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

Overview

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):

• Deletions. A deletion occurs when a portion of a chromosome is missing. A deletion can be as small as a single base pair or can include the loss of several genes. The portion of the chromosome that is missing is called a deficiency.
• Duplications. A duplication occurs when a portion of the chromosome is repeated. In a duplication, a single chromosome can have more than one copy of the same structural gene.
• Inversions. Inversions involve changing the direction of an internal segment within a single chromosome.  Inversions often change the location of a structural gene within a chromosome.
• Translocations. A translocation occurs when a portion of a chromosome becomes attached to a nonhomologous chromosome. For example, a portion of chromosome 1 could be translocated to chromosome 5. There are three types of translocations:
  • Simple (nonreciprocal) translocation. A simple translocation occurs when a segment of one chromosome becomes attached to a nonhomologous chromosome. The chromosome receiving the DNA segment remains intact.
  • Reciprocal translocation. Reciprocal translocations involve nonhomologous chromosomes exchanging pieces.  For example, one copy of chromosome 1 and one copy of chromosome 5 could exchange telomere regions. 
  • Robertsonian translocation. Robertsonian translocations involve the fusion of the long (q) arms of two acrocentric chromosomes.  For example, the q arm of one copy of chromosome 14 can fuse with the q arm of one copy of chromosome 21. 

Deletions

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).

Cri-du-chat

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.

Duplications

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.  

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.

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):

• Pericentric inversion. In a pericentric inversion, one chromosome break occurs in the p arm, while a second break occurs in q arm of the same chromosome.  The central region of the chromosome, including the centromere, is located within the inverted region. Note that a pericentric inversion has the potential to change the position of the centromere within the chromosome.
• Paracentric inversion. In a paracentric inversion, two chromosome breaks occur within the same arm of the chromosome.  The chromosome region between the two breaks is inverted, with the centromere of the chromosome lying outside of the inverted region. As a result, a paracentric inversion does not change the position of the centromere within the chromosome.

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.

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.

• Pericentric inversion. In a pericentric inversion, the centromere lies within the inverted region of the chromosome. When crossing over occurs between the homologous chromosomes and after meiosis is completed, the following gametes are produced:
  • A gamete that contains a chromosome with the normal gene arrangement. This gamete will produce offspring with the normal gene arrangement.
  • A gamete that contains an inversion chromosome. Thus, inversion chromosomes are passed from parents to offspring. The resulting offspring will suffer no negative phenotypic effects.
  • Two gametes that contain abnormal chromosomes. Each abnormal chromosome contains a duplication of some genes and a deletion of other genes. The fertilized egg produced from either of these two gametes is not generally viable.

• Paracentric inversion. In a paracentric inversion, the centromere lies outside of the inverted region of the chromosome. After crossing over between the homologous chromosomes occurs and meiosis is completed, the following gametes are produced (see figure 3.8):
  • A gamete that contains a chromosome with the normal gene arrangement. This gamete will produce offspring with the normal gene arrangement.
  • A gamete that contains an inversion chromosome. The inversion chromosome is passed from parents to offspring. The resulting offspring will suffer no negative phenotypic effects.
  • Two gametes that contain highly abnormal chromosomes. One gamete contains an abnormal chromosome containing duplications and deletions, but more importantly, the chromosome lacks a centromere. This acentric fragment will be lost during cell division. The other gamete will contain an abnormal chromosome that has two centromeres (dicentric chromosome) along with duplications and deletions. Between the two centromeres of this dicentric chromosome is a region called a dicentric bridge. When a dicentric chromosome, attached to opposite spindle poles, tries to separate during anaphase of meiosis, it is torn apart. Breakage produces chromosome fragments that are missing genes.

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.

Reciprocal Translocations

A 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.

