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Modern Genetic Analysis Chapter 4. The Inheritance of Genes
Cell Division

Cell division is the basis for all forms of organismal reproduction. Single-celled organisms divide to reproduce. Cell division in multicellular organisms produces specialized reproductive cells, such as egg and sperm, and is also responsible for the development of a many-celled organism from a single fertilized egg cell. In order for a cell to divide, the genome must also divide, so, in all types of cell division in all organisms, DNA replication precedes cell division.

The main types of cell division are shown in Figure 4-6 on the following page. Broadly they can be grouped into asexual and sexual cell division.

Asexual Cell Division

In prokaryotes there is only one rather simple type of cell division, which produces two identical daughter cells from one progenitor cell. This is asexual cell division, since it involves no sexual union of different individuals. Prior to bacterial cell division, DNA replicates and two full circular genomes result. As the cell divides, one of the daughter DNA molecules passes into each of the daughter cells. The precise mechanism of DNA movement is not known, but in one model the DNA is anchored to the cell membrane, and as the membrane expands to make two cells, the DNA is drawn along with it.

Eukaryotes also show asexual cell division, also making two identical daughter cells from one progenitor cell. This is the type of cell division that converts a single fertilized egg cell, a zygote, into two cells, then four, then eight, and so on until an organism composed of many cells is produced. It is also the type of cell division that generates a population of single-celled organisms from one, for example, in yeasts and protozoans. When a eukaryotic cell divides asexually, the nucleus and its genetic contents must divide too, in a process called mitosis. Both haploid (n) and diploid (2n) cells can divide asexually, at which time their nuclei divide mitotically. Figure 4-7 shows where asexual (mitotic) and sexual (meiotic) cell division occur in the life cycles of humans, plants, and fungi. At mitosis the programmed movements of the chromosomes guarantee that each daughter cell has chromosomes and genes identical with those of the other daughter cell and the original cell.

From any specific stage in a progenitor cell to the same stage in a daughter cell is called one cell division cycle. It is composed of four stages: S (DNA synthesis), M (mitosis), and G1 and G2 (gaps, or intermediate stages), as was shown in Figure 4-6. Passage of the cell into each of these sequential stages is a precisely regulated process, overseen by a battery of diverse genes whose job is to ensure that this sequence is carried out correctly.

During S phase the DNA of each chromosome replicates semiconservatively. The chromosome splits longitudinally to produce a pair of sister chromatids, each of which contains one of the replicated DNA molecules. The chromatids become visible microscopically only during mitosis, when they shorten and thicken as a result of increased coiling of the DNA and its associated histones. However, it is important to remember that the replication into chromatids took place during premitotic S phase. Chromatids and replicated DNA are depicted in Figure 4-8 on the following page. As examples, the figure uses diploid cells of genotype b+/b+, b+/b, and b/b, and haploid cells of genotype b+ and b. It is assumed that the mutant allele b has been formed by replacement of a G·C base pair in the wild-type allele with an A·T base pair in the mutant allele (this is a common type of mutational event).

During mitosis, a network of proteinaceous microtubules called the spindle apparatus forms parallel to the cell axis, connecting the poles of the cell. One to many microtubules from one pole attach to one chromatid, and a similar number from the opposite pole attach to the other chromatid of a chromosome. The attachment point on the chromosome is the centromere, a specific DNA sequence essential for chromatid movement during mitosis. The centromere is replicated during the formation of sister chromatids, and each sister centromere acts as a binding site for a multiprotein complex called the kinetochore. The kinetochores in turn act as the sites for attaching to microtubules. The spindle fibers (microtubules) then pull sister chromatids to opposite poles. Thus each pole receives a copy of each chromosome from the parent cell. The sets of sister chromatids at each pole become incorporated into the nuclei of the two daughter cells. These daughter nuclei are identical with each other and with the nucleus from which they were derived. In the daughter cells, chromatids are again called chromosomes. Note that it is the spindle apparatus and the kinetochore-centromere complex that determine the fidelity of nuclear division.

The main genetic events of the S phase and mitosis are diagrammed in the left and central columns in Figure 4-9 on page 97. The figure uses a haploid of genotype A and a diploid of genotype A/a to show not only that mitosis generates two chromosomally identical cells but also that the specific allelic constitution is also identical. A detailed account of the stages of mitosis is given in Genetics in Process 4-2.

MESSAGE
During mitosis, daughter DNA molecules (visible as sister chromatids) are pulled apart to opposite poles of the cell, where they form two identical nuclei in the daughter cells resulting from cell division.

