The chromosomal basis of heredity lies in the copying of the genome and its transmission from a cell to its progeny during typical cell division and from one generation to the next during reproduction, when single copies of the genome from each parent come together in a new embryo.
To achieve these related but distinct forms of genome inheritance, there are two kinds of cell division, mitosis and meiosis. Mitosis is ordinary somatic cell division by which the body grows, differentiates, and effects tissue regeneration. Mitotic division normally results in two daughter cells, each with chromosomes and genes iden tical to those of the parent cell. There may be dozens or even hundreds of successive mitoses in a lineage of somatic cells. In contrast, meiosis occurs only in cells of the germline. Meiosis results in the formation of reproductive cells (gametes), each of which has only 23 chromosomes—one of each kind of autosome and either an X or a Y. Thus, whereas somatic cells have the diploid (diploos, “double”) or the 2n chromosome complement (i.e., 46 chromosomes), gametes have the haploid (haploos, “single”) or the n complement (i.e., 23 chromosomes). Abnormalities of chromosome number or structure, which are usually clinically significant, can arise either in somatic cells or in cells of the germline by errors in cell division.
The Cell Cycle
A human being begins life as a fertilized ovum (zygote), a diploid cell from which all the cells of the body (estimated to be ~100 trillion in number) are derived by a series of dozens or even hundreds of mitoses. Mitosis is obviously crucial for growth and differentiation, but it takes up only a small part of the life cycle of a cell. The period between two successive mitoses is called inter phase, the state in which most of the life of a cell is spent.
Immediately after mitosis, the cell enters a phase, called G1 , in which there is no DNA synthesis (Fig. 1). Some cells pass through this stage in hours; others spend a long time, days or years, in G1 . In fact, some cell types, such as neurons and red blood cells, do not divide at all once they are fully differentiated; rather, they are permanently arrested in a distinct phase known as G0 (“G zero”). Other cells, such as liver cells, may enter G0 but, after organ damage, return to G1 and continue through the cell cycle.
The cell cycle is governed by a series of checkpoints that determine the timing of each step in mitosis. In addition, checkpoints monitor and control the accuracy of DNA synthesis as well as the assembly and attachment of an elaborate network of microtubules that facilitate chromosome movement. If damage to the genome is detected, these mitotic checkpoints halt cell cycle progression until repairs are made or, if the damage is excessive, until the cell is instructed to die by programmed cell death (a process called apoptosis).
Fig1. A typical mitotic cell cycle, described in the text. The telomeres, the centromere, and sister chromatids are indicated.
During G1 , each cell contains one diploid copy of the genome. As the process of cell division begins, the cell enters S phase, the stage of programmed DNA synthesis, ultimately leading to the precise replication of each chromosome’s DNA. During this stage, each chromosome, which in G1 has been a single DNA molecule, is duplicated and consists of two sister chromatids (see Fig. 1), each of which contains an identical copy of the original linear DNA double helix. The two sister chromatids are held together physically at the centromere, a region of DNA that associates with a number of specific proteins to form the kinetochore. This complex structure serves to attach each chromosome to the microtubules of the mitotic spindle and to govern chromosome movement during mitosis. DNA synthesis during S phase is not synchronous throughout all chromosomes or even within a single chromosome; rather, along each chromosome, it begins at hundreds to thousands of sites, called origins of DNA replication. Individual chromosome segments have their own characteristic time of replication during the 6- to 8-hour S phase. The ends of each chromosome (or chromatid) are marked by telomeres, which consist of specialized repetitive DNA sequences that ensure the integrity of the chromosome during cell division. Correct maintenance of the ends of chromosomes requires a special enzyme called telomerase, which ensures that the very ends of each chromosome are replicated.
The essential nature of these structural elements of chromosomes and their role in ensuring genome integrity is illustrated by a range of clinical conditions that result from defects in elements of the telomere or kinetochore or cell cycle machinery or from inaccurate replication of even small portions of the genome.
By the end of S phase, the DNA content of the cell has doubled, and each cell now contains two copies of the diploid genome. After S phase, the cell enters a brief stage called G2 . Throughout the whole cell cycle, the cell gradually enlarges, eventually doubling its total mass before the next mitosis. G2 is ended by mitosis, which begins when individual chromosomes begin to condense and become visible under the microscope as thin, extended threads, a process that is considered in greater detail in the following section.
The G1 , S, and G2 phases together constitute interphase. In typical dividing human cells, the three phases take a total of 16 to 24 hours, whereas mitosis lasts only 1 to 2 hours (see Fig. 1). There is great variation, however, in the length of the cell cycle, which ranges from a few hours in rapidly dividing cells, such as those of the dermis of the skin or the intestinal mucosa, to months in other cell types.
