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CHAPTER 45

Meiosis

M eiosis (from the Greek, meaning reduction) is a chromosomes from the two parents in each gamete,
specialized program of two coupled cell divisions used and recombination between parental chromosomes
by eukaryotes to maintain the proper chromosome produces novel chromosomes. It works like this.
number for the species during sexual reproduction. It During meiosis, one round of DNA replication and two
also generates novel combinations of genes. Meiosis is rounds of chromosome segregation reduce the number
an ancient process that occurs in virtually all eukaryotes, of chromosomes from 2n to 1n. Each haploid gamete
including the animal, fungal, and plant kingdoms, and is is endowed with a random set of the homologous
thought to have been present in the last eukaryotic chromosomes from the two parents. Prior to meiosis
common ancestor. I the chromosomes duplicate (just like mitosis) (Fig.
Sexually reproducing organisms are typically diploid, 45.1A), but during the first round of segregation (Fig.
with pairs of homologous chromosomes, the two 45.1C) the duplicated chromatids remain paired and the
highly similar but nonidentical copies of each chromo- homologous chromosomes separate randomly between
some, one inherited from each parent. The number of the two daughter cells. Thus each daughter cells ends up
chromosomes is halved during meiosis to form haploid with just one of each pair of homologous chromosomes.
gametes carrying just one set of chromosomes. The This differs from mitosis where the duplicated chroma-
subsequent fusion of male and female gametes restores tids separate, so both daughter cells get the full set of
the diploid chromosome number. This pairing and sub- homologous chromosomes from both parents. During
sequent separation of homologous chromosomes is meiosis II the duplicated chromatids separate and are
made possible by genetic recombination, which occurs partitioned equally between the two daughter cells.
during the lengthy and complex prophase of the first Equally important, homologous chromosomes exchange
meiotic division. DNA sequences during meiotic prophase I, generating
Each human somatic cell has 23 pairs of chromosomes novel chromosomes.
(46 in all). Females have 23 homologous pairs, while The unique segregational events of meiosis usually
males have 22 autosomal pairs and two different sex occur in the first division, termed meiosis I (Figs. 45.1
chromosomes that share a region of homology known and 45.2). Because it culminates in daughter cells carry-
as the pseudoautosomal region. One of each pair is ing just one set of chromosomes instead of two, meiosis
contributed by each parent in the egg and sperm, respec- I is also known as the reductional division. The second
tively. The number of chromosome pairs, 23, is known division, meiosis II, is similar in most respects to mitosis:
as the haploid chromosome number. In animals, the sister chromatids segregate, and the number of chromo-
only haploid cells are gametes (sperm and eggs). At fer- somes remains the same (Box 45.1; see also Chapter 44).
tilization, haploid gametes fuse to form a zygote, restor- Meiosis II is called the equational division.
ing the diploid chromosome number of 46. In plants,
the haploid phase is represented by gametophytes, Meiosis: An Essential Process for
which produce ovules and pollen. In most fungi, such
Sexual Reproduction
as yeasts, haploid and diploid forms are alternate phases
of the life cycle, and both can propagate by mitosis. Sexual reproduction is an important survival strategy
Meiosis changes the genetic makeup of offspring that offers organisms an accelerated mechanism for alter-
relative to parents in two ways: the first round of ing the genetic makeup of offspring. Without meiosis,
meiotic segregation produces novel combinations of there would be no sex, because fusion of diploid gametes

779
780 SECTION X n Cell Cycle

Preparation for meiosis (This step duplicates each chromatid)

A a Centromere Fused sister


centromeres
B b

Premeiotic Meiotic
Two pairs of S phase prophase
homologous
chromosomes

Meiotic prophase (Recombination drives pairing of homologous chromosomes and produces novel chromosomes)
Recombination Chiasmata
nodules
A a A
b a
Meiosis I
B
B b

Leptotene stage Bouquet Zygotene stage Pachytene stage Diplotene stage Diakinesis stage

Meiosis I (Homologous chromosomes randomly separate from one another producing haploid progeny)

Chiasmata A
A b A b
b B
a B B Meiosis I a Meiosis II
a
Interphase
(no S phase)
Metaphase I Anaphase I

Meiosis II (Sister chromatids separate producing one or more gametes)

b B
a

Prophase II Metaphase II Anaphase II Haploid gametes


FIGURE 45.1 OVERVIEW OF THE PHASES OF MEIOSIS. Shown are important structures and the outcome of each stage for a homologous
pair of metacentric chromosomes (A, a) and a homologous pair of telocentric chromosomes (B, b).

would double the number of chromosomes in the chromosomes must first find each other. They do this by
progeny at every generation. undergoing reciprocal recombination (crossover) events
Meiosis I produces random combinations of homolo- that then hold them together until anaphase of meiosis
gous maternal and paternal chromosomes. For each I. Chromosomes and the genes they carry vary hugely
pair of homologs, orientation on the spindle is random between individuals. In humans an average genome
during meiosis I (ie, each homolog has two equivalent varies from the reference genome (see Chapter 7) at
options for the direction to migrate). Thus, for humans 4 to 5 106 sites. These include not only polymorphisms
(with 23 pairs of homologous chromosomes), each (differences of single base pairs), but also thousands
gamete has one of 223 (more than 8 million) possible of longer insertions, deletions, and rearrangements.
complements of maternal and paternal chromosomes. Recombination events that result in a crossover and
This process does not create new versions of genes, exchange chromosomal segments produce new chromo-
but it guarantees the offspring will have novel combi- somes that are a patchwork of segments from the
nations of subtly different (due to polymorphisms) maternal and paternal homologs. The combined effects
chromosomes. of recombination and random assortment of homologs
Meiosis I also produces novel versions of genes and in meiosis I yields a vast number of genetically different
chromosomes by recombinational exchange of DNA gametes. This genetic diversity increases the ability of
segments between homologs. This occurs because to eukaryotic populations to adapt to changing environ-
segregate from one another, each pair of homologous mental conditions.
CHAPTER 45 n Meiosis 781

