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Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002.

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Molecular Biology of the Cell. 4th edition.

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The realization that gametes are haploid, and must therefore be produced by a special type of cell division, came from an observation that was also among the first to suggest that chromosomes carry genetic information. In 1883, it was discovered that, whereas the fertilized egg of a roundworm contains four chromosomes, the nucleus of the egg and that of the sperm each contain only two chromosomes. The chromosome theory of heredity therefore explained the long-standing paradox that the maternal and paternal contributions to the character of the progeny seem to be equal, despite the enormous difference in size between the egg and sperm (see Figure 20-4).

The finding also implied that germ cells must be formed by a special kind of nuclear division in which the chromosome complement is precisely halved. This type of division is called meiosis, from the Greek, meaning diminution. (Mitosis, which refers to the nuclear division that occurs during an ordinary mitotic cell division (discussed in Chapter 18), is from the Greek word mitos, meaning “a thread.” The term refers to the threadlike appearance of the chromosomes as they condense during nuclear division—a process that occurs in both meiotic and mitotic divisions.) The behavior of the chromosomes during meiosis turned out to be considerably more complex than expected. Consequently, it was not until the early 1930s, as a result of painstaking cytological and genetic studies, that the essential events of meiosis were finally established. More recent genetic and molecular studies have begun to identify the meiosis-specific proteins that cause the chromosomes to behave in a special way and mediate the genetic recombination events that occur in meiosis.

Duplicated Homologous Chromosomes Pair During Meiosis

The set of chromosomes of a typical sexually-reproducing organism consists of autosomes, which are common to all members of the species, and sex chromosomes, which are differently allocated according to the sex of the individual. A diploid nucleus contains two closely similar versions of each chromosome. For each of the autosomal chromosome pairs, one member was initially inherited from the male parent (a paternal chromosome) and the other was initially inherited from the female parent (a maternal chromosome). The two versions, which are very similar but not identical in DNA sequence, are called homologs, and in most cells they maintain a completely separate existence as independent chromosomes.

After a chromosome is duplicated by DNA replication, the twin copies of the fully replicated chromosome at first remain tightly linked along their length and are called sister chromatids. In a mitotic cell division, the sister chromatids line up at the equator of the spindle with their kinetochores (protein complexes associated with the centromeres, discussed in Chapter 18) and attached microtubules pointing toward opposite poles. The sister chromatids then separate completely from each other at anaphase to become individual chromosomes. In this manner each daughter cell formed by a mitotic cell division inherits one copy of each paternal chromosome and one copy of each maternal chromosome and is therefore unchanged in its genetic composition from the parent cell.

In contrast, a haploid gamete produced from a diploid cell through meiosis must contain half the original number of chromosomes. It must contain only one chromosome in place of each homologous pair of chromosomes, so it is endowed with either the maternal or the paternal copy of each gene but not both. This requirement makes an extra demand on the machinery for cell division. The mechanism that has evolved to accomplish the additional sorting requires that homologs recognize each other and become physically connected side-by-side along their entire length before they line up on the spindle. How the maternal and the paternal copy of each chromosome recognize each other is still uncertain. In many organisms, the initial association (a process called pairing) seems to be mediated by complementary DNA base-pair interactions at numerous and widely dispersed sites along the chromosomes.

Before the homologs pair, each chromosome in the diploid cell replicates to produce two sister chromatids, just as in a mitotic cell division. It is only after DNA replication has been completed that the special features of meiosis become evident. Each duplicated chromosome pairs with its duplicated homolog, forming a structure called a bivalent, which contains four chromatids. The pairing occurs during a long meiotic prophase, which often lasts for days and can last for years. As we shall see, pairing allows genetic recombination to occur, whereby a fragment of a maternal chromatid may be exchanged for a corresponding fragment of a homologous paternal chromatid. At the subsequent metaphase all of the bivalents line up on the spindle, and at anaphase the two duplicated homologs (each consisting of two sister chromatids) separate from each other and move to opposite poles of the spindle, and the cell divides (Figure 20-6). To produce haploid gametes, however, another cell division is required.

Figure 20-6. Events through the first cell division of meiosis.

