Meiosis: A Pair of Nuclear Divisions

Meiosis consists of two nuclear divisions that reduce the number of chromosomes to the haploid number in preparation for sexual reproduction. Although the nucleus divides twice during meiosis, the DNA is replicated only once. Unlike the products of mitosis, the products of meiosis are different from one an other and from the parent cell. To understand the process of meiosis and its specific details, it is useful to keep in mind the overall functions of meiosis:

To reduce the chromosome number from diploid to haploid

To ensure that each of the haploid products has a complete set of chromosomes

To promote genetic diversity among the products

The first meiotic division reduces the chromosome number

Two unique features characterize the first of the two meiotic divisions, meiosis I. The first is that homologous chromosomes pair along their entire lengths. No such pairing occurs in mitosis. The second is that after metaphase I, the homologous chromosomes separate. The individual chromosomes, each consisting of two sister chromatids, remain intact until the end of metaphase II in the second meiotic division. Like mitosis, meiosis I is preceded by an interphase with an S phase during which each chromosome is replicated. As a result, each chromosome consists of two sister chromatids, held together by cohesin proteins. Meiosis I begins with a long prophase I, during which the chromosomes change markedly. The homologous chromosomes pair by adhering along their lengths, a process called synapsis. This process lasts from prophase I to the end of metaphase I. By the time chromosomes can be clearly seen under light microscope, the two homologs are already tightly joined. This joining begins at the centromeres and is mediated by a recognition of homologous DNA sequences on homologous chromosomes. In addition, a special group of proteins may form a scaffold called the synaptonemal complex, which runs lengthwise along the homologous chromosomes and appears to join them together. The four chromatids of each pair of homologous chromosomes form what is called a tetrad, or bivalent. In other words, a tetrad consists of four chromatids, two each from two homologous chromosomes. For example, there are 46 chromosomes in a human diploid cell at the beginning of meiosis, so there are 23 homologous pairs of chromosomes, each with two chromatids (that is, 23 tetrads), for a total of 92 chromatids during prophase I. Throughout prophase I and metaphase I, the chromatin continues to coil and compact, so that the chromosomes appear ever thicker. At a certain point, the homologous chromosomes seem to repel each other, especially near the centromeres, but they are held together by physical attachments mediated by cohesins. These cohesins are different from the ones holding the two sister chromatids together. Regions having these attachments take on an X shaped appearance and are called chiasmata(from the Greek chiasma, “cross”. A chiasma reflects an exchange of genetic material between nonsister chromatids on homologous chromosomes— what geneticists call crossing over. The chromosomes begin exchanging material shortly after synapsis begins, but chiasmata do not become visible until later, when the homologs are repelling each other. Crossing over increases genetic variation among the products of meiosis by reshuffling genetic information among the homologous pairs. There seems to be plenty of time for the complicated events of prophase I to occur. Whereas mitotic prophase is usually measured in minutes, and all of mitosis seldom takes more than an hour or two, meiosis can take much longer. In human males, the cells in the testis that undergo meiosis take about a week for prophase I and about a month for the entire meiotic cycle. In the cells that will become eggs, prophase I begins long before a woman’s birth, during her early fetal development, and ends as much as decades later, during the monthly ovarian cycle.

Prophase I is followed by prometaphase I, during which the nuclear envelope and the nucleoli disaggregate. A spindle forms and microtubules become attached to the kinetochores of the chromosomes.

In meiosis I, the kinetochores of both chromatids in each chromosome become attached to the same half-spindle.

Thus the entire chromosome, consisting of two chromatids, will migrate to one pole. Which member of a homologous chromosome pair becomes attached to each half-spindle and thus which member will go to which pole, is random.

By metaphase I, all the chromosomes have moved to the equatorial plate. Up to this point, homologous pairs are held together by chiasmata. The homologous chromosomes separate in anaphase I when the individual chromosomes, each still consisting of two chromatids, are pulled to the poles, with one homolog of a pair going to one pole and the other homolog going to the opposite pole. (Note that this process differs from the separation of chromatids during mitotic anaphase.) Each of the two daughter nuclei from this division thus contains only one set of chromosomes, not the two sets that were present in the original diploid nucleus. However, because they consist of two chromatids rather than just one, each of these chromosomes has twice the mass that a chromosome at the end of a mitotic division has.