Spindle
A. Metaphase I Spindle C. Late Spindle pole
Paired sister kinetochores
pole anaphase I pole
being pulled toward poles

X
D. Telophase I
X

Chiasma Chiasma
Spindle
pole Paired sister kinetochores
moving toward poles

B. Early Spindle
anaphase I pole

Spindle Spindle
pole pole Spindle
pole

FIGURE 45.2 FIRST MEIOTIC DIVISION STAGES FROM THE GRASSHOPPER PYRGOMORPHA CONICA (2N IN MALES = 18
AUTOSOMES + 1 X CHROMOSOME). A, Metaphase I. B, Early anaphase I. C, Late anaphase I. D, Telophase I spermatocytes stained with
lactopropionic orcein. All chromosomes are telocentric (see Fig. 7.2). Seven bivalents shown in the metaphase I spermatocyte have a single
chiasma, whereas the two bivalents at the far right and far left have two chiasmata. The sex chromosome (X) remains unpaired and moves to a
single spindle pole. (Courtesy Jos A. Suja and Julio S. Rufas, Universidad Autnoma de Madrid, Spain.)

as chromatin structures called chiasmata (singular:


The Language of Meiosis
chiasma, from the Greek, meaning X-shaped cross).
Meiosis has a language of its own, characterized by a Segregation of homologous chromosomes in meiosis
number of unusual terms, and is easiest to understand I differs from the segregation of sister chromatids during
by focusing on the essential biological processes that are mitosis (Box 45.1), because the paternal and maternal
involved. This reduces the process to only three essential homologous chromosomes segregate randomly to the
key terms: pairing, homologous recombination, and two daughter cells. When homologs orient at the meta-
segregation. This chapter discusses each step in detail, phase plate of the meiosis I spindle, centromeres belong-
so they are defined only briefly here. ing to the two sister chromatids are fused to form a single
Pairing is a two-step alignment of homologous chro- kinetochore that binds microtubules. Cohesion between
mosomes with one another in the nucleus. In alignment, chromosome arms distal to chiasmata (ie on the other
corresponding DNA sequences on the homologous side from the centromere; Figs. 45.2 and 45.10) keeps
chromosome find each other among the billions of base homologous chromosomes paired with one another
pairs of DNA in the nucleus. In many organisms, early until anaphase of meiosis I, counteracting the bipolar
events of recombination drive the homologous pairing pulling force of the spindle on the homologs (Fig. 45.2).
process. In the second stage, synapsis, the paired At anaphase I the distal cohesion is released from chro-
homologous chromosomes become intimately aligned mosomes allowing the chiasmata to separate, and the
along their entire lengths with one another separated two sister chromatids (at least one of which has under-
by approximately 100 nm. A specialized scaffolding gone a crossover exchange) move as a single unit toward
structure called the synaptonemal complex mediates the same spindle pole while the sister chromatids from
this process. other parent move to the other daughter cell. As a result,
Homologous recombination results in physical the two daughter cells produced in meiosis I have a
exchange of DNA between homologous chromosomes haploid number of chromosomes derived randomly from
(a crossover event) and is a key determinant of chromo- the two parents, each with two sister chromatids. Each
some behavior during meiotic prophase. Recombination of the four daughter cells produced in meiosis II has one
drives the pairing process in many organisms and can sister chromatid for each homologous chromosome (ie,
occur without synapsis under certain circumstances. half the number of chromatids as there are chromosomes
Crossover recombination sites are detected by microscopy in somatic cells).
782 SECTION X n Cell Cycle

