Chromosome Structure

Significance: The separation of the alleles in the production of the reproductive cells is a central feature of the model of inheritance. The realization that the genes are located on chromosomes and that chromosomes occur as pairs that separate during meiosis provides the physical explanation for the basic model of inheritance. When chromosome structure is modified, changes in information transmission produce abnormal developmental conditions, most of which contribute to early miscarriages and spontaneous abortions.

Discovery of Chromosomes’ Role in Inheritance

The development of the microscope made it possible to study what became recognized as the central unit of living organisms, the cell. One of the most obvious structures within the cell is the nucleus. As study continued, dyes were used to stain cell structures to make them more visible. It became possible to see colored structures called chromosomes (“color bodies”) within the nucleus that became visible when they condensed as the cell prepared to divide.

The association of the condensed, visible state of chromosomes with cell division caused investigators to speculate that the chromosomes played a role in the transmission of information. Chromosome counts made before and after cell division showed that the chromosome number remained constant from generation to generation. When it was observed that the nuclei of two cells (the egg and the sperm) fused during sexual reproduction, the association between information transport and chromosome composition was further strengthened. German biologist August Weismann, noting that the chromosome number remained constant from generation to generation despite the fusing of cells, predicted that there must be a cell division that reduced the chromosome number in the egg and sperm cells. The reductional division, meiosis, was described in 1900.

Following the rediscovery of Gregor Mendel’s rules of inheritance in 1900, the work of Theodor Boveri and Walter Sutton led to the 1903 proposal that the character-determining factors (genes) proposed by Mendel were located on the chromosomes and that the factor segregation that was a central part of the model occurred because the like chromosomes of each pair separated during the reductional division that occurs in meiosis. This hypothesis, the “chromosome theory of heredity,” was confirmed in 1916 by the observations of the unusual behavior of chromosomes and the determining factors located on them by Calvin Bridges.

Chromosome Structure and Relation to Inheritance

With the discovery of the nucleic acids came speculation about the roles of DNA and the associated proteins. During the early 1900s, it was generally accepted that DNA formed a structural support system to hold critical information-carrying proteins on the chromosomes. The identification of the structure of DNA in 1953 by American biologist James Watson and English physicist Francis Crick and the recognition that DNA, not the proteins, contained the genetic information led to study of chromosome structure and the relationships of the DNA and protein components.

It is now recognized that each chromosome contains one DNA molecule. Each plant and animal species has a specific number of chromosomes. Humans have twenty-three kinds of chromosomes, present as twenty-three pairs. Each chromosome can be recognized by its overall length and the position of constrictions, called centromeres, that are visible only when the cell is reproducing. At all other stages of the cell’s life, the chromosome material is diffuse and is seen only as a general color within the nucleus. When the cell prepares for division, the fibrous DNA molecule tightly coils and condenses into the visible structures. Since there must be information for the two cells that result from the process of division, the chromosomes are present in a duplicated condition when they first become visible.

A major feature of the visible, copied chromosomes is the centromere. This constriction may be located anywhere along the chromosome, so its position is useful for identifying chromosomes. In karyotyping, the standard system used to identify human chromosomes, the numbering begins with the longest chromosome with the constriction nearest the center (chromosome 1), referred to as having a metacentric centromere placement. Chromosomes with nearly the same length but with the centromere constriction removed from the center position have higher numbers (chromosomes 2 and 3) and are referred to as acrocentric. Shorter chromosomes with a centromere near the middle are next, and the numbering proceeds based on the distance the centromere is removed from the central position. Short chromosomes with a centromere near one end have the highest numbers and are referred to as telocentric.

Most of the chromosomes have a centromere that is not centrally located, which results in arms of unequal length. The short arm is referred to as “petite” and is designated the p arm. The long arm is designated the q arm. This nomenclature is useful for referring to features of the chromosome. For example, when a portion of the long arm of chromosome 15 has been lost, the arm is shorter than normal. The loss, a deletion, is designated 15q^- (chromosome 15, long arm, deletion). Prader-Willi syndrome, in which an infant has poor sucking ability and poor growth, and later becomes a compulsive eater, results from this deletion. Cri du chat (“cry of the cat”) syndrome results from 5p^-, a deletion of a portion of the short arm of chromosome 5. The cry of these individuals is like that of a cat, and they are severely mentally retarded and have numerous physical defects.