Figure 20-6

Events through the first cell division of meiosis. For clarity, only one pair of homologous chromosomes is shown. Each chromosome has been duplicated and exists as attached sister chromatids before pairing with its homologous chromosome (homolog), thereby (more...)

Gametes Are Produced by Two Meiotic Cell Divisions

The meiotic cell division just described—referred to as division I of meiosis—does not produce cells with a haploid amount of DNA. Because the sister chromatids behave as a unit, each daughter cell of this division inherits two copies of one of the two homologs. The two copies are identical except where genetic recombination has occurred. The two daughter cells therefore contain a haploid number of chromosomes but a diploid amount of DNA. They differ from normal diploid cells in two ways. First, the two DNA copies of each chromosome derive from only one of the two homologous chromosomes in the original cell (except for the bits exchanged by genetic recombination). Second, these two DNA copies are inherited as joined sister chromatids (see Figure 20-6).

Formation of the actual gamete nuclei can now proceed simply through a second cell division, division II of meiosis, without further DNA replication. The duplicated chromosomes align on a second spindle, and the sister chromatids separate to produce cells with a haploid DNA content. Meiosis thus consists of a single phase of DNA replication followed by two cell divisions. Four haploid cells are therefore produced from each cell that enters meiosis. Meiosis and mitosis are compared in Figure 20-7.

Figure 20-7. Comparison of meiosis and mitotic cell division.

Figure 20-7

Comparison of meiosis and mitotic cell division. As in the previous figure, only one pair of homologous chromosomes is shown. In meiosis, after DNA replication, two nuclear (and cell) divisions are required to produce the haploid gametes. Each diploid (more...)

Occasionally during meiosis, chromosomes fail to separate normally into the four haploid cells, a phenomenon known as nondisjunction. In such abnormal meiotic divisions some of the haploid cells that are produced lack a chromosome, while others have more than one copy. The resulting gametes form abnormal embryos, most of which die. Some survive, however: Down syndrome in humans, for example, is caused by an extra copy of chromosome 21, resulting from nondisjunction during meiotic division I or II. The vast majority of such segregation errors occur during meiosis in females, and the error rate increases with advancing maternal age. The frequency of missegregation in human oocytes is remarkably high (about 10% of meioses), and this is thought to be one reason for the high rate of miscarriages (spontaneous abortions) in early pregnancy.

Genetic Reassortment Is Enhanced by Crossing-over Between Homologous Nonsister Chromatids

Unless they are identical twins, which develop from a single zygote, no two offspring of the same parents are genetically the same. This is because, long before the two gametes fuse at fertilization, two kinds of randomizing genetic reassortment have occurred during meiosis.

One kind of reassortment is a consequence of the random distribution of the maternal and paternal homologs between the daughter cells at meiotic division I, as a result of which each gamete acquires a different mixture of maternal and paternal chromosomes. From this process alone, one individual could, in principle, produce 2n genetically different gametes, where n is the haploid number of chromosomes (Figure 20-8A). In humans, for example, each individual can produce at least 223 = 8.4 × 106 genetically different gametes. But the actual number of variants is very much greater than this because a second type of reassortment, called chromosomal crossing-over, occurs during meiosis. It takes place during the long prophase of meiotic division I (prophase I), in which parts of homologous chromosomes are exchanged. On average, between two and three crossover events occur on each pair of human chromosomes during meiotic division I. This process scrambles the genetic constitution of each of the chromosomes in gametes, as illustrated in Figure 20-8B.

Figure 20-8. Two major contributions to the reassortment of genetic material that occurs in the production of gametes during meiosis.

Figure 20-8

Two major contributions to the reassortment of genetic material that occurs in the production of gametes during meiosis. (A) The independent assortment of the maternal and paternal homologs during the first meiotic division produces 2n different haploid (more...)

During chromosomal crossing-over, the DNA double helix is broken in both a maternal chromatid and a homologous paternal chromatid, so as to exchange fragments between the two nonsister chromatids in a reciprocal fashion by a process known as genetic recombination. The molecular details of this process are discussed in Chapter 5. The consequences of each crossover event can be observed in the microscope at the latest stages of prophase I, when the chromosomes in the bivalents are highly condensed. At this stage, the sister chromatids are tightly apposed along their entire length, and the two duplicated homologs (maternal and paternal) that form each bivalent are seen to be physically connected at specific points. Each connection, called a chiasma (plural chiasmata), corresponds to a crossover between two nonsister chromatids (Figure 20-9). Each of the two chromatids of a duplicated chromosome can cross over with either of the two chromatids of the other chromosome in the bivalent, as illustrated in Figure 20-10.

