Cover1 - Chromosome Structure2 - Chromosome Compaction3 - Chromosome Variation5 - Nucleic Acid Structure6 - DNA Replication7 - Mutations and DNA Repair8 - Polymerase Chain Reaction (PCR)9 - Transcription10 - RNA Modifications11 - Translation12 - Gene Cloning13 - The lac Operon14 - Gene Regulation in Eukaryotes15 - Epigenetics16 - Genome Editing

3 - Chromosome Variation

In the first half of Chapter 3, we will consider deficiencies in chromosome structure. Deficiencies in chromosome structure refer to altering the total amount of genetic information in the genome (deletions, duplications), rearranging the order of genes on a chromosome (inversions), or changing the location of a gene within the genome (translocations).

In the second half of Chapter 3, we will consider situations in which the number of chromosomes in an individual varies (variations in euploidy and aneuploidy).

A. Changes in Chromosome Structure


We have learned that each structural gene is present as a single copy on a particular chromosome.  However, since we have two copies of each chromosome (one copy of the chromosome pair is inherited from the paternal parent; the other member of the pair is inherited from the maternal parent), each structural gene is actually present in two copies per genome. Changes to this general rule include the following (see figure 3.1):

Figure 3.1 Changes in Chromosome Structure (Overview) --- Image created by SL

Key Questions

  • What are the four major types of defects in chromosome structure?
  • What are the differences between the three types of translocations?


One or more breaks in a chromosome can lead to the loss of a portion of the chromosome. This type of chromosomal aberration is called a deletion (see figure 3.2).

A single break in a chromosome can result in a fragment that contains a centromere (is retained by the cell) and a fragment that lacks a centromere (is lost during mitosis). This type of event is called a terminal deletion. Terminal deletions are usually generated by endonuclease damage or by treatments, such as ionizing radiation, that break the DNA backbone.

An interstitial deletion is a deletion that does not involved the telomere. Instead, the interstitial deletion involves interior portions of the chromosome.  Interstitial deletions are generated by defects in synapsis and crossing over during meiosis I (see below).

Figure 3.2 Deletions --- Image created by SL

Key Questions

  • What is the difference between an interstitial and a terminal deletion?


In general, the larger the deletion (or the more genes involved), the more severe the phenotypic consequences. A detrimental phenotype can occur even though the individual may have a normal copy of the homologous chromosome, indicating that most deletions can be classified as dominant mutations.

Cri-du-chat (46, 5p-) is a genetic disease caused by a deletion in the p arm of chromosome 5 that occurs in 1 in 25,000–50,000 live births (see figure 3.3). Cri-du-chat is usually not inherited; instead, the disease is caused by the loss of part of chromosome 5 during meiosis. A cri-du-chat individual usually has one normal copy and a terminal deletion copy of chromosome 5. The deletion in chromosome 5 can be quite small or can encompass much of the p arm; however, it is thought that the absence of a specific gene causes cri-du-chat.  This missing gene encodes the telomerase reverse transcriptase (TERT) portion of telomerase.

The cri-du-chat individual displays mental deficiencies, facial abnormalities, gastrointestinal, and cardiac complications. Those afflicted also tend to vocalize using a catlike cry, due to defects in the formation of the glottis and larynx.


Figure 3.3 Cri-du-chat A) Patient affected with Cri-du-chat --- CriDuChat by Paola Mainardi is licensed under CC BY 2.0  B) Chromosome Abnormality --- Image created by SL

Key Questions

  • What change in chromosome structure produces cri-du-chat?


A gene duplication produces two copies of a structural gene on a single chromosome.  Since the homologous chromosome contributes another copy of the same structural gene, a person with a duplication would now have three copies of the structural gene, instead of two copies.

Duplications and deletions can be produced simultaneously by the misalignment of synapsed homologous chromosomes during meiosis, followed by unequal crossing over (see figure 3.4). Unequal crossing over produces a chromosome product with an interstitial deletion, while simultaneously producing another chromosome product that contains a duplication.

As the region of the chromosome that is duplicated gets larger, the phenotypic effect on the individual becomes more severe. One example of a disease caused by a duplication is the neuropathic disease Charcot-Marie-Tooth disease type 1A (CMT type 1A), produced from a duplication on chromosome 17.

Figure 3.4 Unequal Crossing Over Produces an Interstitial Deletion and a Duplication --- Image created by SL

Key Questions

  • How can a meiosis defect produce both a deletion and a duplication?
  • What human disease is caused by a duplication?

