In the second article of our series on genetics, Adrián J Gonzáles and colleagues consider metosis and meiosis—the two main types of cell division

The cycle of life

Life is full of cycles, but no one would exist without the cell cycle. The cell cycle is controlled by genetic cues that lead to the growth, functioning, death, and division of cells, which is how cells propagate.

Cell division can happen in two main ways—mitosis or somatic cell division and meiosis restricted to the germ cell progeny. In a successful somatic cell cycle the entire genetic material is duplicated once and is distributed evenly in two daughter cells during mitosis. This begins during part of the cell cycle called the interphase, which includes different stages: G1, S, and G2. Once cells stop dividing they enter a different part of interphase called G0.

Interphase
Gap 1 (G1)—In this stage, the cell has recently undergone mitosis. It starts to grow and perform different and specific metabolic activities. The 23 pairs of chromosomes or diploid (somatic) number of chromosomes are uncoiled and gene transcripts (mRNA) are made from them. This is then translated into proteins to maintain cell functions (see studentBMJ 2004;12:316-7).¹ This stage can either last up to 11 hours or continue throughout the cell’s lifespan if the cell does not divide again. Cells only divide if necessary—mature lymphocytes do not divide unless they are stimulated and fibroblasts only divide when a wound needs repairing.

DNA Synthesis (S)—This lasts about eight hours and is the phase in which DNA is replicated. Now each chromosome consists of two sister chromatids— each chromatid is a full copy of the DNA double helix. G1 chromosomes consist of a single chromatid; after S phase they duplicate themselves and have sister chromatids with identical DNA content. At this point the cell has 46 pairs of chromosomes. This replication will allow daughter cells to have the same genetic material and information as the mother cell. G2 and mitosis will be delayed or aborted if DNA duplication is not complete or important errors during the S phase have occurred.

Gap 2 (G2)—The chromosome number and shape remains the same. Gene transcription and translation occurs rapidly. Because many proteins are needed for mitosis, cytoplasm grows and cellular organelles duplicate.

Mitosis (M)
After the above careful preparation, the cell is ready to divide (fig 1). This division has been separated into four stages and has different duration depending on cell population and nutrients available. In vitro lymphocytesfrom the same person show marked variation of the time needed to complete the cell cycle depending on the nutrient characteristics of the culture media.²
Prophase—Chromosomes start condensation by folding loops around a chromatin fibre on the chromosome scaffold. This inhibits gene transcription and facilitates chromosome segregation. In this phase the nuclear membrane fades away, allowing cytoplasmic microtubules to come in contact with chromosomes.
Metaphase—All chromosomes approach the midline pulled by microtubules and contractile proteins that form the mitotic spindle.3 The sister chromatids remain bonded at the centromere and at multiple points of the chromosome structure. Once the chromosomes are completely aligned they form the metaphase plate.
Anaphase—The proteins that bind sister chromatids are cleaved, so centromeres from each sister chromatid separate and the chromatids progress to opposite poles of the cell.
Telophase—Chromosomes continue to shorten and condense, which began after the S phase. Nuclear membranes appear enveloping the set of chromosomes in a new nucleus. Cytokinesis or cytoplasmic division occurs generating two equal daughter cells.

Fig 1 & 2- Click on the thumbnails to view the full image and description

After mitosis, cells enter G1 and prepare for another cell division, but cells that do not divide enter a different stage, called G0, remaining metabolically active and waiting for signals to divide. For example, fibroblasts remain in G0 until a platelet growth factor activates them to start the healing process after a person is wounded. Nerve cells and lens cells can remain in G0 forever.

Molecular control of the cell cycle

Cell cycle progression is regulated by cyclins. These are proteins that appear at specific steps or checkpoints in the cell cycle and bind to specific cyclin dependent kinases that phosphorylate certain target proteins. These proteins are usually those that control transcription factors that promote cells to go forward through the cycle. The correct synchrony of several checkpoints is essential for normal cell cycle progression.^{3, 4}

Meiosis

Meiosis produces oocytes and spermatozoids (gametes), which have 23 chromosomes each (fig 2). Oocytes and spermatozoids also have a characteristic shape which helps them find each other in the fallopian tube. If they are successful, pregnancy will occur and each gamete will contribute an equal number of chromosomes to the new human being, which should have 23 pairs of homologous chromosomes.

Meiosis consists of two consecutive cell divisions (meiosis I and meiosis II) without DNA duplication between them. Like mitosis, both meiotic divisions have a prophase, metaphase, anaphase, and telophase, but each involves different processes.

Meiosis I

Prophase I is the most complex part of meiosis, and is subdivided into five stages—leptotene, zygotene, paquitene, diplotene, and diakinesis. During the entire prophase, previously duplicated chromosomes condense. During paquitene homologous chromosomes pair themselves and exchange segments of DNA between them to make new genomic combinations. This is called chromosome recombination and is the main cause of genetic variation.³

Metaphase I and anaphase I are different from that of mitosis because the centromere does not separate, so it is the duplicated homologous chromosomes that segregate into each daughter cell. After meiosis I has ended, the daughter cells have 23 previously duplicated chromosomes (haploid chromosome number).

