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Mitosis
After DNA replication the cell enters another gap-phase (G2) before mitosis begins. The duration of G2 is much shorter than G1, however, some cells can be arrested in G2, leaving them with a fully replicated set of chromosomes. Before the cell finally divides into two individual cells, the nuclear DNA has to be sorted into two sets of chromosomes, so that each daughter cell the correct number of chromosomes in a process called mitosis . This is an enormous task, considering that the nuclear DNA of a human cell stretched out would have a length of 20 miles. Any error in the replication or in the separation of the copied chromosomes could cause problems for the divided cells. Mitosis, the separation of nuclear DNA and formation of two separate nuclei proceeds through several stages, beginning with the prophase

Fig. 9.8     Fig. 9.8 cont.     Prophase
During the prophase the chromatin fibers of the DNA become condensed into the familiar shape of the chromosomes. In addition, two kinetochores develop near the centromer region of each chromosomes, one kinetochore on each chromatid. Also during the prophase the centrioles are duplicated and start their migration toward opposite sides of the nucleus. Both centrioles have microtubules radiating out , which form a spindle. At later stages of mitosis this spindle will pull the duplicated chromosomes apart. At the end of the prophase, the lamin undercoat of the nuclear envelope is phosphorylated. The nuclear membrane loses its support and it disintegrates during the prometaphase .

Metaphase
The microtubules of the two centrioles attach themselves to the kinetochores and start pulling the chromosomes in opposite direction from each other. This motion results in an alignment of the chromosomes between the two spindle poles. Human chromosome mapping is done with chromosomes which are arrested in metaphase. Addition of colchicine to white blood cells stops cell division at the metaphase.
Anaphase
In the anaphase the chromatids which are joined at the centromer are released from each other and each chromatid is pulled in opposite direction toward the spindle poles This pulling is caused by a shortening of the microtubules, which are attached to the kinetochores. While the metaphase lasts a longer time, the pulling apart of the chromatids in the anaphase takes only a few minutes.

Telophase
After the chromosomes are separated the microtubules disintegrate and the chromosomes revert back to their amorphous shape (chromatin fibers). The nuclear envelope forms around the each of the separated DNA . At this stage mitosis has ended.

Cytokinesis
figure     The division of the cytoplasm called cytokinesis begins usually during the late anaphase. A rigid layer of microfilaments contracts and pushes the plasma membrane inwards. This depression is called cleavage furrow and it cuts the cell into half.

Cell cycle control

The entrance into the S-phase and mitosis is controlled and by cyclin dependent kinases (cdk). Cyclin is a protein which regulates the activity of cdk’s. Once active these kinases will phosphorylate other enzymes which in turn control key functions in the cell cycle . Naming a few:

• replication factors, which initiate DNA synthesis,
• enzymes phosphorylate histones. This causes the amorphous chromatin to condensate into chromosomes
• enzymes that catalyze the depolymerization of microtubules, causing the disappearance of the spindle
• enzymes which phosphorylate components of the nuclear envelope, leading to its disintegration

The activation mechanism of the cdk is very complex. During G2, cyclin B levels (mitotic cyclin) are gradually increasing. When high enough cdc2 (a specific cdk) can interact with cyclin B to form a complex, which however remains inactive. After phosphorylation and partial hydrolysis of two phosphates cdc2 becomes active. However, this activity does not last very long, since another phosphatase is activated during cdc2 activation, which hydrolyzes the remaining phosphate, rendering cdc2 kinase inactive.
cdc activation/deactivation

Tumor suppressor gene
Mutations of the genes which code for proteins and enzymes involved in the regulation of the cell cycle can result in uncontrolled growth and cause the cell to become cangerous. About 50% of all human tumors cells show a mutation in a single gene called p53 tumor suppressor gene.

This gene codes for a polypeptide with a molecular weight of 53 dalton. The p53 protein is a transcription factor, i.e. it controls the expression of other genes such as the p21 inhibitor gene. The p21 protein inhibits the activity of cdc2/cyclin E which causes the cell to enter mitosis. A mutation in p53 prevent the expression of p21 which open the unrestricted entrance of the cell into mitosis. This uncontrolled cell division results in tumor formation.
The p53 protein is expressed if DNA dammage has occured. This causes the replication to stop because of cdk inhibition, preventing that the error is transmitted to the daughter cell. Apparently the p53 protein stimulates also DNA repair. Thus, after inhibition is reversed DNA replication can continue. If the DNA repair was not successful, p53 can trigger cell death.