breaks using the corresponding DNA sequence on a


BOX 45.1 Important Differences Between Meiosis
sister chromatid as a template. Meiotic cells usually use
and Mitosis
a homologous chromosome. The mechanism for this
Meiosis involves two cell divisions. The two meiotic difference in selectivity is not yet fully understood.
divisions are preceded by a round of DNA replication. Spo11, together with essential accessory proteins,
There is no DNA replication between meiosis I and generates programmed double-strand DNA breaks early
meiosis II. during meiotic prophase (Fig. 45.3). Similar to type II
The products of meiosis are haploid. The products DNA topoisomerases (see Fig. 8.16), Spo11 cleaves both
of mitosis are diploid. DNA strands in a reaction that produces a covalent
The products of meiosis are genetically different. linkage between a tyrosine of the enzyme and the cleaved
After recombination and random assortment of homologs
phosphodiester backbone. However, Spo11 does not
in meiosis I, the sister chromatids that segregate in meiosis
reseal the breaks; instead it remains attached to one
II are different from each other. In normal mitosis, sister
chromatids are identical. strand of DNA at the broken end. In mice, Spo11 creates
Prophase is longer in meiosis I. Proper orientation about 10-fold more DNA breaks than ultimately recom-
and segregation of homologous chromosomes is achieved bine to produce reciprocal DNA exchanges between
thanks to the pairing, synapsis (synaptonemal complex homologous chromosomes or crossovers. Repair of
formation), and recombination that occur in a lengthened Spo11-mediated DNA double-strand breaks can also
prophase during meiosis I. In humans, prophase in mitosis result in noncrossover events known as gene conver-
takes an hour, whereas meiotic prophase lasts many days sions (Box 45.2 and Fig. 45.3IJ).
in males and many years in females. DNA double-strand breaks generated by Spo11 are
Recombination is increased in meiosis. The required for the initial lengthwise alignment of homolo-
recombination rate is 100- to 1000-fold higher in prophase
gous chromosomes in many organisms, including mice,
I of meiosis than in mitosis. The process has two main
plants, and yeast. In mice lacking Spo11, recombination
consequences: the formation of chiasmata and the intro-
duction of genetic variation. Chiasmata are structures that is not initiated, and synapsis, if it occurs at all, is aberrant,
physically link the homologous chromosomes after cross- often involving nonhomologous chromosomes (Fig.
over and play an essential role in meiotic chromosome 45.4). Gametes in these mutant mice die by apoptosis
segregation. early in meiotic prophase. Spo11-induced double-strand
Kinetochore behavior differs in meiosis. During breaks are not required for synapsis of homologous
meiosis I, kinetochores of sister chromatids attach to chromosomes in the nematode Caenorhabditis elegans
spindle microtubules emanating from the same pole. and the fruit fly Drosophila melanogaster. How these
Homologous kinetochore pairs connect to opposite poles. organisms pair their homologs without recombination is
In mitosis and meiosis II, sister kinetochores attach to still mysterious.
spindle microtubules coming from opposite poles.
Once the DNA double-strand breaks are produced,
Chromatid cohesion differs in meiosis. Sister
the MRN (Mre11/Rad50/Nbs1) endonuclease nicks the
chromatid cohesion is essential for orientation of bivalents
(paired homologous chromosomes) on the metaphase single-stranded DNA, releasing Spo11. The DNA ends
I spindle. During anaphase of meiosis I, cohesion is that lost Spo11 then undergo further processing, as Exo1
destroyed between sister chromatid arms, and chiasmata exonuclease, chews back the 5 strands of the double
are released to allow segregation of homologs. Cohesion helix (a process called resection) leaving single-stranded
at sister centromeres persists until the onset of anaphase DNA tails with 3 termini (Fig. 45.3C; see also Fig. 43.14).
II, when it is lost to permit segregation of sisters. In pro- The MRN and Exo1 nucleases also function in somatic
metaphase of meiosis II, sister chromatids are joined only DNA repair.
by the centromeres, whereas at the beginning of mitotic Next, the Rad51 and Dmc1 proteins drive a search of
prometaphase, sisters are joined all along the arms. the 3 single-stranded DNA tails for complementary DNA
sequences of the other chromosomes. Rad51 and Dmc1
are related to the Escherichia coli RecA protein used for
homologous recombination in bacteria. Rad51 and Dmc1
coassemble along 3 single-stranded DNA tails and use
Recombination
adenosine triphosphate (ATP) hydrolysis to catalyze a
Although meiotic recombination is similar to the process strand exchange reaction with an intact homologous
of homologous recombinational repair of double-strand DNA duplex. The Rad51-and-Dmc1-decorated nucleo-
DNA breaks in somatic cells (review Box 43.1 and Fig. protein filament disrupts the targeted homologous
43.14 as a prelude to studying meiotic recombination), double helix, displacing one of the two DNA strands.
the two processes differ in two respects. First, meiotic This allows formation of new Watson-Crick base pairs
cells use a specialized enzyme called Spo11 to create between the invading 3 single-stranded DNA and the
double-strand DNA breaks on purpose. Second, somatic complementary strand of the target DNA. Following
cells with replicated chromosomes usually repair DNA strand invasion and exchange, new DNA synthesis
5' 3'
A Cohesin
3' 5'
5' 3'
3' 5' Paired homologous
5' 3' chromosomes
3' 5'
5' 3'
3' 5'

Double-strand break Spo11 cuts DNA, remaining


covalently attached to one strand
B

Red enzymes are


meiosis specific Spo11 released by MRN complex (Rad50/
5' to 3' resection
Exo1 resects one DNA strand Mre11/Nbs1)
Green enzymes also
function in somatic C
repair

Initial strand invasion, Rad51 + Dmc1


DNA synthesis
D

Second end capture,


synthesis, ligation Strand displacement
E H

Formation of double
Holliday junction Strand annealing

F I

Holliday
junction

Holliday junction
= Resolvase cutting sites Synthesis, ligation
resolution

G J

+ +

Crossover Noncrossover

FIGURE 45.3 EVENTS OF RECOMBINATION. Recombination occurs between homologous chromosomes rather than between sister
chromatids. A, Paired homologous chromosomes. Sister chromatids are held tightly together by cohesin, shown here schematically as hoops.
B, Spo11 makes a double-strand break, remaining attached to the DNA. C, Removal of Spo11 and resection of the break. D, First strand invasion.
At this point, the pathway splits in two, one outcome leading to a crossover and the other to a noncrossover. Crossover pathway: E, The
second resected strand establishes base-pairing interactions with the displaced DNA strand of its homologous partner. New DNA synthesis fills
the gaps. F, The resulting molecule contains a double Holliday junction in which the DNA is fully base-paired (see Fig. 43.14B). If the resolvase
(nuclease) cuts the double Holliday junction asymmetrically as shown (ie, one vertical and one horizontal cut), the result is a crossover (G). If the
cuts are symmetrical, a noncrossover molecule is produced. Noncrossover pathway: H, In most cases, the invading DNA, strand is ejected
prior to stabilization and formation of a double Holliday junction. I, DNA gap-filling and ligation yield a noncrossover chromosome (J).
784 SECTION X n Cell Cycle