In some organisms, there is a telophase I, with the reappearance of the nuclear envelopes. When there is a telophase I, it is followed by an interphase, called interkinesis, similar to the mitotic interphase. During interkinesis the chromatin is partially uncoiled; however, there is no replication of the genetic material, because each chromosome already consists of two chromatids. Furthermore, the sister chromatids in interkinesis are generally not genetically identical, because crossing over in prophase I has reshuffled genetic material between the maternal and paternal chromosomes. In other organisms, the chromosomes move directly into the second meiotic division.

The second meiotic division separates the chromatids

Meiosis IIis similar to mitosis in many ways. In each nucleus produced by meiosis I, the chromosomes line up at equatorial plate at metaphase II. The centromeres of the sister chromatids separate because of cohesin breakdown, and the daughter chromosomes move to the poles in anaphase II. The three major differences between meiosis II and mitosis are:

DNA replicates before mitosis, but not before meiosis II.

In mitosis, the sister chromatids that make up a given chromosome are identical. In meiosis II, they may differ over part of their length if they participated in crossing over during prophase I.

The number of chromosomes on the equatorial plate in meiosis II is half the number in the mitotic nucleus.

The result of meiosis is four nuclei; each nucleus is haploid and has a single set of unreplicated chromosomes that differs from other such sets in its exact genetic composition. The differences among the haploid nuclei result from crossing over during prophase I and from the random segregation of homologous chromosomes during anaphase I.

Meiosis leads to genetic diversity

What are the consequences of the synapsis and segregation of homologous chromosomes during meiosis? In mitosis, each chromosome behaves independently of its homolog; its two chromatids are sent to opposite poles at anaphase. If a mitotic division begins with x chromosomes, we end up with x chromosomes in each daughter nucleus, and each chromosome consists of one chromatid. Each of the two sets of chromosomes (one of paternal and one of maternal origin) is divided equally and distributed equally to each daughter cell.

In meiosis, chromosomes of maternal origin pair with their paternal homologs during synapsis. Separation of the homologs during meiotic anaphase I ensures that each pole receives one member of each homologous pair. For example, at the end of meiosis I in humans, each daughter nucleus contains 23 of the original 46 chromosomes. In this way, the chromosome number is decreased from diploid to haploid. Furthermore, meiosis I guarantees that each daughter nucleus gets one full set of chromosomes.

The products of meiosis I are genetically diverse for two reasons:

Synapsis during prophase I allows the maternal chromosome in each homologous pair to exchange segments with the paternal one by crossing over. The resulting recombinant chromatids contain some genetic material from each parent.

It is a matter of chance which member of a homologous pair goes to which daughter cell at anaphase I. For example, if there are two homologous pairs of chromosomes in the diploid parent nucleus, a particular daughter nucleus could get paternal chromosome 1 and maternal chromosome 2, or paternal 2 and maternal 1, or both maternal, or both paternal. It all depends on the way in which the homologous pairs line up at metaphase I. This phenomenon is termed independent assortment. Note that of the four possible chromosome combinations just described, two produce daughter nuclei that are the same as one of the parental types (except for any material exchanged by crossing over). The greater the number of chromosomes, the less probable that the original parental combinations will be reestablished, and the greater the potential for genetic diversity. Most species of diploid organisms do indeed have more than two pairs of chromosomes. In humans, with 23 chromosome pairs, 223 (8,388,608) different combinations can be produced, just by the mechanism of independent assortment. Taking the extra genetic shuffling afforded by crossing over into account, the number of possible combinations isvirtually infinite.

Meiotic Errors

In the complex process of cell division, things occasionally go wrong. A pair of homologous chromosomes may fail to separate during meiosis I, or sister chromatids may fail to separate during meiosis II or during mitosis. This phenomenon is called nondisjunction. Conversely, homologous chromosomes may fail to remain together. These problems can result in the production of aneuploid cells. Aneuploidyis a condition in which one or more chromosomes are either lackingor present in excess.