Meiosis
In sexual reproduction each parent who has two genes for nearly every trait will pass one gene to the offspring. If the each pair of genes would be identical then the offspring would be identical to the parents, in other words it would be a clone. However, the genes for a particular trait can be different . Different forms of the same gene are called alleles Sexual reproductions will create new combinations of alleles in the offspring, which is the basis of evolutionary change.
The paragraph below has been reworded, please discard the original version
Meiosis is a series of chromosomal divisions after replication. It is a process which has some similarities to mitosis. Meiosis is restricted to the sex cells that give rise to the gametes ( the ovum and sperm) cells. These precursor cells (oocytes and spermatocytes) to egg and sperm have a diploid number of chromosomes, i.e. each chromosome as an almost identical copy. During meiosis the diploid number of chromosomes is reduced by half to the haploid number: 2N (diploid) ---------- N (haploid). After meiosis human gametes, the ovum and sperm have only 23 chromosomes.

Stages of meiosis     Fig. 9.14     Fig. 9.14 cont.     Fig. 9.14 cont.     Fig. 9.14 cont.
Like mitosis, meiosis is preceded by DNA replication. The almost identical pair of chromosomes to be copied consist of a maternal and a paternal chromosome (i.e. one originates from the mother, the other one originates from the father). The duplicated chromosomes are joined by their centromere. The replication below is shown for a single pair of chromosomes (out of 23 pairs)

Meiosis 1
Meiosis is divided into two stages: meiosis 1 and meiosis 2. Meiosis 1 begins with a prophase 1, in which the replicated chromosomes pair with each other in a parallel arrangement. The close proximity of the two parental chromatids allows the exchange of corresponding segments of the two chromatids in a process called crossing over. Crossing over is essentially a process by which genetic information is exchanged between the parental chromosomes.

The next stage of meiosis is metaphase 1. A spindle apparatus forms which attaches microtubules to the kinetochores and starts pulling apart the parallel aligned chromosomes . During anaphase 1 the chromosomes have moved toward the spindle poles. The movement of the chromosomal pair is random, i.e. there is no preference which pair (paternal or maternal) is moving to a particular pole. You can calculate the number of possible combinations for the movement of e.g. 4 chromosomal pairs (= 8 possible combinations of maternal and paternal chromosomal pairs) The possible combinations for 23 chromosomal pairs is over 8 million. Thus, it is highly unlikely that the mixing of the traits will result in identical or nearly identical offspring.

Anaphase is followed by cytokinesis and telophase. The two newly formed cells will have a haploid number of still replicated chromosomes

Meiosis 2
During meiosis 2 the two sister chromatids of the replicated chromosomes are separated. The mechanism is similar to mitosis. First two pairs of centrioles forming a spindle apparatus are moving to oppsite sides of the nucleus. The microtubules of the assembly make contact to the kinetochores and through elongation and shortening of the microtubules the chromosomes are lined up between the two poles (metaphase 2). During the anaphase II the sister chromatids are separated and each individual chromosome is pulled toward opposite poles. In the telophase 2 the nuclear envelope is formed and cyctokinesis causes the formation of daughter cells.

A summary of the events in meiosis 1 and 2 is shown below. Only two pairs of chromosomes (out of the 23 pairs of human chromosomes) are considered. All possible alignments of paternal and maternal chromosomes are shown, leading to the formation of 16 gametes. Among the 16 possible gametes, 4 have different combinations of paternal and maternal chromosomes. Crossing over was not considered in the figure below.

Fertilization
Egg: The eggs of non-mammalian animals are huge cells which contain large amounts yolk to sustain the development of the embryo. Mammalian eggs are much smaller (human egg : 0.1mm diameter) since the nutrition for the embryo comes from the mother. A developing egg is called oocyte, whereas a mature egg is called ovum. Oocytes in mammals are formed between the 3 rd and 8 th month of gestation. During this early development, after crossing over has occurred they remain in prophase 1. After the female becomes sexually mature, the replicated DNA of the oocytes divides into two daughter nuclei followed by cyctokinesis. This first meiotic division is asymmetric. One of the cells produced is called the secondary oocyte, whereas the other cell is very small and is called polar body. The secondary oocyte undergoes meiosis 2 . The developmental stage in which the oocyte is released from the ovaries is different for different species. In human eggs the development stops at metaphase 2 and continues only after fertilization. At this stage meiosis 2 will be completed and a second polar body as well as the mature egg are formed.

Sperm: While the eggs are considered non motile the sperm is motile. Immature diploid sperm cells (spermatogonia) begin to mature into spermatocytes during puberty . The spermatocytes enter meiosis 2 , become secondary spermatocytes and continue through meiosis 2 to produces haploid spermatids. Spermatids develop into mature sperms.

The scheme below shows the formation of sperm in male animals, the formation of an egg in female animals and fertilization . For clarity only one chromosome is considered.

Uterine cycle
sex determination