BOX 45.2 Brief Overview of Genetic Terminology

A comprehensive introduction to the field of genetics is 50% of the time as a result of the random distribution of
beyond the scope of this text. However, here are a number chromosomes to the two spindle poles. If they are on the
of terms used by geneticists that will assist in the understand- same chromosome, they will be linked to one another unless
ing of the discussion of genetic recombination and its role the chromosome undergoes a genetic recombination event
in meiosis (also see Box 6.1). between them. The greater the separation of two markers
The genotype of an organism is the combination of along one chromosome, the more likely it is for such an
genes present on the chromosomes of that organism. The intervening recombination event to occur.
phenotype is the physical manifestation of the action of Two types of recombination events occur during meiosis
these gene products (ie, the appearance and macromolecular (Fig. 45.3). The first of thesenoncrossover events (fre-
composition of the organism). In discussing recombination, quently referred to as gene conversion)may involve the
scientists typically refer to the presence or absence of spe- loss of one or more genetic markers. Noncrossover events
cific genetic markers. Each genetic marker is a particular are the most common outcome of the programmed double-
DNA sequence in or around a gene that can be monitored strand DNA breaks that occur during leptotene. They are
by examining the phenotypes of the cells that carry it. thought to involve the invasion of a double helix by a region
A genetic marker might be the presence of a functional of single-stranded DNA with complementary sequence but
gene, a mutation with altered activity, or simply a polymor- then ejection of this sequence before assembly of a Holliday
phism of DNA sequence that has no known functional junction and completion of recombination.
consequence. The second type of recombination eventcrossing
A haploid organism has one copy of each chromosome. overinvolves the physical breakage and reunion of DNA
A diploid organism has two homologous copies of each strands on two different chromosomes, typically producing
chromosome. A diploid organism that is homozygous for a a balanced exchange of DNA sequences. This is what most
particular genetic marker has the same sequence of that people think of as recombination. In recombination by cross-
particular region of the DNA on both the maternal and ing over, the makeup of genetic markers remains constant;
paternal homologous chromosomes. A heterozygous organ- it is the linkage between different markers that changes.
ism has different forms of the genetic marker on the two The normal separation of chromosomes or chromatids is
homologous chromosomes. Although the physical events of referred to as disjunction (disjoining). Mistakes in this sepa-
genetic recombination occur in both homozygotes and het- ration are referred to as nondisjunction. Nondisjunction in
erozygotes, they are most readily detected in the latter. meiosis I and II results in the production of gametes with
Two genetic markers located on different chromosomes either too many or too few chromosomes, a condition
will separate from one another in the anaphase of meiosis I known as aneuploidy.

restores sequences that may have been lost or damaged


A B
at the position of the original DNA double-strand break.
Mutants lacking Dmc1 are defective in homologous
chromosome pairing and interhomolog recombination.
As a result, Dmc1 is thought to facilitate the search for
homologous chromosomes as a DNA repair template,
rather than sister chromatids as in somatic DNA repair.
Rad51p and Dmc1p are found in structures called
early recombination nodules that are distributed
along the chromosome axes early in meiosis (Fig. 45.9).
Dmc1 functions only in meiosis, but Rad51 has other
essential functions.
It is now believed that noncrossover events arise
primarily from recombination intermediates that involve
FIGURE 45.4 PAIRING OF HOMOLOGOUS CHROMOSOMES
IS SEVERELY DISRUPTED IN THE SPO11 MUTANT. Pachytene
a relatively transient single strand invasion of the
chromosomes from wild-type mice (A) and mice in which the Spo11 homologous chromosome followed by restorative DNA
gene has been disrupted (B). SYC3 (axial elements) and centromeres synthesis and disassembly of the joint molecule interme-
are red. SYCP1 (in transverse filaments, which are seen only when diate. Crossovers, on the other hand, are thought to arise
synapsis has occurred) is green. (From Baudat F, Manova K, Yuen JP, predominantly through a pathway that involves stable
etal. Chromosome synapsis defects and sexually dimorphic meiotic
progression in mice lacking Spo11. Mol Cell. 2000;6:989998.)
branched intermediates known as Holliday junctions
(Fig. 45.3FG; see also Fig. 43.14B), which are then
cleaved by resolvases such as Gem1 to form (predomi-
nantly) crossover products.
CHAPTER 45 n Meiosis 785

Most sexually reproducing organisms depend on Tracking the Homologous Chromosomes


recombination during meiosis to produce haploid
gametes, but fruit flies and yeast have other systems for
Through the Stages of Meiotic Prophase I
segregating homologs in meiosis I. These mechanisms, Pairing and recombination of homologous chromosomes
collectively known as achiasmate segregation, allow take place during prophase of meiosis I. Five stages of
the segregation of chromosomes that have not under- meiotic prophase are used to describe the process: lep-
gone crossover recombination. One model for the achi- totene, zygotene, pachytene, diplotene, and diakinesis
asmate segregation in flies proposes that nonrecombined (Fig. 45.1B).
chromosomes remain paired at the end of meiotic pro- Leptotene (from the Greek, meaning thin ribbon)
phase owing to stickiness of heterochromatin and, as a starts with the first visible condensation of the chromo-
result, segregate properly during anaphase I of meiosis. somes. Paired sister chromatids become visible as linear
In a rare but notable example, the spermatocytes of D. arrays of loops flanking a single dense protein-containing
melanogaster males do not recombine at all, yet still axis (Fig. 45.5AB). This axis consists of proteins that
segregate their chromosomes happily during meiosis I. play a role in mitotic chromosome structure as well as
This might be regarded as a cruel joke of evolution by proteins specialized for meiotic chromosomes. For
those students who find all the Greek terms of meiotic example, the cohesin complex with several specialized
nomenclature to be daunting. However, meiosis without meiosis-specific subunits is a prominent component of
recombination is clearly the exception, and in most this axial structure (see Fig. 8.18). According to recent
species meiosis depends on recombination in both males models, recombination begins during leptotene with the
and females. formation of DNA double-strand breaks. By the end of