Sexual Cell Division

Although some bacteria have a simple form of sexual reproduction (see Chapter 9), there is no associated specialized cell division. However, most eukaryotic organisms can reproduce sexually, and during the sexual part of the life cycle specialized sexual cell divisions occur. In plants and animals, the sexual cell divisions result in eggs and sperm (gametes); in fungi, sexual cell divisions result in sexual spores such as ascospores. The starting point for sexual cell division is always a diploid cell called a meiocyte (Figure 4-6). In most complex organisms, such as animals and flowering plants, the cells of the organism are normally diploid and the meiocytes are simply a subpopulation of cells that are set aside for sexual divisionfor example, those found in testes and ovaries in animals. In haploid organisms a transient diploid meiocyte is constructed as part of the normal reproductive cycle (Figure 4-7). In all eukaryotes the meiocyte divides twice, resulting in four haploid cells called a tetrad. The two nuclear divisions that accompany the two sexual cell divisions are called meiosis.

In contrast to mitosis, whose aim is a conservative propagation of one genotype, meiosis is a diversity-generating process. It shuffles allelic combinations so that if the meiocyte contains heterozygous pairs of al-leles (and most do), the cells that represent the products of meiosis (that is, the cells of the tetrads) will contain many different combinations of these alleles. The main sites of meiosis are depicted in the life cycle diagrams in Figure 4-7.

Meiosis is preceded by the DNA synthesis phase in the diploid meiocyte. This achieves the same result as the S phase before a diploid mitosiseach chromosome in the two sets is replicated into a pair of sister chromatids, precisely as shown in Figure 4-8. Just before the first nuclear division, homologous chromosomes pair along their lengths, so that now for each chromosomal type there are two pairs of sister chromatids juxtaposed, making a bundle of four also called a tetrad. Figure 4-9 shows a meiotic tetrad of homologous chromosomes. (Contrast this stacking of homologs with metaphase in mitosis, in which chromosomes line up side by side, instead.) At the tetrad stage a remarkable process occurs: paired nonsister chromatids exchang homologous sections of DNA through breakage and reunion of their arms at points called crossovers.

At the first division of meiosis, centromeres act as though they are still undivided, although it is known that replication of the centromeric DNA has occurred. Spindle fibers from each pole attach and pull homologous centromeres, together with their sister chromatids, to opposite poles (Figure 4-9). Therefore in the two cells formed by the first division the number of centromeres is halved. At the second division of meiosis the centromeres divide, and spindle fibers attach and pull one sister chromatid to each pole (Figure 4-9). Hence overall the two divisions of meiosis produce four cells, each of which contains the haploid number of chromosomes. This is inevitable because there is only one doubling of genetic material (premeiotic S phase) and two halvings of the genetic material, occurring during the two cell divisions. As we have seen, this group of four haploid cells (which constitute the products of a single meiosis) is also called a tetrad; the bundle of four chromatids that constitutes a tetrad is partitioned at meiosis into these four cells. In the products of meiosis, chromatids are once again called chromosomes. Figure 4-9 shows that if a diploid meiocyte is heterozygous (for example A/a) then half the haploid products of meiosis will carry the A allele and half will carry a. These alleles are said to segregate at meiosis because they separate into different haploid cells.

Some key features of meiosis are as follows:

1. There is one round of DNA replication but two rounds of nuclear division (usually two rounds of cell division as well). Thus, at the end of meiosis, the number of chromosomes per cell is halved.
2. At the first meiotic division, homologous centromeres are pulled to opposite poles of the cell by spindle fibers. Because spindle fibers from one pole attach randomly to either of a pair of homologous chromosomes (through their centromeres), heterologous centromeres and their attached chromosomes combine randomly. This independent assortment results in many different genotypes and is one source of the diversity produced by meiosis.
3. Early in the first meiotic division, there is exchange of chromosomal material between homologous chromatids as a result of crossing-over. Crossovers serve two roles. First, they are the other great source of genotypic diversity, since no two crossed-over chromatids are exactly the same. Second, the exchange events that occur between homologous chromatids in the tetrad serve to hold the tetrad together until the homologs pull apart at the end of the first division. This ensures proper chromosome segregation and prevents the formation of products of meiosis bearing abnormal chromosome numbers.

MESSAGE
The process of meiosis starts with diploid meiocytes in the reproductive tissue and produces an array of haploid cells with diverse genotypes.

The differences between meiosis and mitosis are summarized in Figure 4-10. Meiosis itself is described in more detail in Genetics in Process 4-3.

© 1999 by W. H. Freeman and Company. All rights reserved.