Duplications Can Produce Gene Families

Small duplications can sometime be beneficial and are important in the formation of gene families, closely related genes that have similar but not identical functions. For example, the globin family of genes is thought to have been formed by multiple duplications from a single ancestral globin gene (see figure 3.5). To form the globin gene family, the ancestral globin gene was duplicated to produce two identical genes on the same chromosome. These two genes then accumulated mutations independently over the course of thousands of generations to become specialized in their respective functions. Later, these two genes duplicated additional times followed by divergence through the continued accumulation of mutations. The current globin gene family, consisting of fourteen member genes, includes genes that encode the protein subunits of hemoglobin, which is specialized to carry oxygen in the bloodstream, and the protein subunits of myoglobin, which carries oxygen within muscles. The globin family of genes is a good example of how gene duplication can produce the genetic variability to result in evolutionary change.

Figure 3.5 The Globin Family --- Image created by SL

Key Questions

  • Describe how a gene duplication can produce a gene family.

Types of Inversions

Inversions involve the rearrangement of genes along a chromosome. In essence, a portion of a chromosome has been flipped in the opposite direction. An inversion can be thought of as breaking the chromosome in two places, flipping the DNA between the breaks, and sealing the DNA breaks. The total amount of genetic material (number of genes) in the chromosome does not change. Inversions are quite common; about 2% of the human population carries a detectable inversion.

There are two types of inversions (see figure 3.6):

Most inversions have no phenotypic consequences; however, if one of the chromosome breaks that form an inversion occurs within a gene, then a change in phenotype can occur. For example, in type A hemophilia, the breakpoint of an inversion in the X chromosome occurs within the factor VIII gene. The Factor VIII protein is required for proper blood clotting, so this inversion results in a nonfunctional protein, leading to a deficiency in clotting (hemophilia).

Sometimes the change in the position of a gene within the genome can alter the transcription of the gene or other genes nearby. This alteration of gene expression by an inversion is called a position effect. In some cases, the position effect can result in the overexpression of proteins that regulate the cell cycle, producing cancer.

Figure 3.6 Pericentric and Paracentric Inversions --- Image created by SL

Key Questions

  • What is the difference between a pericentric and a paracentric inversion?
  • What human disease is caused by an inversion?

Crossing Over in Inversion Heterozygotes

An inversion heterozygote is an individual who has a chromosome with a normal allele arrangement, while the homologous chromosome contains an inversion. An inversion heterozygote has a normal phenotype but produces gametes with abnormal chromosomes.

Defective gametes are produced because of events during prophase I of meiosis. Recall that homologous chromosomes synapse (align) during prophase I. For the normal chromosome and the inversion chromosome to synapse properly in an inversion heterozygote, one of the two chromosomes within the homologous chromosome pair forms an inversion loop. After the inversion loop is formed during synapsis, crossing over occurs between the two chromosomes. Abnormal chromosomes are produced after the crossover structures are resolved.


Figure 3.7 Meiosis in an Individual Heterozygous for a Pericentric Inversion --- Image created by SL

Figure 3.8 Meiosis in an Individual Heterozygous for a Paracentric Inversion --- Image created by SL

50% of the gametes produced by pericentric and paracentric inversion heterozygotes fail to produce viable offspring. Thus, inversion heterozygotes have a 50% reduction in fertility.

Key Questions

  • Describe the four gametes produced by an individual who carries a pericentric inversion.
  • Describe the four gametes produced by an individual who carries a paracentric inversion.
  • What is a dicentric bridge, and why does it produce lethal products? 

Reciprocal Translocations

translocation occurs when a piece of a chromosome becomes attached to a nonhomologous chromosome. Translocations can be balanced, meaning that the total amount of genetic material in the individual does not change. Balanced translocations often do not have phenotypic consequences. Translocations can also be unbalanced; the nonhomologous chromosome pairs that have exchanged DNA also suffer duplications or deletions. Our discussion will focus mainly on balanced translocations.

As mentioned earlier, there are three types of translocations: simple translocations, reciprocal translocations, and Robertsonian translocations.  Reciprocal translocations are formed by two general mechanisms (see figure 3.9):

Figure 3.9 Mechanisms for Producing Reciprocal Translocations --- Image created by SL

Key Questions

  • What processes generate reciprocal translocations?

Meiosis in Cells with Reciprocal Translocations

How do nonhomologous chromosomes that have experienced a reciprocal translocation synapse and then segregate in meiosis I?

During synapsis, the two pairs of homologous chromosomes that include individual chromosomes that have suffered a reciprocal translocation attempt to synapse and form an unusual structure called a translocation cross.