Aneuploidy can give rise to genetic abnormalities

One reason for aneuploidy may be a lack of cohesins. Recall that these molecules, formed during prophase I, hold the two homologous chromosomes together into metaphase I. They ensure that when the chromosomes line up at the equatorial plate, one homolog will face one pole and the other homolog will face the other pole. Without this “glue,” the two homologs may line up randomly at metaphase I, just like chromosomes during mitosis, and there is a 50 percent chance that both will go to the same pole. If, for example, during the formation of a human egg, both members of the chromosome 21 pair go to the same pole during anaphase I, the resulting eggs will contain either two of chromosome 21 or none at all. If an egg with two of these chromosomes is fertilized by a normal sperm, the resulting zygote will have three copies of the chromosome: it will be trisomicfor chromosome 21. Achild with an extra chromosome 21 demonstrates the symptoms of Down syndrome: impaired intelligence; characteristic abnormalities of the hands, tongue, and eyelids; and an increased susceptibility to cardiac abnormalities and diseases such as leukemia. If an egg that did not receive chromosome 21 is fertilized by a normal sperm, the zygote will have only one copy: it will be monosomicfor chromosome 21. Other abnormal chromosomal events can also occur. In a process called translocation, a piece of a chromosome may break away and become attached to another chromosome. For example, a particular large part of one chromosome 21 may be translocated to another chromosome. Individuals who inherit this translocated piece along with two normal chromosomes 21 will have Down syndrome. Trisomies (and the corresponding monosomies) are surprisingly common in human zygotes, with 10–30 percent of all conceptions showing aneuploidy. But most of the embryos that develop from such zygotes do not survive to birth, and those that do often die before the age of 1 year. Trisomies and monosomies for most chromosomes other than chromosome 21 are lethal to the embryo. At least one-fifth of all recognized pregnancies are spontaneously terminated during the first 2 months, largely because of such trisomies and monosomies. (The actual proportion of spontaneously terminated pregnancies is certainly higher, because the earliest ones often go unrecognized.)

Polyploids can have difficulty in cell division

As we saw earlier in our discussion of sexual life cycles, both diploid and haploid nuclei can divide by mitosis. Multicellular diploid and multicellular haploid individuals both develop from single-celled beginnings by mitotic divisions. Likewise, mitosis may proceed in diploid organisms even when a chromosome is missing from one of the haploid sets or when there is an extra copy of one of the chromosomes (as in people with Down syndrome). Organisms with complete extra sets of chromosomes may sometimes be produced by artificial breeding or by natural accidents. Under some circumstances, triploid (3n), tetraploid (4n), and higher-order polyploidnuclei may form. Each of these ploidy levels represents an increase in the number of complete sets of chromosomes present. If a nucleus has one or more extra full sets of chromosomes, its abnormally high ploidy in itself does not prevent mitosis. In mitosis, each chromosome behaves independently of the others. In meiosis, by contrast, homologous chromosomes must synapse to begin division. If even one chromosome has no homolog, anaphase I cannot send representatives of that chromosome to both poles. Adiploid nucleus can undergo normal meiosis; a haploid one cannot. Similarly, a tetraploid nucleus has an even number of each kind of chromosome, so each chromosome can pair with its homolog. But a triploid nucleus cannot undergo normal meiosis because one-third of the chromosomes would lack partners. This limitation has important consequences for the fertility of triploid, tetraploid, and other chromosomally unusual organisms. Modern bread wheat plants are hexaploids, the result of naturally occurring crosses between three different grasses, each having its own diploid set of 14 chromosomes. Over a period of 10,000 years, humans have selected favourable varieties of these hybrids to produce modern wheat strains.

Cell Death

As we mentioned at the start of this chapter, an essential role of cell division in complex eukaryotes is to replace cells that die. In humans, billions of cells die each day, mainly in the blood and in the epithelia lining organs such as the intestine. Cells die in one of two ways. The first, necrosis, occurs when cells either are damaged by poisons or are starved of essential nutrients. These cells usually swell up and burst, releasing their contents into the extracellular environment.). The scab that forms around a wound is a familiar example of necrotic tissue. More typically, cell death in an organism is due to apoptosis(from the Greek, “falling off”). Apoptosis is a genetically programmed series of events that result in cell death. Why would a cell initiate apoptosis, which is essentially “cell suicide”? There are two possible reasons:

The cell is no longer needed by the organism. For example, before birth, a human fetus has weblike hands with connective tissue between the fingers. As development proceeds, this unneeded tissue disappears as its cells undergo apoptosis.

