TOPICS & REFERENCES

• Chromosome Mutations: Variation in

Number and Arrangement
• Variation in chromosome number.
• Structural variations of Chromosomes –
deletions,
duplications,
inversions,
translocations,
fragile sites.
• Aneuploidy, polyploidy.
• Monosomy;
• Trisomy - Down syndrome; Edwards
syndrome; Patau syndrome.
• Cri-du-Chat syndrome;
• Williams syndrome.
• Fragile-X syndrome.
 Variation in chromosome number
• Variation in chromosome number ranges from the addition or loss of one or more chromosomes to the addition
of one or more haploid sets of chromosomes.
• In the general condition known as aneuploidy, an organism gains or loses one or more chromosomes but not a
complete set. The loss of a single chromosome from an otherwise diploid genome is called monosomy. The
gain of one chromosome results in trisomy.
• These changes are contrasted with the condition of euploidy, where complete haploid sets of chromosomes
are present.
• If more than two sets are present, the term polyploidy applies. Organisms with three sets are specifically
triploid, those with four sets are tetraploid, and so on.
• Cases that include the gain or loss of
chromosomes, it is useful to examine how
such aberrations originate. As you may recall,
the gain (47,XXY) or loss (45,X) of an
X chromosome
from an otherwise diploid genome affects
the phenotype, resulting in
Klinefelter syndrome or Turner syndrome.
Human females may contain extra
X chromosomes (e.g., 47,XXX, 48,XXXX),
and some males contain
an extra Y chromosome (47,XYY).
 Nondisjunction
Such chromosomal variation originates as a random error during the production of gametes, a
phenomenon referred to as nondisjunction, whereby paired homologs fail to disjoin during segregation.
This process disrupts the normal distribution of chromosomes into gametes. The results of nondisjunction
during meiosis I and meiosis II for a single chromosome of a diploid organism
 Deletion
• When a chromosome breaks in one or more places and a
portion of it is lost, the missing piece is called a deletion (or a
deficiency).
• The deletion can occur either near one end or within the
interior of the chromosome. These are terminal
• and intercalary deletions, respectively
• The portion of the chromosome that retains the centromere
region is usually maintained when the cell divides, whereas
the segment without the centromere is eventually lost in
progeny cells following mitosis or meiosis.
• For synapsis to occur between a chromosome with a large
intercalary deletion and a normal homolog, the unpaired
region of the normal homolog must “buckle out” into a
deletion, or compensation, loop
• If only a small part of a chromosome is deleted, the organism might
survive.
• However, a deletion of a portion of a chromosome need not be very
great before the effects become severe.. If even more genetic
information is lost as a result of a deletion, the aberration is often
lethal, in which case the chromosome mutation never becomes
available for study.
Cri du Chat syndrome in humans
Williams syndrome
 Inversions
• The inversion, another class of structural variation, is a type of chromosomal aberration in which a segment
of a chromosome is turned around 180 degrees within a chromosome. An inversion does not involve a loss of
genetic information but simply rearranges the linear gene sequence. An inversion requires breaks at two
points along the length of the chromosome and subsequent reinsertion of the inverted segment. By forming
a chromosomal loop prior to breakage, the newly created “sticky ends” are brought close together and
rejoined.
• The inverted segment may be short or quite long and may or may not include the centromere. If the
centromere is not part of the rearranged chromosome segment, it is a paracentric inversion. If the
centromere is part of the inverted segment, it is described as a pericentric inversion. Although inversions
appear to have a minimal impact on the individuals bearing them, their consequences are of great interest to
geneticists. Organisms that are heterozygous for inversions may produce aberrant gametes that have a major
impact on their offspring.
Translocations
• Translocation, as the name implies, is the movement of a
chromosomal segment to a new location in the genome.
Reciprocal translocation, for example, involves the
exchange of segments between two nonhomologous
chromosomes. The least complex way for this event to
occur is for two nonhomologous chromosome arms to come
close to each other so that an exchange is facilitated. If the
exchange includes internal chromosome segments, four
breaks are required, two on each chromosome.
• The genetic consequences of reciprocal translocations are,
in several instances, similar to those of inversions. For
example, genetic information is not lost or gained. Rather,
there is only a rearrangement of genetic material. The
presence of a translocation does not, therefore, directly alter
the viability of individuals bearing it.
Robertsonian translocation
 Translocations in humans: Familial Down syndrome.
• Research conducted since 1959 has revealed numerous
translocations in members of the human population. One
common type of translocation involves breaks at the extreme
ends of the short arms of two nonhomologous acrocentric
chromosomes. These small segments are lost, and the larger
segments fuse at their centromeric region. This type of
translocation produces a new, large submetacentric or
metacentric chromosome, often called a Robertsonian
translocation.
• One such translocation accounts for cases in which Down
syndrome is familial (inherited). Earlier in this chapter, we
pointed out that most instances of Down syndrome are due to
trisomy 21. This chromosome composition results from
nondisjunction during meiosis in one parent. Trisomy accounts
for over 95 percent of all cases of Down syndrome. In such
instances, the chance of the same parents producing a second
affected child is extremely low. However, in the remaining
families with a Down child, the syndrome occurs with much
greater frequency over several generations—it “runs in families.”
 Fragile sites in human
• In cells derived from certain individuals, a specific area along one
of the chromosomes failed to stain, giving the appearance of a gap.
In other individuals whose chromosomes displayed such
morphology, the gaps appeared at other positions within the set of
chromosomes. Such areas eventually became known as fragile
sites, since they appeared to be susceptible to chromosome
breakage when cultured in the absence of certain chemicals such
as folic acid, which is normally present in the culture medium.
The cause of the fragility at these sites is unknown.
• However, since they represent points along the chromosome that
are susceptible to breakage, these sites may indicate regions where
the chromatin is not tightly coiled. Note that even though almost
all studies of fragile sites have been carried out in vitro using
mitotically dividing cells, interest in them increased when clear
associations were established between several of these sites and a
corresponding altered phenotype, including mental retardation
and cancer.
 Fragile-x syndrome
• While most fragile sites do not appear to be associated with any clinical syndrome, individuals
bearing a folate-sensitive site on the X chromosome exhibit the fragile- X syndrome (FXS), the
most common form of inherited mental retardation.
This syndrome affects about 1 in 4000 males and 1 in 8000 females.
Since affected females usually carry only one fragile X chromosome, the disorder is considered a
dominant trait.
Fortunately, penetrance is not complete, and the trait is fully expressed in only about 30 percent of
fragile-X–bearing females and 80 percent of fragile-X– bearing males.
In addition to mental retardation, affected males have characteristic long, narrow faces with
protruding chins, enlarged ears, and increased testicular size.
• A gene that spans the fragile site, FMR1, is now known to be responsible for this syndrome. It is one
of many genes in which a sequence of three nucleotides is repeated many times, expanding the
size of the gene. Such trinucleotide repeats are also characteristic of other human disorders,
including Huntington disease and myotonic dystrophy. In FMR1, the trinucleotide sequence CGG is
repeated in an untranslated area adjacent to the coding sequence of the gene (called the
“upstream” region). The number of repeats varies within the human population, and a high number
correlates directly with expression of FXS. Normal individuals have between 6 and 54 repeats,
whereas those with 55 to 230 repeats are unaffected but are considered “carriers” of the disorder.
More than 230 repeats lead to expression of the syndrome.
Fragile-X syndrome