Mitosis
During the mitotic phase of the cell cycle, an elaborate apparatus ensures that each of the two daughter cells receives a complete set of genetic information. This result is achieved by a mechanism that distributes one chromatid of each chromosome to each daughter cell (Fig. 2). The process of distributing a copy of each chromosome to each daughter cell is called chromosome segregation. The importance of this process for normal cell growth is illustrated by the observation that many tumors are invariably characterized by a state of genetic imbalance resulting from mitotic errors in the distribution of chromosomes to daughter cells.
Fig2. Mitosis. Only two chromosome pairs are shown. For details, see text.
The process of mitosis is continuous, but five stages (see Fig. 2) are distinguished: prophase, prometaphase, metaphase, anaphase, and telophase.
• Prophase. This stage is marked by gradual condensation of the chromosomes, formation of the mitotic spindle, and formation of a pair of centrosomes, from which microtubules radiate and eventually take up positions at the poles of the cell.
• Prometaphase. Here, the nuclear membrane dissolves, allowing the chromosomes to disperse within the cell and to attach, by their kinetochores, to microtubules of the mitotic spindle.
• Metaphase. At this stage, the chromosomes are maximally condensed and line up at the equatorial plane of the cell.
• Anaphase. The chromosomes separate at the centromere, and the sister chromatids of each chromosome now become independent daughter chromosomes, which move to opposite poles of the cell.
• Telophase. Now, the chromosomes begin to decondense from their highly contracted state, and a nuclear membrane begins to re-form around each of the two daughter nuclei, which resume their inter phase appearance. To complete the process of cell division, the cytoplasm cleaves by a process known as cytokinesis.
There is an important difference between a cell entering mitosis and one that has just completed the process. A cell in G2 has a fully replicated genome (i.e., a 4n complement of DNA), and each chromosome consists of a pair of sister chromatids. In contrast, after mitosis, the chromosomes of each daughter cell have only one copy of the genome. This copy will not be duplicated until a daughter cell in its turn reaches the S phase of the next cell cycle (see Fig. 1). The entire process of mitosis thus ensures the orderly duplication and distribution of the genome through successive cell divisions.
The Human Karyotype
The condensed chromosomes of a dividing human cell are most readily analyzed at metaphase or prometaphase. At these stages, the chromosomes are visible under the microscope as a so-called chromosome spread; each chromosome consists of its sister chromatids, although in most chromosome preparations, the two chromatids are held together so tightly that they are rarely visible as separate entities.
As stated earlier, there are 24 different types of human chromosomes, each of which can be distinguished cytologically by a combination of overall length, location of the centromere, and sequence content, the latter reflected by various staining methods. The centromere is apparent as a primary constriction, a narrowing or pinching-in of the sister chromatids due to formation of the kinetochore. This is a recognizable cytogenetic landmark, dividing the chromosome into two arms, a short arm designated p (for petit) and a long arm designated q.
Fig. 3 shows a prometaphase cell in which the chromosomes have been stained by the Giemsa-staining (G-banding) method. Each chromosome pair stains in a characteristic pattern of alternating light and dark bands (G bands) that correlates roughly with features of the underlying DNA sequence, such as base composition (i.e., the percentage of base pairs that are GC or AT) and the distribution of repetitive DNA elements. With such banding techniques, all of the chromosomes can be individually distinguished, and the nature of many structural or numerical abnormalities can be determined.
Fig3. A chromosome spread prepared from a lymphocyte culture that has been stained by the Giemsa-banding (G-banding) technique. The darkly stained nucleus adjacent to the chromosomes is from a different cell in interphase, when chromosomal material is diffuse throughout the nucleus. (Courtesy Stuart Schwartz, University Hospitals of Cleveland, Ohio.)
Although experts can often analyze metaphase chromosomes directly under the microscope, a common procedure is to cut out the chromosomes from a digital image or photomicrograph and arrange them in pairs in a standard classification (Fig. 4). The completed picture is called a karyotype. The word karyotype is also used to refer to the standard chromosome set of an individual (“a normal male karyotype”) or of a species (“the human karyotype”) and, as a verb, to the process of pre paring such a standard figure (“to karyotype”).
Fig4. A human male karyotype with Giemsa banding (G-banding). The chromosomes are at the prometaphase stage of mitosis and are arranged in a standard classification, numbered 1 to 22 in order of length, with the X and Y chromosomes shown separately. Courtesy Stuart Schwartz, University Hospitals of Cleveland, Ohio.
Unlike the chromosomes seen in stained preparations under the microscope or in photographs, the chromosomes of living cells are fluid and dynamic structures. During mitosis, the chromatin of each interphase chromosome condenses substantially (Fig. 5). When maximally condensed at metaphase, DNA in chromosomes is approximately 1/10,000 of its fully extended state. When chromosomes are prepared to reveal bands (as in Figs. 3 and 4), as many as 1000 or more bands can be recognized in stained preparations of all the chromosomes. Each cytogenetic band therefore contains as many as 50 or more genes, although the density of genes in the genome, as mentioned previously, is variable.
Fig5. Cycle of condensation and decondensation as a chromosome proceeds through the cell cycle.