Figure 20-9. Paired homologous chromosomes during the transition to metaphase of meiotic division I.

Figure 20-9

Paired homologous chromosomes during the transition to metaphase of meiotic division I. A single crossover event has occurred earlier in prophase to create one chiasma. Note that the four chromatids are arranged as two distinct pairs of sister chromatids. (more...)

Figure 20-10. Bivalents with three chiasmata resulting from separate crossover events.

Figure 20-10

Bivalents with three chiasmata resulting from separate crossover events. (A) In this drawing, chromatid 1 has undergone an exchange with chromatid 3, and chromatid 2 has undergone exchanges with chromatid 3 and 4. Note that the sister chromatids of the (more...)

At this stage of meiosis, each pair of duplicated homologs is held together by at least one chiasma. Many bivalents contain more than one chiasma, indicating that multiple crossovers can occur between homologs.

Chiasmata Have an Important Role in Chromosome Segregation in Meiosis

In addition to reassorting genes, chromosomal crossing-over is crucial in most organisms for the correct segregation of the two duplicated homologs to separate daughter nuclei. This is because the chiasmata created by crossover events have a crucial role in holding the maternal and paternal homologs together until the spindle separates them at anaphase I (see Figure 20-9). Before anaphase I, the two poles of the spindle pull on the duplicated homologs in opposite directions, and the chiasmata resist this pulling. In mutant organisms that have a reduced frequency of meiotic chromosome crossing-over, some of the chromosome pairs lack chiasmata. These pairs fail to segregate normally, and many of the resulting gametes contain too many or too few chromosomes.

The duplicated homologs are held together at chiasmata only because the arms of sister chromatids are glued together along their length by proteins called cohesins (discussed in Chapter 18; see Figure 20-9). In Drosophila, for example, if a meiosis-specific cohesin is defective, sister chromatids separate prior to metaphase I and, as a consequence, the homologs segregate abnormally.

As illustrated in Figure 20-11, the arms of sister chromatids suddenly become unglued at the start of anaphase I, when the cohesins holding the arms together are degraded, allowing the duplicated homologs to separate and be pulled to opposite poles of the spindle. The sister chromatids of each duplicated homolog remain attached at the centromere by meiosis-specific cohesins, which are degraded at anaphase of meiotic division II (anaphase II); only then can the sister chromatids separate.

Figure 20-11. Comparison of the mechanisms of chromosome alignment (at metaphase) and separation (at anaphase) in meiotic division I and meiotic division II.

Figure 20-11

Comparison of the mechanisms of chromosome alignment (at metaphase) and separation (at anaphase) in meiotic division I and meiotic division II. The ungluing of the sister chromatid arms allows the duplicated homologs to separate at anaphase I, while an (more...)

In meiotic division II, as in a mitotic division, the kinetochores on each sister chromatid have attached kinetochore microtubules pointing in opposite directions, so that the chromatids are drawn into different daughter cells at anaphase. In meiotic division I, by contrast, the kinetochores on both sister chromatids behave as a single functional unit, as their attached kinetochore microtubules all point in the same direction so that the sister chromatids stay together when the duplicated homologs separate (see Figure 20-11). In budding yeasts, a meiosis-specific protein located at the kinetochores of meiosis I chromosomes has been shown to be required for this special behavior.

Pairing of the Sex Chromosomes Ensures That They Also Segregate

We have seen that duplicated homologous chromosomes must pair and form at least one chiasma during the first meiotic division if they are to segregate accurately between the daughter cells. But what happens to the sex chromosomes? Female mammals have two X chromosomes, which can pair and segregate like other homologs. But males have one X and one Y chromosome, and these chromosomes are not homologous. Yet, they must pair and then cross over during the first metaphase of meiosis if the sperm are to contain either one Y or one X chromosome and not both or neither. The crossovers are possible because of a small region of homology between the X and the Y at one end of these chromosomes. The two chromosomes pair and cross over in this region during prophase I. The chiasmata resulting from this genetic recombination keep the X and Y chromosomes connected on the spindle so that only two types of sperm are normally produced: sperm containing one Y chromosome, which will give rise to male embryos, and sperm containing one X chromosome, which will give rise to female embryos.