Some chromosomes have additional constrictions referred to as secondary constrictions. The primary centromere constrictions are located where the spindle fibers attach to the chromosomes to move them to the appropriate poles during cell division. The secondary constrictions are sites of specific gene activity. Both of these regions contain DNA base sequence information that is specific to their functions.

Histones

The DNA of the chromosomes is wound around special proteins called histones. This results in an orderly structure that condenses the DNA mass so that the bulky DNA does not require as much storage space. The wrapped DNA units then fold into additional levels of compaction, by means of a process called condensation. The exact processes involved in these higher levels of folding are not fully understood, but the overall condensation reduces the bulk of the DNA nearly one thousandfold. If the DNA is removed from a condensed chromosome, the proteins remain and have nearly the same shape as the chromosome, indicating that it is the proteins that form the chromosome shape. The presence of these proteins and the fact that the DNA is wrapped around them raises many questions about how the DNA is copied in preparation for cell division and how the DNA information is read for gene activity. These are areas of active research.

The histone proteins form a structure called a “nucleosome” (“nuclear body”). There are four kinds of histones, and two of each kind join together to form a cylinder-shaped nucleosome structure. The fibrous DNA molecule wraps around each nucleosome approximately two and one-half times with a sequence of unwound DNA between each nucleosome along the entire length of the DNA molecule. The structure, called chromatin, looks like a string of beads when isolated sections are viewed with an electron microscope. When the chromatin is digested with enzymes that break the DNA backbone in the unwound regions, repeated lengths of chromatin are recovered, showing that the nucleosome wrapping is very regular. These nucleosome regions join together to form the additional folding as the chromosome condenses when the cell prepares for division.

In addition to the histone proteins, nonhistone proteins attach to the chromatin. With an electron microscope, chromatin loops can be seen extending from a protein matrix. There is evidence that these loops represent replication units along the chromosome, but how the DNA molecule is freed from the histone proteins to be replicated is a major unsolved puzzle.

The condensation of the chromatin is not uniform over the entire chromosome. In the regions immediately adjacent to the centromere, the chromatin is tightly condensed and remains that way throughout the visible cycle. All of the available evidence indicates that this chromatin does not contain actively expressed genes. It also replicates later than the remaining DNA. This more highly condensed chromatin is called heterochromatin (“the other chromatin”). The remaining chromatin is referred to as euchromatin (“true chromatin”) because it contains actively expressed genes and it replicates as a unit.

Giemsa Stain and Chromosome Painting

When chromosomes are treated with a dye called Giemsa stain, regular banding patterns appear. The bands vary in width, but their positions on the individual chromosomes are consistent. This makes the bands useful in identifying specific chromosome regions. When a chromosome has a structural modification, such as an inversion—which results when two breaks occur and the region is reversed when the fragments are rejoined—the change in the banding pattern makes it possible to recognize where it has occurred. When a loss of a chromosomal region produces a deficiency disorder, changes in the banding patterns of a chromosome can identify the missing region. Karyotype analysis is a useful tool in genetic counseling because disorders caused by chromosome structure modifications can be identified. Associations between disorders and missing chromosome regions are useful in identifying which functions are associated with specific regions. Other stains produce different banding patterns and, when used in combination with the Giemsa banding patterns, allow diagnosis of structure modifications that can be quite complex.

It is also possible to use fluorescent dyes, in a process called chromosome painting, to identify the DNA of individual chromosomes, which allows the recognition of small regions that have been exchanged between chromosomes that are too small to be recognized otherwise. Color differences within chromosomes or at their tips clearly show which chromosomes have exchanged DNA, how much DNA each has exchanged, and where on the chromosomes the exchanges have taken place. Many cancer cells, for example, have multiple chromosome modifications, with DNA from two or three chromosomes associated in one highly modified chromosome structure.