Meiosis
Meiosis, the process by which diploid cells give rise to haploid gametes, involves a type of cell division that is unique to germ cells. In contrast to mitosis, meiosis consists of one round of DNA replication followed by two rounds of chromosome segregation and cell division (see meiosis I and meiosis II in Fig. 6). As outlined here and illustrated in Fig. 7, the overall sequence of events in male and female meiosis is the same; however, the timing of gametogenesis is very different in the two sexes, as we will describe more fully later in this chapter.
Fig6. A simplified representation of the essential steps in meiosis, consisting of one round of DNA replication followed by two rounds of chromosome segregation, meiosis I and meiosis II.
Fig7. Meiosis and its consequences. A single chromosome pair and a single crossover are shown, leading to formation of four distinct gametes. The chromosomes replicate during interphase and begin to condense as the cell enters prophase of meiosis I. In meiosis I, the chromosomes synapse and recombine. A crossover is visible as the homologues align at metaphase I, with the centromeres oriented toward opposite poles. In anaphase I, the exchange of DNA between the homologues is apparent as the chromosomes are pulled to opposite poles. After completion of meiosis I and cytokinesis, meiosis II proceeds with a mitosis-like division. The sister kinetochores separate and move to opposite poles in anaphase II, yielding four haploid products.
Meiosis I is also known as the reduction division because it is the division in which the chromosome number is reduced by half through the pairing of homologues in prophase and by their segregation to different cells at anaphase of meiosis I. Meiosis I is also notable because it is the stage at which genetic recombination (also called meiotic crossing over) occurs. In this process, as shown for one pair of chromosomes in Fig. 7, homologous segments of DNA are exchanged between nonsister chromatids of each pair of homologous chromosomes, thus ensuring that none of the gametes produced by meiosis will be identical to another. The conceptual and practical consequences of recombination for many aspects of human genetics and genomics are substantial and are outlined in the box at the end of this section.
Prophase of meiosis I differs in a number of ways from mitotic prophase, with important genetic consequences, because homologous chromosomes need to pair and exchange genetic information. The most critical early stage is called zygotene, when homologous chromosomes begin to align along their entire length. The process of meiotic pairing—called synapsis—is normally precise, bringing corresponding DNA sequences into alignment along the length of the entire chromo some pair. The paired homologues—now called bivalents—are held together by a ribbonlike proteinaceous structure called the synaptonemal complex, which is essential to the process of recombination. After synapsis is complete, meiotic crossing over takes place during pachytene, after which the synaptonemal complex breaks down.
Metaphase I begins, as in mitosis, when the nuclear membrane disappears. A spindle forms, and the paired chromosomes align themselves on the equatorial plane with their centromeres oriented toward different poles (see Fig. 7).
Anaphase of meiosis I again differs substantially from the corresponding stage of mitosis. Here, it is the two members of each bivalent that move apart, not the sister chromatids (contrast Fig. 7 with Fig. 2). The homologous centromeres (with their attached sister chromatids) are drawn to opposite poles of the cell, a process termed disjunction. Thus the chromosome number is halved, and each cellular product of meiosis I has the haploid chromosome number. The 23 pairs of homologous chromosomes assort independently of one another, and as a result the original paternal and maternal chromosome sets are sorted into random combinations. The possible number of combinations of the 23 chromosome pairs that can be present in the gametes is 223 (>8 million). Owing to the process of crossing over, however, the variation in the genetic material that is transmitted from parent to child is actually much greater than this. As a result, each chromatid typically contains segments derived from each member of the original parental chromosome pair, as illustrated schematically in Fig. 7. For example, at this stage, a typical large human chromosome would be composed of three to five segments, alternately paternal and maternal in origin, as inferred from DNA sequence variants that distinguish the respective parental genomes (Fig. 8).
Fig8. The effect of homologous recombination in meiosis. In this example, representing the inheritance of sequences on a typical large chromosome, an individual has distinctive homologues, one containing sequences inherited from his father (blue) and one containing homologous sequences from his mother (purple). After meiosis in spermatogenesis, he transmits a single complete copy of that chromosome to his two offspring. However, as a result of crossing over (arrows), the copy he transmits to each child consists of alternating segments of the two grandparental sequences. Child 1 inherits a copy after two crossovers, whereas child 2 inherits a copy with three crossovers.
After telophase of meiosis I, the two haploid daughter cells enter meiotic interphase. In contrast to mitosis, this interphase is brief, and meiosis II begins. The notable point that distinguishes meiotic and mitotic interphase is that there is no S phase (i.e., no DNA synthesis and duplication of the genome) between the first and second meiotic divisions.
Meiosis II is similar to an ordinary mitosis, except that the chromosome number is 23 instead of 46; the chromatids of each of the 23 chromosomes separate, and one chromatid of each chromosome passes to each daughter cell (see Fig. 7). However, as mentioned earlier, because of crossing over in meiosis I, the chromosomes of the resulting gametes are not identical (see Fig. 8).
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