Having considered the general way in which chromosomes behave and segregate during meiosis, we now return to the process of genetic recombination that occurs during the long prophase of meiotic division I and has such an important role in reassorting genes during gamete formation.

Meiotic Chromosome Pairing Culminates in the Formation of the Synaptonemal Complex

A series of complex events occurs during the long prophase of meiotic division I: duplicated homologous chromosomes pair, genetic recombination is initiated between nonsister chromatids, and each pair of duplicated homologs assembles into an elaborate structure called the synaptonemal complex. In some organisms, genetic recombination begins before the synaptonemal complex assembles and is required for the complex to form; in others, the complex can form in the absence of recombination. In all organisms, however, the recombination process is completed while the DNA is held in the synaptonemal complex, which serves to space out the crossover events along each chromosome.

The prophase of meiotic division I is traditionally divided into five sequential stages—leptotene, zygotene, pachytene, diplotene, and diakinesis—defined by the morphological changes associated with the assembly (synapsis) and disassembly (desynapsis) of the synaptonemal complex. Prophase begins with leptotene, when the duplicated paired homologs condense. At zygotene, the synaptonemal complex begins to develop between the two sets of sister chromatids in each bivalent. Pachytene begins when synapsis is complete, and it generally persists for days, until desynapsis begins the diplotene stage, in which the chiasmata are first seen (Figure 20-12).

Figure 20-12. Chromosome synapsis and desynapsis during the different stages of meiotic prophase I.

Figure 20-12

Chromosome synapsis and desynapsis during the different stages of meiotic prophase I. (A) A single bivalent is shown. The pachytene stage is defined as the period during which a fully formed synaptonemal complex exists. At leptotene, the two sister chromatids (more...)

The synaptonemal complex consists of a long, ladderlike protein core, on opposite sides of which the two duplicated homologs are aligned to form a long linear chromosome pair (Figure 20-13). The sister chromatids in each homolog are kept tightly packed together, with their DNA extending from their own side of the protein ladder in a series of loops. In the central region, a central element is connected by transverse filaments to lateral elements that run along each pair of sister chromatids, forming the sides of the ladder.

Figure 20-13. A mature synaptonemal complex.

Figure 20-13

A mature synaptonemal complex. Only a short section of the long ladderlike complex is shown. A similar synaptonemal complex is present in organisms as diverse as yeasts and humans.

Several protein components of the synaptonemal complex have been identified and localized to specific structures of the complex. Yeast mutants that lack specific components have provided insights into the functions of the complex and some of its proteins. One yeast protein, for example, seems to nucleate the assembly of the lateral elements: if this protein is defective, these elements fail to form. Another yeast protein helps to form the transverse filaments: if this protein is absent, homolog pairing occurs without intimate synapsis, while an abnormally long mutant form of the protein creates a larger than normal separation between the two lateral elements of the synaptonemal complex.

Recombination Nodules Mark the Sites of Genetic Recombination

The crossover events that take place during the prophase of meiotic division I can occur nearly anywhere along a chromosome. They are not distributed uniformly, however: there are recombination “hot spots,” where double-stranded DNA breaks seem to be preferentially induced by the meiotic endonuclease called Spo11. Moreover, both genetic and cytological experiments indicate that the occurrence of one crossover event decreases the probability of a second occurring at a nearby chromosomal site. This “interference” seems to ensure that the limited number of crossovers are spread out so that even small chromosomes get at least one, as required for the homologs to segregate normally. Although the molecular basis of the interference is unknown, the synaptonemal complex is thought to mediate the process.

There is strong indirect evidence that the general genetic recombination events in meiosis are catalyzed by recombination nodules. These are very large protein complexes that sit at intervals on the synaptonemal complex, placed like basketballs on a ladder between the two homologous chromosomes (see Figure 20-13). These nodules contain Rad51, which is the eucaryotic version of the RecA protein, which mediates general recombination in E. coli (discussed in Chapter 5). They seem to mark the site of a multienzyme “recombination machine” that interacts with local regions of DNA on the maternal and paternal chromatids across the 100-nm-wide synaptonemal complex.