The longer cells live, the more prone they are to genetic damage that could lead to cancer. This is especially true of cells in the blood and intestine, which are exposed to high levels of toxic substances. Such cells normally die after only days or weeks. Like the cell division cycle, the cell death cycle is controlled by signals which may come either from inside or outside the cell. These signals include the lack of a mitotic signal (such as a growth factor) and the recognition of DNA damage. Many of the drugs used to treat diseases of excess cell proliferation, such as cancer, work through these signals. The events of apoptosis are very similar in most organisms. The cell becomes isolated from its neighbors, chops up its chromatin into nucleosome-sized pieces, and then fragments itself (Figure ). In a remarkable example of the economy of nature, the surrounding living cells usually ingest the remains of the dead cell. The genetic signals that lead to apoptosis are also common to many organisms.

2.2.2. Genetics: Mendel and Beyond

Much of the early study of biological inheritance was done with plants and animals of economic importance.

Records show that people were deliberately crossbreeding date palm trees and horses as early as 5,000years ago. By the early nineteenth century, plant breeding was widespread, especially with ornamental flowers such as tulips. Half a century later, Gregor Mendel used the existing kno wledge of plant reproduction to design and conduct experiments on inheritance. Although his published results were neglected by scientists for more than 30 years, they ultimately became the foundation for the science of genetics.

Plant breeders showed that both parents contribute equally to inheritance

Plants are good experimental subjects for the study of genetics. Many plants are easily grown in large quantities, produce large numbers of offspring (in the form of seeds) and have relatively short generation times. In most plant species, the same individuals have both male and female reproductive organs, permitting each plant to reproduce as a male, as a female or as both. Best of all, it is often easy to control which individuals mate. Some discoveries that Mendel found useful in his studies had been made in the late eighteenth century by a Germanbotanist, Josef Gottlieb Kölreuter. He had studied the offspring of reciprocal crosses, in which plants are crossed (mated with each other) in opposite directions. For example, in one cross, males that have white flowers are mated with females that have red flowers, while in a complementary cross, red-flowered males and white-flowered females are mated. In Kölreuter’s studies, such reciprocal crosses always gave identical results showing that both parents contributed equally to the offspring. Although the concept of equal parental contributions was an important discovery, the nature of what exactly the parents were contributing to their offspring—the units of inheritance—remained unknown. Laws of inheritance proposed at the time favored the concept of blending. If a plant that had one form of a characteristic (say, red flowers) was crossed with one that had a different form of that characteristic (blue flowers), the offspring would be a blended combination of the two parents (purple flowers). According to the blending theory, it was thought that once heritable elements were combined, they could not be separated again (like inks of different colors mixed together). The red and blue genetic determinants were thought to be forever blended into the new purple one. Then, about a century after Kölreuter completed his work, Mendel began his.

Mendel brought new methods to experiments on inheritance

Gregor Mendel was an Austrian monk, not an academic scientist, but he was qualified to undertake scientific investigations. Although in 1850 he had failed an examination for a teaching certificate in natural science, he later undertook in-tensive studies in physics, chemistry, mathematics, and various aspects of biology at the University of Vienna. His work in physics and mathematics probably led him to apply experimental and quantitative methods to the study of heredity, and these methods were the key ingredients in his success. Mendel worked out the basic principles of inheritance in plants over a period of about 9 years. His work culminated in a public lecture in 1865 and a detailed written publication in 1866. Mendel’s paper appeared in a journal that was received by 120 libraries and he sent reprinted copies (of which he had obtained 40) to several distinguished scholars. However, his theory was not accepted. In fact, it was ignored. The chief difficulty was that the most prominent biologists of Mendel’s time were not in the habit of thinking in mathematical terms, even the simple terms used by Mendel. Even Charles Darwin, whose theory of evolution by natural selection depended on genetic variation among individuals, failed to understand the significance of Mendel’s findings. In fact, Darwin performed breeding experiments on snapdragons similar to Mendel’s on peas and got data similar to Mendel’s but he missed the point, still relying on the concept of blending. Whatever the reasons, Mendel’s pioneering paper had no discernible influence on the scientific world for more than 30 years. Then, in 1900, after meiosis had been observed and described, Mendel’s discoveries burst into prominence as a result of independent experiments by three plant geneticists, Hugo DeVries, Carl Correns and Erich von Tschermak. Each carried out crossing experiments and obtained quantitative data about the progeny; each published his principal findings in 1900; each cited Mendel’s 1866 paper. They immediately realized that chromosomes and meiosis provided a physical explanation for the theory that Mendel had proposed to explain the data from his crosses. As we go through Mendel’s work, we will describe first his experiments and conclusions, and then the chromosomal explanation of his theories.