Chromosome Disorders

At the ends of the chromosomes are structures called telomeres, which are composed of specific repetitive DNA sequences that help protect the ends of chromosomes from damage and prevent DNA molecules from sticking together. Research that began in the early 1990s led to the discovery that the telomere regions of the chromosomes are shortened at each DNA replication. When the telomeres have been reduced to some critical point, the cell is no longer able to divide and often dies not long after, a phenomenon called apoptosisapoptosis. Other observations indicate that the telomere is returned to its normal length in tumor cells, suggesting that this might contribute to the long life of tumor cells, possibly making them immortal. The relationship of cell age to telomere length and the mechanisms that lead to telomere shortening are not understood clearly, but this is an area of active research because it has implications for aging and cancer treatment.

The DNA of each chromosome carries a unique part of the information code in the sequence of the bases. The specific sequences are in linear order along the chromosome and form linked sequences of genes called linkage groups. When the like chromosomes pair and separate during meiosis, one copy of each chromosome is transmitted to the offspring. During meiosis, there may be an exchange of material between the paired chromosomes, but this does not change the information content because the information is basically the same for both chromosomes in any region. There may be differences in the coding sequences, but functionally, the same informational content is transmitted. Extreme changes in chromosome structure that result in the moving of information to another chromosome may have consequences for how specific information is expressed; a change in position might result in different regulation or in changes in how the information is transmitted during meiosis.

Each chromosome has a specific arrangement of genes. Although homologous chromosomes exchange DNA during meiosis, as long as this process occurs normally, the gene arrangement on the chromosomes remains unchanged. Position affects result when genes are moved to different regions of the same chromosome or to another chromosome. A normal allele may show a mutant phenotype expression in a new position in the chromosome set. The best-known case occurs when a gene is placed adjacent to a heterochromatic region. The relocated DNA is condensed like the heterochromatic-region DNA and normally active genes now remain inactive. Ninety percent of patients with the disorder chronic myeloid leukemia have an exchange of material, called a translocation, between chromosomes 9 and 22. Chromosome 22 is shorter than normal and is called the Philadelphia chromosome, after the city in which it was discovered. The placing of a specific gene from chromosome 9 within the broken region adjacent to a gene on chromosome 22 causes the uncontrolled expression of both of the genes and uncontrolled cell reproduction, the hallmark of leukemia.

The separation of like chromosomes during meiosis occurs because the two chromosome arms are attached to a specific centromere. When the centromere is moved to one of the poles, the arms are pulled along, ensuring movement of all of the material of the paired chromosomes to the opposite poles and inclusion in the newly formed cells. Translocations occur when chromosomes are broken and material is placed in the wrong position by the repair system, causing a chromosome region to become attached to a different centromere. This leads to an inability to properly separate the regions of the arm, which can result in duplication of some of the chromosomal regions (when two copies of the same arm move to one cell) or deficiencies (when none of the material from a chromosome arm moves into a cell). This is a common outcome with translocation heterozygotes (individuals with both normal chromosomes and translocated chromosomes in the same cells). Pairing of like chromosome regions occurs, but rather than two chromosomes paired along their entire lengths, the arms of the two translocated chromosomes are paired with the arms of their normal pairing partners. The separation of the chromosomes produces duplications of material from one chromosome arm or a deficiency of that material 50 percent of the time. If these cells are involved in fertilization, the offspring will show duplication or deficiency disorders.

Key terms

• histones: a class of proteins associated with DNA
• homologous chromosomes: chromosomes that have identical physical structure and contain the same genes; humans have twenty-two pairs of homologous chromosomes and a pair of sex chromosomes that are only partially homologous
• karyotyping: an analysis or physical description of all the chromosomes found in an organism’s cells; often includes either a drawing or photograph of the chromosomes
• spindle fibers: minute fibers composed of the protein tubulin that are involved in distributing the chromosomes during cell division

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