• Chromosome breakage and defective DNA repair. Some chemicals or environmental agents can cause chromosomes to break at internal sites, forming reactive ends not protected by telomeres. Recall that telomeres are the structures found on the ends of linear eukaryotic chromosomes that are designed to prevent chromosome ends from sticking together (see Part 1). Cells contain repair enzymes to handle these situations, and in most cases, quickly repair these breaks. When nonhomologous chromosomes are broken simultaneously, the repair enzymes can sometimes inadvertently join nonhomologous chromosomes together, resulting in a reciprocal translocation.
• Nonhomologous chromosomes crossing over. If two nonhomologous chromosomes synapse and undergo crossing over during meiosis I, a reciprocal translocation occurs.

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:

• Alternate segregation (common). The chromosomes diagonal from each other segregate into the same cell at the conclusion of meiosis I. For example, the normal copy of chromosome 5 and 13 segregate with each other into the same daughter cell and the two translocation chromosomes segregate with each other into the same cell. After meiosis II, there are two normal gametes and two gametes that carry translocations. All four gametes produced by alternate segregation are capable of producing viable offspring.
• Adjacent-1 segregation (common). The two chromosomes on the bottom half of the cross (normal chromosome 13 and translocation chromosome 5) segregate with each other into the same daughter cell. The two chromosomes on the top half of the cross (normal chromosome 5 and translocation chromosome 13) segregate with each other into the same daughter cell at the conclusion of meiosis I. After meiosis II, all four gametes carry duplications and deletions and therefore are not generally viable.
• Adjacent-2 segregation (rare). The two chromosomes on the right half of the cross (normal chromosome 5 and translocation chromosome 5) segregate with each other into the same daughter cell. The two chromosomes on the left half of the cross (normal chromosome 13 and translocation chromosome 13) segregate into the same daughter cell at the conclusion of meiosis I. One daughter cell receives, in essence, both copies of chromosome 5; the other daughter cell receives both copies of chromosome 13. Since both copies of chromosome 5 end up in the same cell and both copies of chromosome 13 end up in the same cell, adjacent-2 segregation can be considered a nondisjunction event (see below). After meiosis II, all four gametes carry duplications and deletions and are not generally viable.

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:

• Normal.  When the normal gamete produced by the carrier parent fuses with a normal gamete from the other parent during fertilization, an offspring is produced that contains two copies of chromosomes 14 and 21. This offspring is phenotypically normal.
• Balanced carrier. When a gamete containing the Robertsonian translocation between chromosomes 14 and 21 fuses with a normal gamete from the other parent during fertilization, a carrier offspring that contains one copy of chromosome 14, one copy of chromosome 21, and a Robertsonian translocation chromosome is produced. The total chromosome number in this person is 45 due to the loss of the short arms of chromosomes 14 and 21. This carrier is phenotypically normal but can produce familial Down syndrome offspring in the next generation.
• Familial Down syndrome. A gamete that contains the Robertsonian translocation between chromosomes 14 and 21 and a copy of chromosome 21 can fuse with a normal gamete from the other parent during fertilization. The offspring contains two copies of chromosome 21, one copy of chromosome 14, and the Robertsonian translocation chromosome. Since there are three copies of the long arm of chromosome 21 (trisomy-21), Down syndrome results. A familial Down syndrome patient has 46 total chromosomes.
• Unbalanced, lethal (three types of gametes). Fifty percent of the gametes produced by a balanced carrier individual will not produce viable offspring. The resulting offspring produced from these gametes are either missing chromosome 14, missing chromosome 21, or have an extra copy of chromosome 14.