For example, suppose a translocation cross is produced from a normal copy of chromosome 5, a normal copy of chromosome 13, and two translocation chromosomes in which chromosomes 5 and 13 have undergone a reciprocal translocation. Prior to meiosis, these four chromosomes are copied by DNA replication to produce eight sister chromatids. During synapsis, the normal copy of chromosomes 5 and 13 are diagonal from each other and the two translocation chromosomes are diagonal from each other within the translocation cross structure. The chromosomes in the translocation cross can then segregate during meiosis I in three possible ways (see figure 3.10):


Figure 3.10 Formation of a Translocation Cross and Meiotic Chromosome Segregation – Top) A reciprocal translocation produces a translocation cross during meiosis. Bottom) Chromosome segregation during meiosis I and II. --- Image created by SL.

Key Questions

  • Which segregation pattern produces normal gametes?
  • Why does adjacent-2 segregation occur so rarely?

Robertsonian Translocations

A rare form of Down syndrome called familial Down syndrome is inherited (see figure 3.11). In familial Down syndrome, a phenotypically normal parent can contain a translocation. Such an individual would carry normal copies of chromosomes 14 and 21 and a chromosome that contains a fusion between the long arms of chromosome 14 and 21. In this person, the short arms of chromosome 14 and 21 have been lost, but since these regions do not carry vital genetic information, the individual can tolerate these losses. This type of translocation, involving the fusion of the long arms of two acrocentric chromosomes, is called a Robertsonian translocation. The Robertsonian translocation, which involves only chromosomes 13, 14, 15, 21, and 22, is the most common chromosome abnormality in humans.

A problem occurs during meiosis in this balanced carrier individual. The three chromosomes replicate, synapse, and attempt to segregate during anaphase of meiosis I and II. There are six possible types of gametes that can be produced by the carrier individual:


Figure 3.11 Robertsonian Translocation - A) Chromosomes of a carrier and a familial Down Syndrome patient B) Mechanism of Robertsonian Translocation C) Familial Down Syndrome Pedigree D) Gametes Produced by a Familial Down Syndrome Carrier --- Images created by SL

Key Questions

  • What is a Robertsonian translocation?
  • What chromosomes are involved in familial Down syndrome?
  • How many total chromosomes are observed in a balanced carrier individual?
  • How many total chromosomes are observed in a familial Down syndrome patient?
  • What genes are located on the p arms of the five acrocentric chromosomes (see Part 1 reading). Why would the loss of a few copies of these genes not be lethal to the cell?

B. Changes in Chromosome Number

Euploidy and Aneuploidy

Sometimes the total number of chromosomes within an individual can vary. These variations in chromosome number are placed into two categories (see figure 3.12):


Figure 3.12 Changes in Chromosome Number (Overview) --- Image created by SL

Key Questions

  • What is meant by variations in euploidy?
  • What does aneuploidy mean?
  • How many chromosomes are found in a trisomic human cell?
  • How many chromosomes are found in a monosomic human cell?
  • How many chromosomes are found in a triploid human cell?

Aneuploidy and Gene Expression

A phenotypically normal individual has two copies of most structural genes. When the number of genes controlling a trait is out of balance (one copy of a gene; more than two copies of a gene), the phenotype is often affected in a negative way.

In trisomic individuals (three copies of a particular chromosome), the gene products produced from the three copies of the chromosome are 150% of the normal expression level. These individuals produce too much protein product, so the phenotype is negatively affected (see figure 3.12).

In the case of monosomy (one copy of a particular chromosome), the single copy of the chromosome can only produce gene products at 50% of the normal level. These individuals produce lower amounts of protein product, so the phenotype is negatively affected. Monosomic cells or individuals also have a second problem. In monosomic cells, recessive lethal alleles cannot be “masked” by the normal, dominant allele from the homologous chromosome.

In a trisomic or monosomic individual, the overproduction or underproduction of the gene products of hundreds of genes generally decreases the viability of these individuals.  It is worth noting that there are many natural varieties of plants that have variations in euploidy or aneuploidy, indicating that plants can better tolerate variations in chromosome number than most animals.

Key Questions

  • Why does trisomy have negative phenotypic consequences?
  • What are the two reasons that monosomy produces negative phenotypic effects?

Aneuploidy in Humans

About 30% of all fertilization events in humans produce an embryo that is aneuploid. In most cases, the embryo does not survive. That being said, there are several aneuploid human conditions that result in live births.  These aneuploid conditions in humans include:

The aneuploid conditions described above are the result of chromosome nondisjunction, a defect in chromosome segregation during meiosis (see below).