A. Early leptotene C. Early zygotene E. Pachytene

Sex
chromosomes

B. Late leptotene D. Late zygotene F. Diplotene


Chiasma

FIGURE 45.5 IMMUNOFLUORESCENCE IMAGES OF PROPHASE I SUBSTAGES IN MOUSE SPERMATOCYTES. These images
demonstrate the pairing and synapsis of homologous chromosomes revealed by visualizing the synaptonemal complex proteins SYCP3 (a
component of the axial elements [red]) and SYCP1 (a component of the transverse filaments that is present only when homologs are synapsed
[green]). Centromeres are blue. (Courtesy Paula Cohen, Cornell University, Ithaca, NY.)
786 SECTION X n Cell Cycle

A B C D E F G

0 hr 2 hr 8 hr

I Telomere

Nuclear
envelope

FIGURE 45.6 CHROMOSOMAL MOVEMENTS DURING EARLY MEIOTIC PROPHASE. AG, Pairing of homologous chromosomes during
leptotene in the ascomycete Sordaria. Scale bar is 1 m in AF and 5 m in G. AB, In early leptotene, homologous chromosomes (visualized
in panels AF by electron microscope reconstructions of serial-sectioned nuclei) are not yet aligned with one another. CE, In mid-leptotene,
regions of some homologs begin to align. (In panel D, only the telomeres have aligned. In panel E, the pair of homologs is fully aligned.) F, The
alignment of homologs is complete by late leptotene. G, The alignment of homologs also can be seen by light microscopy using Spo76-GFP, a
component of the chromosome axes. HI, Stages of formation of the bouquet arrangement in rye. H, Telomeres (green) were detected in nuclei
by in situ hybridization (see Fig. 8.10) after 0, 2, and 8 hours in culture. Chromatin is red. I, Three-dimensional models of the nuclei (nuclear
periphery [red dots], telomere position [green stars]). (AG, Modified from Tesse S, Storlazzi A, Kleckner N, etal. Localization and roles of Ski8p
protein in Sordaria meiosis and delineation of three mechanistically distinct steps of meiotic homolog juxtaposition. Proc Natl Acad Sci U S A.
2003;100:1286512870. Copyright 2003 National Academy of Sciences. HI, Modified from Carlton PM, Cowan CR, Cande WZ. Directed motion
of telomeres in the formation of the meiotic bouquet revealed by time course and simulation analysis. Mol Biol Cell. 2003;14:28322843.)

leptotene, homologous chromosomes are aligned loosely the chromosomes parallel to each other. In C. elegans
about 400 nm apart (Fig. 45.6DG). special chromosome regions known as pairing centers
During leptotene, one or both telomeres attach to the mediate chromosome movement instead of telomeres;
inner surface of the nuclear envelope and move actively in budding yeast, the telomeres are linked to actin instead
around the nuclear surface until they coalesce near the of microtubules, and D. melanogaster may have lost
centrosome (spindle pole body in yeasts [Fig. 45.6]). such a mechanism altogether.
These movements and clustering of telomeres depend During the transition from leptotene to the zygotene
on cytoplasmic microtubules. Telomeres are linked to (Greek, yoke ribbon) stage of prophase, clustering
microtubules through a pair of nuclear envelope proteins of chromosome ends at the nuclear envelope reaches
known as the LINC (linker of nucleoskeleton and cyto- its peak, with the bouquet arrangement of chromo-
skeleton) complex (see Fig. 9.8). Telomere clustering somes. During this stage homologous chromosomes
peaks at the leptotenezygotene transition with the begin to achieve their maximal alignment as well,
chromosomes radiating into the nuclear interior like a through the initiation of synapsis (Fig. 45.5CD). Syn-
bouquet of flowers, hence the name bouquet stage. apsis involves the assembly of the axial element. This
Bouquet formation is a nearly universal feature of this protein scaffold forms part of the synaptonemal
phase of meiosis and the movements of tethered telo- complex when pairing is complete.
meres help homologs find each other through physical In pachytene (from the Greek, meaning thick
alignment. Thus, telomere clustering per se may not be ribbon), synapsis is complete, with the homologous
the goal of this movement. The details vary among dif- chromosome axes joined together along their lengths
ferent organisms. In fission yeast dynein motors and by synaptonemal complexes (Fig. 45.5E). During pachy-
microtubule dynamics in the cytoplasm move the telo- tene, crossover-designated recombination intermediates
mere cluster from one end of the cell to the other every mature into Holliday junction-containing structures
10 minutes or so. These horsetail movements stretch within the context of the full-length synaptonemal
CHAPTER 45 n Meiosis 787

