized by a
normal gamete, they have either an extra chromosome
(trisomy) or are missing a chromosome (monosomy).
Disorders Associated with Aneuploidy
Three well-known autosomal chromosome disorders
associated with trisomies of entire autosomes are
sometimes found in live births. These are trisomy 21
(Down syndrome), trisomy 13, and trisomy 18. Growth
retardation, mental retardation, and multiple congenital
anomalies are associated with all three trisomies.
However, each has distinctive morphological
characteristics, which are presumably determined by the
extra dosage of the specific genes on the additional
chromosome.
Down syndrome (chromosome 21) is the most frequent
trisomy found in humans, and one of the most common
conditions encountered in genetic counseling. General
characteristics are mental retardation, distinctive palm
prints, and a common facial appearance. The average
life expectancy is now much greater thanks to
improvements in medical care. Generally, individuals
with Down syndrome have affable personalities and are
able to be partially independent. The incidence of Down
syndrome is about 1 in 800 children and is often
associated with later maternal age (as may also be the
case with other aneuploids).
Down syndrome appears to be related to the difference
in gamete formation (gametogenesis) between males
and females. In females, oocytes are formed before
birth and held in a static state until ovulation. In the case
of older mothers, an oocyte may be in this stage for more
than forty years, during which time environmental factors
may affect the genetic material. In trisomy 13 and
trisomy 18 patients, congenital abnormalities are much
more severe. These individuals generally do not live
much beyond birth. Both trisomy 13 and trisomy 18 result
in syndromes characterized by specific dysmorphic
features and severe organ malformations.
In addition to trisomies involving the autosomal
chromosomes, aneuploidy may also involve the sex
chromosomes. Two examples are Turner's syndrome
and Klinefelter's syndrome. As mentioned previously,
Turner's syndrome is a monosomy involving the X
chromosomes. Turner's syndrome females possess
forty-five chromosomes (45, X) as compared to clinically
normal forty-six (46, XX). They are usually sterile and
short in stature with some neck webbing. Klinefelter's
syndrome patients have a trisomy involving the sex
chromosomes and thus have forty-seven chromosomes
(47, XXY). Klinefelter's syndrome individuals are sterile
males possessing some female characteristics. These
chromosome abnormalities are of interest especially for
their implications in infertility and abnormal development.
Abnormalities of Chromosomal Structure
Four types of structural changes may occur in
chromosomes: duplications, deletions, translocations,
and inversions. All may result when there is breakage of
the chromosomes and a rejoining or loss of chromosome
fragments. If the same broken ends rejoin, the
chromosome becomes intact once again. The resulting
effects of such events depend on how large they are and
where they occur on the chromosome. Rearrangements
may occur in many forms and are less common than
abnormalities of chromosome number.
The most common type of rearrangement is called a
balanced translocation because the amount of genetic
information within that cell is normal even though it is
repositioned. Therefore the individual with a balanced
translocation may appear normal. However, there will be
a risk to the children of a carrier of a balanced
translocation since that person is likely to produce
unbalanced gametes (bearing too little or too much
genetic information), and therefore the risk of having
abnormal offspring is increased. Rearrangements such
as aneuploidy may be found in all cells of an individual,
or they may occur only in a percentage of an individual's
cells. This latter condition is known as mosaicism. In
general, mosaic individuals show a less severe
expression of their syndrome than those with
chromosome abnormalities in all their cells.
Unbalanced Chromosome Rearrangements
A rearrangement is considered unbalanced if it results in
extra or missing information. Structural rearrangements
may be caused by a number of factors including
chemicals, some viral infections, and ionizing radiation.
Because the complement of DNA or genetic material in
the chromosomes is greater or less than the complement
of DNA in a normal set of chromosomes, there is likely to
be abnormal development.
Deletions
A deletion is the loss of a segment of a chromosome.
The amount of deleted material may be any length from
a single base to a large piece of the chromosome. The
result is a chromosomal imbalance, with the individual
being monosomic or possessing half of the required
genes present in a normal individual for the segment of
DNA missing. Only small deletions are tolerated, and the
effect on the individual will depend upon the size of the
deleted segment and the number and functionality of the
genes that are contained within it. Larger deletions and
the deletion of an entire chromosome always result in
nonviable embryos. Cri du Chat's ("cat's cry") syndrome
individuals have a deletion of the short arm of
chromosome 5. Although they possess the usual signs of
chromosomal anomalies, such as mental retardation and
low birth weight, their appearance is not extraordinarily
different from normal individuals. One peculiarity is that
affected infants make an unusual cry resembling that of
a cat, hence the name of the syndrome. Two other
interesting diseases are Prader-Willi's syndrome and
Angelman's syndrome. In both cases, patients with these
diseases possess a deletion in the long arm of
chromosome 15. Interestingly, the deletion is in the same
location, but the resulting syndrome depends on whether
the deletion was in the maternal or paternal
chromosome.
Duplications
Duplications also result from the reuniting of broken
pieces of homologous chromosomes. In some cases
the chromosome pieces rejoin in such a way that there is
a doubling, or redundancy, of a portion of the
chromosome. This changes the number of genes
present and may result in a problem with health,
development, or growth.
Large insertions and deletions prevent the production of
useful proteins. The effect of smaller insertions or
deletions depends upon how many bases are involved.
Sometimes an entire gene can be inserted (in
duplications) or deleted. The effect depends upon where
in the genome the changes occur and how many base
pairs are involved.
Inversions
An inversion is the rotation of a broken chromosome
segment in such a way that it rejoins the chromosome in
a reversed state, or is flipped, end to end. Inversions are
usually characterized by whether the centromere is
included in the inverted segment. Inversions containing
the centromere are called pericentric. Those not
containing the centromere are called paracentric.
Although an inversion does not change the overall
content of cellular DNA and can be considered a
balanced translocation, it can affect a gene at many
levels because it alters the normal DNA sequence. The
gene may not produce its corresponding protein at all, or
a nonfunctioning protein may result. There is a common
inversion seen in human chromosomes involving
chromosome 9. A small pericentric inversion is present in
approximately 1 percent of tested individuals. There
appears to be no detrimental effect on the carrier, and it
does not appear to cause miscarriage or unbalanced off-
spring.
Recurrence Risk
Chromosomal aberrations may be inherited from a
parent, and because of this many families seek genetic
counseling in order to determine if a genetic disorder will
recur in another member of the same generation or in
generations that will follow. The family needs to know the
genetic risk, also known as the recurrence risk, and any
means by which transmission may be prevented. A
recurrence risk will be calculated based on the accuracy
of the diagnosis, the pedigree of the family, and the
known genetic mechanisms of the disorder in question.
see also Birth Defects; Chromosome Banding; Crossing
Over; Down Syndrome; Meiosis; Mutation;
Nondisjunction; Prenatal Diagnosis.
Jacqueline Bebout Rimmler
Bibliography
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Haines, Jonathan L., and Margaret A. Pericak-
Vance. Approaches to Gene Mapping in Complex
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Klug, William S., and Michael R. Cummings. Concepts of
Genetics. Upper Saddle River, NJ: Prentice Hall, 1997.
Thompson, Margaret W., Roderick R. McInnes, and
Willard F. Huntington. Genetics in
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