Meiosis II is very similar to somatic cell mitosis without previous DNA duplication, but with centromere separation. In the male this produces 4 spermatozoids but in the female only 1 ovule, carrying both types of mature germ cells with 23 single chromosomes (fig 2).

Errors in chromosome segregation

Thousands of cell divisions occur each day in millions of living organisms and genetic material is almost always distributed evenly. Sometimes, however, it goes wrong: mistakes in cell division alter chromosome segregation. When this happens in germ cells it will affect every cell of the newly formed human being.

One error that is often found is aneuploidy, when chromosome(s) are gained or lost. Aneuploidy results mainly from a meiotic misdivision and is responsible for about 50% of first trimester spontaneous abortions and several well known human syndromes. It results from a failure of homologous chromosomes to segregate (non-disjunction) or incomplete chromosome migration (anaphase lag) during meiosis I or II, generating gametes with 23+1 or 23-1 chromosomes.

When a gamete with 23+1 chromosomes is fertilised by a normal gamete with 23 chromosomes, a 46+1 trisomic) zygote occurs—for example, in Down’s syndrome. When a gamete with 23-1 chromosomes is fertilised by a normal gamete, a 45 (monosomic) zygote results—for example, in Turner’s syndrome.

The most common example of a 46+1 zygote is Down’s syndrome, which affects about 1 in 700 live births and is the most common genetic cause of mental retardation.5 Because of the presence of an extra chromosome 21 (trisomy 21), the phenotype may in some cases include serious congenital malformations such us congenital heart defects (the most common one occurring in about 30% of people with Down’s syndrome), duodenal stenosis or atresia, imperforate anus, and Hirshsprung’s disease. People with Down’s syndrome are at an increased risk of developing leukaemia and Alzheimer’s disease.^{6, 7}

Mapping of chromosome 21 has allowed geneticists to associate clinical characteristics of the syndrome with genes in the Down’s syndrome ritical region located in the 23 region of the long arm of chromosome 21.⁸

In addition to complete chromosome gain or loss, structural changes can affect phenotype without an apparent change in chromosome number. These types of chromosome structural anomalies can be balanced or unbalanced.³

Balanced structural chromosome anomalies change a chromosome’s gene location without gene gain or loss. One example is reciprocal translocations in which two nonhomologous chromosomes’ fragments trade places. Carriers of balanced translocations have a higher risk of producing unbalanced gametes, giving rise to unbalanced zygotes resulting usually in partial trisomies and monosomies.

Unbalanced structural chromosome anomalies usually affect cell function to a lesser extent than complete trisomies or monosomies. Partial trisomies represent a triple dose of genes of a particular chromosome segment and partial monosomies a single dose of it. Examples of the first, are trisomy of the short arm of chromosome 9 and part of the long arm of chromosome 13, and examples of the last are Turner’s syndrome due to deletion of the short arm of one X chromosome and the cat cry syndrome due to a deletion of the short arm of chromosome 5.

The flow of genetic information occurs everywhere, from cells to their progenies and from parents to their offspring. But it also occurs within and between human populations, resulting in genetic drift—an important source of human variation. A normal genetic flow depends on a perfect process. When it becomes imperfect, somatic cell aneuploidy and loss of cell cycle control is one of the most important events in human cancer, which we will describe in a later article.

Adrián J González interim, medial genetics
Email: grangeroloco@hotmail.com

Luis R Macias second year resident

Regina Gómez-Palacio second year resident

Osvaldo M Mutchinick chief, Department of Genetics, National Institute of Medical Sciences and Nutrition "Salvador Zubirán", Mexico



studentBMJ 2004;12:349-392 October ISSN 0966-6494

1. Wilson EB. The cell in development and inheritance. 2nd ed. New York: Macmillan, 1925.
2. Mutchinick O, Ruz L, Casas L. Time of first generation metaphases. I: The effect of various culture media and of fetal calf serum in human lymphocyte cultures. Mut Res 1980;72:127-34.
3. Barton N, Goldstein L. Going mobile: microtubule motors and chromosome segregation. Proc Natl Acad Sci USA 1996;93:1735-42.
4. Griffiths AJF, Miller JH, Suzuki DT, Lewontin RC, Gelbart WM. Introduction to genetic analysis. 7th ed. New York: WH Freeman, 2000.
5. Cooper GM. The cell: a molecular approach. 2nd ed. Sunderland, MA: Sinauer Associates, 2000.
6. Hassold TJ, Jacobs PA. Trisomy in man. Annu Rev Genet 1984;18:69-97.
7. Online mendelian inheritance in man. Baltimore, MD: Johns Hopkins University. www.ncbi.nlm.nih.gov/omim (accessed 14 Sep 2004).
8. 1. Gardiner K, Davisson M. The sequence of human chromosome 21 and implications for research into Down syndrome. Genome Biol 2000;1(2):REVIEWS0002.

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