There are two main types of recombination nodule. Early nodules are present before pachytene and are thought to mark the sites of the initial DNA-strand-exchange events of the recombination process. Late nodules are less numerous, are present during pachytene, and are thought to mark the sites where the initial strand-exchange events are being resolved as stable crossovers. Proteins known to be involved in general recombination have been identified in recombination nodules, and there is a strong correspondence between the number and distribution of late nodules and the number and distribution of crossovers. Moreover, meiosis-specific versions of proteins involved in mismatch DNA repair (discussed in Chapter 5) are also located in late nodules, where they help to resolve recombination intermediates as stable crossovers.

The occurrence of crossovers has enabled geneticists to map the relative positions of genes on chromosomes, as we now explain. Such maps have been crucial in the cloning of human disease genes.

Genetic Maps Reveal Favored Sites for Crossovers

On average, a human chromosome participates in two or three crossover events during meiosis, and every chromosome participates in at least one. Thus, whereas two genes very close to each other on a chromosome almost always end up together in the same gamete after meiosis, two genes located at the opposite ends of a chromosome are no more likely to end up together than are genes located on different chromosomes. One can therefore determine whether two genes—a gene with a mutant form causing congenital deafness, for example, and a second gene with a mutant form causing muscular dystrophy—are located close together on the same chromosome. This is done by measuring the frequency with which a child inherits the mutant forms of both genes from a parent that carries one mutant and one nonmutant version of each of them. If the two mutant genes are on different chromosomes, one will be inherited without the other 50% of the time, as chromosomes are independently segregated at meiosis. The same result is expected, however, if the two mutant genes are far apart on the same chromosome, as one or more crossover events will separate them at meiosis. To determine whether genes are on the same chromosome and, if so, how close they are to one another, human geneticists measure the frequency of coinheritance of many genes in large numbers of families. In this way, they can discover not only the neighbors of a particular gene but also the neighbors of the neighbors and thereby work their way down an entire chromosome. By this means, they have defined 24 linkage groups, one corresponding to each human chromosome (22 autosome pairs plus 2 sex chromosomes).

Using such measurements, geneticists have constructed detailed genetic maps of the entire human genome, in which the distance between each pair of neighboring genes is displayed as the percentage recombination between them. The standard unit of genetic distance is the centimorgan (cM), which corresponds to a 1% probability that two genes will be separated by a crossover event during meiosis. A typical human chromosome is more than 100 centimorgans long, indicating that more than one crossover is likely to occur on a typical human chromosome.

Another way to construct a genetic map is to measure the coinheritance of short DNA sequences (called DNA markers) that differ between individuals in the population—that is, that are polymorphic (see p. 464). Genetic maps constructed in this way have two advantages over genetic maps constructed by tracing the phenotypes of individuals that inherit mutant genes. First, they can be more detailed, as there are large numbers of DNA markers that can be measured. Second, they can reveal the real distance in nucleotide pairs between the markers, so that genetic distances in centimorgans can be compared directly with true physical distances along a chromosome.

A direct comparison of genetic and physical distances on part of a budding yeast chromosome is shown in Figure 20-14. As the entire DNA sequence of this organism's genome is known, the physical map indicates the true distances between the DNA markers. The regions of the genetic map that are expanded in comparison with the physical map indicate recombination “hotspots,” where crossovers during meiosis occur with an unusually high frequency. Regions that are contracted indicate recombination “coldspots,” where crossovers occur with unusually low frequency. Human genetic maps show similar expansions and contractions. A likely explanation for the hotspots is that they contain an abundance of sites where the DNA helix is cut by the meiotic endonuclease (Spo11) that creates the double-strand DNA breaks that begin the recombination process (see Figure 5-56).

Figure 20-14. Comparison of the physical and genetic maps of part of chromosome I in budding yeast.

Figure 20-14

Comparison of the physical and genetic maps of part of chromosome I in budding yeast. The DNA markers shown are various genes. A indicates a region where the genetic map is contracted owing to decreased frequency of crossing-over. B indicates a region (more...)