complex. The final resolution of these recombination The earliest pairing events in meiosis involve a ten-
intermediates into crossovers occurs close to the time of dency of homologous chromosome territories to move
synaptonemal complex disassembly, dispersal of the together in the nucleus even before leptotene chromo-
bouquet of chromosomes and exit from pachytene. The some condensation. The mechanism is unknown. As
crossovers then mature into structures called chiasmata double-strand breaks created by Spo11 initiate the
that link homologous chromosomes through meiosis I recombination pathway during leptotene, the condensing
metaphase. homologous chromosomes align with one another at a
Early in diplotene (from the Greek, meaning double distance of about 400 nm (Figs. 45.6 and 45.7). Genetic
ribbon), the synaptonemal complex disassembles, analysis in budding yeast revealed that mutants defective
telomeres detach from the nuclear membrane, and chro- in the earliest stages of recombination are also defective
mosomes begin to condense in preparation for division in homolog pairing.
(Fig. 45.5F). The duplicated sister chromatids remain
closely associated, and chiasmata hold the homologous Replicating DNA
Interphase Sister Sister
chromosomes together, although their axes tend to drift chromatid 3 chromatid 4
Sister
apart in the absence of synaptonemal complex. This chromatid 1 Sister
chromatid 2 Cohesin
part of meiotic prophase may last for days or years,
depending on the sex and organism (up to 45 years or
more in female humans).
Oocytes (immature eggs) actively transcribe their Sister chromatids
linked by cohesin
chromosomes during diplotene, as they store up materials in premeiotic
for use during the first few divisions of embryonic devel- S phase
opment. Transcription can be so active that DNA loops
are massively coated with nascent RNA transcripts whose Leptotene
associated proteins are visible by light microscopy in Initiation of
recombination
oocytes of most animals (except mammals). Chromo- Pairing of Chromatid
somes at this stage are known as lampbrush chromo- homologous axis
somes (see Fig. 8.12). chromosomes
Diakinesis (from the Greek, meaning across move- Zygotene
ment) is the prometaphase of meiosis I. Following Assembling
central element of Synapsis
nuclear envelope breakdown, homologous chromo- synaptonemal complex
somes shorten and condense. At metaphase I, the biva-
lents (pairs of homologous chromosomes) are aligned Axial
Pachytene (lateral)
at a metaphase plate (Figs. 45.1, 45.2, and 45.12). The elements
two homologs (each a pair of tightly linked sister chro- Transverse
matids) are attached to opposite poles of the meiotic filaments
spindle, which applies force, attempting to pull them Central
apart. Cohesion of the arms distal to chiasmata resists element
these pulling forces. The homologs separate and move
to opposite spindle poles during anaphase I when the
cohesion along the chromosome arms is released. The Diplotene followed
sister chromatids move together to one pole, because by diakinesis
Chromatin
they remain linked by cohesion at their centromeres, Disassembling loops
synaptonemal
where the cohesion complex is protected by a shugoshin complex
protein (see later).
After telophase I, cells enter a brief interkinesis
Chiasma
during which there is no DNA replication. The second
Time

meiotic division is mechanistically similar to mitosis


except that the number of chromosomes is reduced by
half. Additionally, in the eggs of most female vertebrates,
meiosis is arrested at metaphase II until fertilization.

Pairing and Synapsis in More Detail


Pairing describes the side-by-side alignment of homolo-
gous chromosomes at a distance. Homologs are paired FIGURE 45.7 CHROMOSOMAL PAIRING IN MEIOTIC PRO-
in nonmeiotic (somatic) cells in a few organisms, such PHASE. Structural organization of homologous chromosomes and
as the fruit fly D. melanogaster, but not in vertebrates. synaptonemal complex during various stages of meiotic prophase.
788 SECTION X n Cell Cycle

The process of homolog alignment almost certainly events will mature into crossovers. By pachytene, a
involves the invasion of neighboring DNA duplexes by continuous synaptonemal complex assembles along the
single-stranded DNA complexed with Rad51 and Dmc1. full length of the aligned homologous chromosomes
Thus, recombination has important roles both in the (Fig. 45.5CE).
exchange of genetic material and in the mechanics of It was once thought that the synaptonemal complex
chromosome behavior during meiotic prophase. Recom- aligns homologous chromosomes in preparation for
bination is probably not the only factor driving homolog recombination, but it is now clear that homolog pairing
pairing, however. Pairing is reduced but not absent in and (in many organisms) the initiation of recombination
yeast meiotic cells lacking both Rad51 and Dmc1, and precedes synapsis. Thus, synapsis is a downstream
homologous chromosomes still pair in some systems that consequence of early steps in recombination in some
lack recombination (eg, certain D. melanogaster recom- well-studied organisms including yeast and mammals.
bination mutants), synaptonemal complex formation However, under certain artificial circumstances, even
(asynaptic mutants in yeast), or both (eg, normal D. nonhomologous chromosomes can undergo synapsis.
melanogaster males). Another longstanding model proposed that the synapto-
Homolog pairing initiated during leptotene be nemal complex promotes the resolution of crossover-
comes much more intimate during synapsis as the designated recombination intermediates. However, analysis
chromosomes are linked by transverse fibers to form of budding yeast mutants missing certain synaptonemal
the synaptonemal complex. This structure looks complex proteins indicates that the structure per se is
roughly like railroad tracks linked by transverse bands dispensable for the formation of crossovers and that the
(Figs. 45.7 and 45.8). Each of the two outer rails, 90 resulting chiasmata can hold homologous chromosomes
to 100 nm apart, is the axis of a pair sister chromatids. paired until anaphase of meiosis I.
They are traditionally termed lateral elements, but What then is the function of the synaptonemal
for the sake of simplicity, we refer to them as axial complex? One possibility is that it may have a key role
elements. Thin transverse filaments oriented perpen- in crossover interference (see later), which ensures that
dicular to the axial elements appear to connect homolog crossovers are distributed broadly across the genome.
axes to each other and to the central element (the Another interesting possibility is that the synap-
third rail). Synaptonemal complex formation begins tonemal complex communicates information about
during zygotene at a limited number of sites along the meiotic chromosomes (such as homolog alignment and
paired homologous chromosomes where recombination the formation of crossover-designated recombination