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):

• Variations in euploidy.  Variations in euploidy involve changes in the total number of chromosome sets in a cell or individual. Recall that a chromosome set is all of the chromosomes inherited from one parent.  Variations in euploidy involves organisms or cells that are:
  • Haploid (n; n = the number of chromosomes within a set). Haploid organisms or cells have one chromosome set (i.e., one copy of every chromosome). Haploid is the normal state for gamete cells and some eukaryotic organisms.
  • Diploid (2n). Diploid organisms or cells have two chromosome sets. One chromosome set is inherited from the paternal parent; one chromosome set is inherited from the maternal parent.  Diploid is the normal state for many eukaryotic organisms and for most of the cells in the human body.
  • Triploid (3n). Triploid organisms or cells have three chromosome sets. Triploid is an abnormal state for most organisms.
  • Polyploid. Polyploid organisms or cells have more than two chromosome sets.
• Aneuploidy. Aneuploidy involves changes to the number of chromosomes within a set. Aneuploidy occurs when an individual is missing or has an additional chromosome. Aneuploidy of the sex chromosomes is usually better tolerated than aneuploidy of the autosomes (non-sex chromosomes) in many organisms.  Aneuploidy includes:
  • Trisomy (2n+1). A trisomic organism or cell has one more chromosome than normal. Trisomy is usually better tolerated than monosomy.
  • Monosomy (2n-1). A monosomic organism or cell is missing a single chromosome.
  • Disomy (2n). Disomy is the normal state in which an organism or cell has two copies of a particular chromosome.
  • Nullisomy (2n-2). An organism or cell that is nullisomic is missing both copies of the chromosomes that constitute a homologous chromosome pair.

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.  

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:

• Trisomy 13 (47,13+). Trisomy 13 produces Patau syndrome, which occurs in 1 in 19,000 births. Patau syndrome causes mental and motor deficiencies, cleft palate, polydactyly (extra digits), microcephaly (a small head), defects in several organs, and an early death (usually by 3 months of age).
• Trisomy 18 (47, 18+). Trisomy 18 produces Edwards syndrome, which occurs in 1 in 8,000 births. Edwards syndrome causes skeletal abnormalities such as elongated skulls, deformed hips, and facial deformities. Most infants with this syndrome are females, and death usually occurs within 4 months after birth.
• Trisomy 21 (47, 21+). Trisomy 21 causes the conventional form of Down syndrome, which occurs in 1 in 800 births. Down syndrome results in mental deficiencies, almond-shaped eyes, flattened faces, round heads, and a short stature. There is another type of Down syndrome called familial (inherited) Down syndrome. Familial Down syndrome is caused by a Robertsonian translocation (see above).
• XXY (47, XXY). An individual with XXY sex chromosomes has Klinefelter syndrome, which occurs in 1 in 1000 male offspring. Klinefelter syndrome results in infertility (no sperm production) and the formation of breast tissue.
• XYY (47, XYY). An individual with XYY sex chromosomes has Jacobs syndrome, which occurs in 1 in 1000 male offspring. Jacobs syndrome produces mild phenotypic effects.
• XXX (47, XXX). An individual with XXX sex chromosomes has Triplo-X syndrome, which occurs in 1 in 1500 female offspring. Triplo-X syndrome produces mild phenotypic effects.
• XO (45, X). An individual with a single X chromosome has Turner syndrome, which occurs in 1 in 5000 female offspring. Turner syndrome females are short, have a webbed neck, and have reduced fertility.

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.

Endopolyploidy

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.

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.

• Meiosis I nondisjunction. During meiosis I nondisjunction, the chromosomes within a homologous pair fail to separate from each other and instead segregate into the same daughter cell. All gamete cells produced from meiosis I nondisjunction are aneuploid. These aneuploid gametes will produce 50% trisomic offspring and 50% monosomic offspring.
• Meiosis II nondisjunction. In meiosis II nondisjunction, meiosis I proceeds normally; however, nondisjunction occurs in one of the two daughter cells. During meiosis II nondisjunction, the sister chromatids that constitute one duplicated chromosome fail to separate from each other. Two of the resulting haploid gametes are normal, while two of the gametes are aneuploid. Collectively, these gametes will produce 50% normal offspring, 25% trisomic offspring, and 25% monosomic offspring.

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.

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.

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.