Key Questions

  • The aneuploidies described above are essentially the only ones that result in live human births. Why do you think these aneuploidies are viable while aneuploidies of other chromosomes are not?


Some tissues in an animal can contain cells that have more than two chromosome sets, whereas the somatic cells in the rest of the animal are diploid. This situation is called endopolyploidy. For example, human liver cells can vary in euploidy (some cells are 4n, 8n, or 16n). Endopolyploidy allows liver cells to increase the production of proteins encoded by genes on these chromosomes to meet the metabolic demands of the body.

The fruit fly Drosophila is a diploid organism containing four pairs of homologous chromosomes. However, the salivary glands of the fruit fly contain higher variations in euploidy. To produce so many copies of the same chromosome, the homologous chromosomes pair with each other and then undergo several rounds of DNA replication without cell division. Replication in this way produces a polytene chromosome, a bundle of attached sister chromatids that lie parallel to each other.

Key Questions

  • What is endopolyploidy?
  • Provide two examples of endopolyploidy.

Meiotic Nondisjunction

Nondisjunction occurs when chromosomes do not separate properly in anaphase of either meiosis or mitosis.

Meiotic nondisjunction produces aneuploid gamete cells that either have an extra chromosome or lack a chromosome (see figure 3.13). After fertilization, the offspring will be aneuploid. Meiotic nondisjunction can occur during anaphase of either meiosis I or meiosis II.

The aneuploid conditions discussed above (conventional Down syndrome, Klinefelter syndrome, Turner syndrome, etc.) are thought to be produced from either meiosis I or meiosis II nondisjunction.

On rare occasions, all chromosomes in a cell display nondisjunction and fail to separate properly during either meiosis I or II. This event is called complete nondisjunction and produces diploid gametes. If a diploid gamete fuses with a normal gamete, a triploid offspring is produced.

Figure 3.13 Meiotic Nondisjunction.  A homologous chromosome pair in the maternal parent experiences nondisjunction in meiosis I (left), while the sister chromatids fail to separate in the maternal parent during meiosis II nondisjunction (right).  The paternal parent contributes a copy of the same chromosome (in blue). --- Image created by SL

Key Questions

  • What happens during meiosis I nondisjunction?
  • Describe the four gametes produced by meiosis I nondisjunction.
  • What happens during meiosis II nondisjunction?
  • Describe the four gametes produced by meiosis II nondisjunction.

Mitotic Nondisjunction

Nondisjunction can also occur during mitosis (mitotic nondisjunction). During mitotic nondisjunction, the sister chromatids that constitute one chromosome fail to separate from each other during anaphase. Mitotic nondisjunction produces one daughter cell with three copies of a chromosome (trisomic), while the other daughter cell has one copy of the chromosome (monosomic) (see figure 3.14). All future daughter cells produced from the trisomic cell will also be trisomic, whereas all daughter cells produced from the monosomic cell will also be monosomic. Because of this, mitotic nondisjunction produces a mosaic phenotype. When aneuploid somatic cells divide, a patch of monosomic tissue is produced, whereas another patch of tissue is trisomic.

Sometimes chromosomes lose their attachment to the mitotic spindle during anaphase.  A detached chromosome fails to be retained in the nucleus, and is degraded by nucleases in the cytoplasm. This event produces one daughter cell with two copies of a chromosome (disomic), while the other daughter cell has one copy of the chromosome (monosomic). All future daughter cells produced from the monosomic cell will be monosomic. This failure of a chromosome to attach to the mitotic spindle also results in a mosaic phenotype.

Figure 3.14 Mitotic Nondisjunction --- Image created by SL

Key Questions

  • Describe the two processes that cause mitotic nondisjunction.

Review Questions

Fill in the Blanks:

  1. A _________________________ is a change in chromosome structure that produces an acentric fragment and a dicentric chromosome during meiosis.
  2. The disease ______________________ is caused by an inversion within the X chromosome.
  3. A(n) __________________ and a(n) _____________________ are two changes in chromosome structure that alter the amount of genetic information found on a chromosome or in the genome.
  4. ___________ % of the gametes produced by a meiosis II nondisjunction event will result in trisomic offspring.
  5. A terminal deletion in chromosome _________ causes ___________________, a disease that results in a malformation of the glottis and larynx.
  6. Nondisjunction in _____________ can produce trisomic and monosomic somatic cells.
  7. The term _______________ can describe an individual with 2n-2
  8. The globin gene family arose due to a __________________________.
  9. A ____________________ translocation involves only the acrocentric chromosomes.
  10. Reciprocal translocations of the __________________ segregation type result in two normal gametes and two balanced translocation gametes.

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