A B C

CE

LE
CE

FIGURE 45.8 ELECTRON MICROGRAPHS OF THE SYNAPTONEMAL COMPLEX. A, Low-magnification view of maize synaptonemal
complexes stained with silver. The lateral (LE) and central elements (CE) are clearly seen. B, A negatively stained cricket synaptonemal complex
following treatment with deoxyribonuclease (DNase). The central element (CE) and transverse filaments (arrow) are visible. C, A whole mount of
a silk moth zygotene chromosome. Cells in meiotic prophase were swollen and then lysed under gentle conditions with detergent. The chromo-
somes were then centrifuged onto thin carbon films so that they could be examined by electron microscopy. The axial elements are easily seen
on this chromosome. Chromatin loops radiate outward from both the unpaired axial elements and the paired lateral elements (where synapsis
has occurred). (A, Modified from Gillies CB. Electron microscopy of spread maize pachytene synaptonemal complexes. Chromosoma.
1981;83:575591. B, Modified from Solari AJ, Moses MJ. The structure of the central region in the synaptonemal complexes of hamster and
cricket spermatocytes. J Cell Biol. 1973;56:145152, copyright the Rockefeller University Press. C, From Rattner JB, Goldsmith M, Hamkalo BA.
Chromatin organization during meiotic prophase of Bombyx mori. Chromosoma. 1980;79:215224.)
CHAPTER 45 n Meiosis 789

intermediates) to the cell-cycle pathways that control Several protein components of the axial elements
progression through the substages of meiosis. (sister chromatid axes) have also been identified. One of
these, SYCP3, interacts with both the cohesin complex
(see Fig. 8.18) and Rad51p and Dmc1p. In SYCP3 knock-
Synaptonemal Complex Components out mice, the axial elements are much less prominent, and
Both genetic and biochemical approaches have identi- the axis of the condensed chromosome is about twofold
fied components of the synaptonemal complex. The longer. Other proteins of the synaptonemal complex,
budding yeast protein Zip1 (mammalian SYCP1) com- including SYCP1, do not assemble properly, and as a result
prises the transverse filaments oriented perpendicular to chromosomes in male germ cells lack chiasmata, are
chromosome axes in mature synaptonemal complex, unpaired, and cells die in pachytene/diplotene. Humans
between the axial elements (Fig. 45.9). Mammalian with mutations in genes for cohesin subunits lack chias-
SYCP1 and Zip1 both consist of an extensive coiled-coil mata, fail to complete meiosis, and are infertile.
flanked by two globular domains but lack amino acid
sequence similarity. Altering the length of the Zip1
coiled-coil changes the spacing between axial elements
Chiasmata
in the synaptonemal complex. Chiasmata are specialized chromatin structures that link
homologous chromosomes together until anaphase I
(Figs. 45.1 and 45.10). They form at sites where pro-
Leptotene SYCP3 + grammed DNA breaks generated by Spo11 undergo the
Paired sister SYCP2,
chromatids Cohesin full recombination pathway to generate crossovers.
Axial element It is not known how crossover events, which repre-
(chromosome axis)
sent exchanges of DNA sequence information, are turned
Chromatin loops into chiasmata. The ultrastructure of chiasmata remains
Time

Rad51, Dmc1 a mystery, but presumably each chiasma consists of two


Early recombination
nodule (may be site of
unperturbed sister chromatid arms intertwined with two
noncrossover events) recombinant arms in which the DNA molecules and their
SYCP1
associated protein structures have been spliced. This
Zygotene (yeast Zip1) DNA complex is held in place on the chromosome by
Synaptonemal complex
Zip2/Zip4, Zip3
(yeast synapsis
cohesion of the distal sister chromatid arms between the
assembles from initiation complex) chiasma and the telomeres. Chiasmata too close to telo-
site of crossover (late Mlh1/Mlh3,
recombination nodule)
Msh4/Msh5 meres can be unstable, presumably because the short
SYCE2, length of sister chromatid arms between them and the
TEX12
telomeres is insufficient for stable cohesion. This can
FIGURE 45.9 PROTEINS OF THE SYNAPTONEMAL COMPLEX.
lead to failure of chromosome segregation in meiosis.
Homologous chromosomes and synaptonemal complex showing the A single chiasma can link homologous chromosomes
locations of some protein constituents. together during meiosis I. Humans have 39 such arms

A B C Microtubules
Fused sister
kinetochores
Paired sister
chromatids
(maternal
homolog)
Distal cohesin
and Aurora B

Chiasma
Paired sister
AIR-2 chromatids
(paternal
Arrows point to chiasmata REC-8 REC-8 homolog)

FIGURE 45.10 BIVALENTS (PAIRED HOMOLOGOUS CHROMOSOMES) ARE HELD TOGETHER BY CHIASMATA AFTER DISAS-
SEMBLY OF THE SYNAPTONEMAL COMPLEX. A, Three diplotene bivalents from the grasshopper species Chorthippus jucundus are held
together by three (left), one (middle), and four (right) chiasmata. The middle cross-shaped bivalent is telocentric; the other two longer bivalents
are submetacentric. (For an explanation of the terminology, see Fig. 7.2.) Lactopropionic orcein staining. B, Caenorhabditis elegans chromosomes
at metaphase I. Aurora B kinase AIR-2 (red) is located distal to chiasmata. Cohesin subunit REC-8 (green) is all along the chromosomes.
C, Explanatory diagram. (A, Courtesy Jos A. Suja and Julio S. Rufas, Universidad Autnoma de Madrid, Spain. B, Courtesy Josef Loidl, Max
Perutz Labs, Vienna Biocenter, Austria.)
790 SECTION X n Cell Cycle

A. Normal B. Infertile male

SB
SB

FIGURE 45.11 ABNORMAL PACHYTENE CHROMOSOMES IN AN INFERTILE MALE. A, Normal pachytene chromosome spread from
a testis biopsy showing synaptonemal complexes (red), MLH1 foci (recombination sites [green]), and centromeres (blue). B, Abnormal pachytene
spread from an infertile patient containing one synaptonemal complex with an area of asynapsis and one synaptonemal complex with a gap
(arrows). SB, sex body (the paired X and Y chromosomes). (Courtesy Rene H. Martin, University of Calgary, Alberta, Canada.)