Meiosis Ends with Two Successive Cell Divisions Without DNA Replication

Prophase I can occupy 90% or more of the time taken by meiosis. Although it is traditionally called prophase, it actually resembles the G2 phase of a mitotic cell division. The nuclear envelope remains intact and disappears only when the meiotic spindle begins to form, as prophase I gives way to metaphase I. After prophase I is completed, two successive cell divisions follow without an intervening period of DNA synthesis. These divisions produce four cells from one and bring meiosis to an end (see Figure 20-7).

Meiotic division I is far more complex and requires much more time than either mitosis or meiotic division II. Even the preparatory DNA replication during meiotic division I tends to take much longer than an ordinary S phase, and cells can then spend days, months, or even years in prophase I, depending on the species and on the gamete being formed (Figure 20-15).

Figure 20-15. Comparison of times required for each of the stages of meiosis.

Figure 20-15

Comparison of times required for each of the stages of meiosis. (A) Approximate times for a male mammal (mouse). (B) Approximate times for the male tissue of a plant (lily). Times differ for male and female gametes (sperm and eggs, respectively) of the (more...)

When meiotic division I ends, nuclear membranes re-form around the two daughter nuclei, and the brief interphase of division II begins. During this period, the chromosomes may decondense somewhat, but usually they soon recondense and prophase II begins. (Because there is no DNA synthesis during this interval, in some organisms the chromosomes seem to pass almost directly from one division phase into the next.) Prophase II is brief: the nuclear envelope breaks down as the new spindle forms, after which metaphase II, anaphase II, and telophase II usually follow in quick succession. After nuclear envelopes have formed around the four haploid nuclei produced at telophase II, cytokinesis occurs, and meiosis is complete (see Figure 20-7).

As in mitosis, a separate set of kinetochore microtubules is present on each sister chromatid at metaphase II, and these two sets of microtubules extend in opposite directions (see Figure 20-11). In mitosis, however, the sister chromatids are glued together along their length, as well as at the centromere, and both types of contact are released at the start of anaphase. In meiosis, by contrast, the sister chromatids come apart in two steps—their arms have separated at anaphase I, while their centromeres remain attached, separating only at anaphase II (see Figures 20-7 and 20-11).

The principles of meiosis are the same in plants and animals and in males and females. But the production of gametes involves more than just meiosis, and the other processes required vary widely among organisms and are very different for eggs and sperm. We shall focus our discussion of gametogenesis mainly on mammals. As we shall see, by the end of meiosis a mammalian egg is fully mature, whereas a sperm that has completed meiosis has only just begun its differentiation. Before discussing these gametes, however, we consider how certain cells in the mammalian embryo become committed to developing into germ cells and how these cells then become committed to developing into either sperm or eggs, depending on the sex of the individual.


The formation of both eggs and sperm begins in a similar way, with meiosis. In this process two successive cell divisions following one round of DNA replication give rise to four haploid cells from a single diploid cell. Meiosis is dominated by prophase of meiotic division I, which can occupy 90% or more of the total meiotic period. As it enters this prophase, each chromosome consists of two tightly joined sister chromatids. The two replicated homologs present in each diploid nucleus then pair to form a bivalent, consisting of four chromatids. Chromosomal crossover events occur during this time. Each results in the formation of a chiasma, which helps hold each pair of homologs together during metaphase I. Crossing-over has an important role in reassorting genes during gamete formation, and it allows geneticists to map the relative positions of genes on chromosomes. The pairing of homologs culminates in the formation of a synaptonemal complex, which somehow serves to spread out the crossover events along the chromosomes. At anaphase of the first meiotic cell division, the arms of the sister chromatids suddenly become unglued, causing one member of each chromosome pair, still composed of a pair of sister chromatids linked at their centromeres, to be distributed to each daughter nucleus. A second cell division cycle, without DNA replication, then rapidly ensues; in anaphase II, each sister chromatid separates from its sister and is segregated into a separate haploid nucleus.

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By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2002, Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter; Copyright © 1983, 1989, 1994, Bruce Alberts, Dennis Bray, Julian Lewis, Martin Raff, Keith Roberts, and James D. Watson .
Bookshelf ID: NBK26840