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 on a chromosome (deletions, duplications), rearranging the order of genes on a chromosome (inversions), or moving genes from one chromosome to a nonhomologous chromosome (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 homologous chromosome pair is inherited from dad; the other member of the pair is inherited from mom), 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).  The Robertsonian translocation in not shown in the image.  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 and a fragment that lacks a centromere. The centromere region is retained by the cell, while the fragment that lacks the centromere is lost during cell division. This type of event is called a terminal deletion. Terminal deletions are usually generated by endonuclease damage or by environmental factors, such as ionizing radiation, that break the DNA backbone.

An interstitial deletion is a deletion that does not involve 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. Moreover, a detrimental phenotype can occur even though the individual may have a normal copy of the homologous chromosome, indicating that most deletions are dominant mutations.

Cri-du-chat (46, 5p-) is an example genetic disease caused by a deletion in the p arm of chromosome 5.  Cri-du-chat 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 the p arm of chromosome 5 during meiosis. A cri-du-chat individual usually has one normal copy of chromosome 5 and a terminal deletion copy of the same chromosome. 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 telomerase reverse transcriptase (TERT).  We will learn about the function of TERT in Part 6.

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

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 two gametes that contain normal chromosomes, a gamete with an interstitial deletion chromosome, and a gamete that contains a chromosome with a duplication.  

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 sometimes 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 gene family in humans 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; one gene became a hemoglobin gene, the other became a myoglobin gene. Later, the hemoglobin gene 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 gene family is a good example of how gene duplication can produce the genetic variability necessary to drive evolution.

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 single 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. Interestingly, inversions are quite common; about 2% of the human population carry 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 on the X chromosome occurs within the factor VIII gene. The Factor VIII protein is required for proper blood clotting, so this inversion produces a nonfunctional protein, leading to a deficiency in clotting (hemophilia).

Sometimes the change in the position of a structural gene on a chromosome alters 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 non-viable gametes.

Defective gametes are produced by the inversion heterozygote individual because of events during meiosis. Recall that prior to meiosis, the two chromosomes within a homologous chromosome pair are copied by DNA replication, producing four sister chromatids (see figure 3.7).  DNA replication is followed by synapsis (alignment) of the homologous chromosomes during prophase I. For the normal chromosome and the inversion chromosome to synapse properly in an inversion heterozygote individual, 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. As mentioned earlier, there are three types of translocations: simple translocations, reciprocal translocations, and Robertsonian translocations.  We will focus on reciprocal 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 to form gametes in meiosis I?

During synapsis, the two pairs of homologous chromosomes (four total chromosomes) that include two individual chromosomes that have suffered a reciprocal translocation attempt to synapse.  Because of the reciprocal translocation, the four chromosomes synapse to form a translocation cross (see figure 3.10).

For example, suppose a translocation cross is produced from a normal copy of chromosome 5, a normal copy of chromosome 13, and a situation in which the other copies of 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 (see figure 3.10). The chromosomes in the translocation cross can then segregate during anaphase I in three possible ways:


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 carry a translocation. Such an individual would carry normal copies of chromosomes 14 and 21 and a chromosome that contains a fusion between the long (q) arms of chromosome 14 and 21. In this balanced carrier person, the short (p) arms of chromosome 14 and 21 have been lost, but since these regions carry repetitive sequences that are found on other chromosomes in the genome, the individual can tolerate the loss of the two p arms. 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 a 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 offspring 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) Offspring Produced by a Familial Down Syndrome Carrier --- Images created by SL

Key Questions

  • What is a Robertsonian translocation?
  • Which 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).  The percentages below each chromosome pair indicates the level of gene expression (transcription) for the genes found on the particular chromosomes. --- 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? (Note: human somatic cells contain 46 chromosomes.)
  • 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 structural genes is out of balance, the phenotype is often affected in a negative way.  For example, in trisomic individuals with three copies of a particular chromosome, the proteins produced from the three chromosomes 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, the single copy of the chromosome can only produce proteins at 50% of the normal level. Since these individuals produce lower amounts of protein product, 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 animal, the overproduction or underproduction of protein product decreases viability.  However, it is worth noting that there are many natural varieties of plants that tolerate higher variations in euploidy just fine.  For example, wheat plants are hexaploid, some potato varieties are tetraploid, and wild strawberry plants can be octaploid.  

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 to birth. That being said, there are some 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) in one of the parents.

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 tetraploid or octaploid). Endopolyploidy allows liver cells to increase the production of protein products to meet the unique metabolic demands placed on the liver.

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. Endopolyploidy occurs when the homologous chromosomes pair with each other and then undergo several rounds of DNA replication without cell division. DNA replication in this way produces polytene chromosomes, a thick bundle of identical DNA molecules, lying 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 resulting offspring will be trisomic or monosomic. Meiotic nondisjunction can occur during anaphase of either meiosis I or meiosis II.

The aneuploid human conditions described above (e.g., 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 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. As a result, mitotic nondisjunction produces a mosaic phenotype with some trisomic tissues in the body, while other tissues are monosomic. 

Sometimes chromosomes lose attachment to the mitotic spindle during anaphase.  A detached chromosome is not 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.  This figure highlights the fates of the sister chromatids derived from the two copies of chromosomes 2 and 14. --- 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.
  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 a cell with 2n-2 chromosomes.
  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 translocation gametes.

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