on the 23 pairs of homologous chromosomes, if one Cohesion and Chromosomal Movements


excludes the five acrocentric short arms, which do not
normally undergo crossovers. Remarkably, there is typi-
During Meiosis I
cally only one chiasma produced for most arms; human Chromosomes in mitosis achieve a dynamic alignment at
males typically have 46 to 53 chiasmata (Fig. 45.11). metaphase as a result of a balance of forces in the spindle.
Even more remarkably, that single chiasma can hold In mitosis, the two kinetochores of the sister chromatids
homologous stably paired for over 40 years in human are attached to microtubules emanating from opposite
females, yet still be released on schedule when the spindle poles, and each chromatid is pulled toward the
oocyte matures into an egg. pole that its kinetochore faces (Fig. 45.12A).
Only a small fraction of DNA breaks formed by Spo11 In meiosis I, homologs linked by chiasmata (called
mature into full crossovers, because a mechanism called bivalents) are balanced at the metaphase plate, but the
crossover interference decreases the likelihood that organization differs in three important ways from mitosis.
DNA breaks near a crossover-designated recombination First, the two kinetochores of the sister chromatids are
event will also become crossovers. This interference fused and act as a single unit oriented toward one spindle
tends to spread crossovers apart across the genome. If pole. The structure of the meiosis I kinetochore is most
all breaks had an equal probability of forming crossovers, easily explained if the two kinetochores are each rotated
small chromosomes might be left without a crossover in 90 degrees toward one another relative to their position
a significant fraction of meiotic nuclei if large chromo- on mitotic chromosomes and then fused (Fig. 45.12A).
somes used all of the structural components necessary In yeast, this coorientation of sister kinetochores requires
to form crossovers and chiasmata. the presence of a meiosis-specific kinetochore protein
Crossover interference has been defined genetically spo13 (meikin in vertebrates)that associates with
for almost 100 years, but its mechanism is not certain. sister kinetochores from pachytene until anaphase of
Interference may be mediated by the synaptonemal meiosis I. Spo13/meikin recruits polo kinase to kineto-
complex. Organisms such as the fission yeast Schizosac- chores, but the critical kinase substrates are not known.
charomyces pombe and the mold Aspergillus nidulans Second, the physical connection between the fused
that naturally lack synaptonemal complex also lack kinetochores is not broken in anaphase I. As a result, at
interference. Furthermore, the frequency of meiotic anaphase the two homologs with their paired sister
recombination is directly proportional to the length of chromatids move in opposite directions.
the synapsed chromosome axis (ie, the length of the A third major difference between bivalents in meiosis
synaptonemal complex), rather than the actual length I and mitotic chromosomes is that cohesion of homolo-
of DNA in the chromosome. For example, in human gous chromosome arms distal to chiasmata (Figs. 45.2
females, the synaptonemal complex is roughly 50% and 45.10) rather than cohesion between sister chroma-
longer than in males, and females undergo recombina- tids at centromeres resists the poleward pulling of
tion about twice as frequently as males. However, other the kinetochores at the spindle midzone at metaphase I
observations suggest that interference may be established (Fig. 45.12B). This reflects specialized behavior of the
before the synaptonemal complex forms. meiotic cohesin complex in which the meiosis-specific
CHAPTER 45 n Meiosis 791

A. Kinetochore movement
Kinetochore

90 rotation
Microtubules of kinetochores

Sister chromatids
Mitosis Meiosis Meiosis

B. Centromere behavior in meiosis

Paired sister
kinetochores
Microtubules
Chiasmata
Recombination
2
Arms of sisters Homolog
separate pairing
Paired Paired sister
homologs chromatids
Anaphase I Metaphase I Leptotene
Chiasmata released
Homologs separate

Sister Sisters
centromeres segregate
separate
Paired
sisters
Anaphase I Metaphase II Anaphase II
FIGURE 45.12 CHROMOSOMAL BEHAVIOR DURING MEIOSIS I AND II. During meiosis I, sister chromatids are tightly paired along their
lengths, sister kinetochores are fused, and homologs are held together at the metaphase plate by chiasmata. During anaphase I, loss of cohesion
between the arms of sister chromatids releases the chiasmata and allows homologous chromosomes to segregate to opposite spindle poles.
During metaphase of meiosis II, sister chromatids are held together only at their centromeres. Release of centromeric cohesion at meiosis II allows
the sister chromatids to segregate to opposite spindle poles.

Rec8 and Rad21L proteins replace Scc1 (see Figs. 8.18 sister chromatid centromeres tightly paired until ana-
and 44.16). After premeiotic DNA replication, the phase of meiosis II. This protection requires a class of
meiotic cohesion complex keeps sister chromatids proteins called Shugoshins (from the Japanese, meaning
together all along the arms. The cohesin complex plus guardian spirit), which recruit the protein phosphatase
synaptonemal complex proteins SYCP3 and SYCP2 are 2A (PP2A). Rec8 must be phosphorylated for separase to
required for assembly of the dense axial elements that cleave it efficiently, so the localized phosphatase can
extend along the length of the chromosome during block the cleavage reaction. Cleavage of centromeric
synapsis. Rec8 releases sister chromatid cohesion at the onset of
In mitosis, cohesion is released between sister chro- anaphase II similar to the release of cohesion during
matid arms during prometaphase, but in meiosis I it is mitosis (see Fig. 44.16).
retained distal to chiasmata until the onset of anaphase
(Figs. 45.7 and 45.12), when Rec8 and Rad21L along Behavior of the Sex Chromosomes
the chromosome arms are cleaved by a protease called
in Meiosis
separase (see Fig. 44.16). Separation of sister chromatid
arms allows the chiasmata to resolve (untangle), and Of the 46 human chromosomes, two sex chromosomes
the homologous chromosomes segregate to opposite carry genes that define the sex of the individual. The
spindle poles. other 22 pairs of chromosomes are called autosomes.
In the meantime, the Rec8 and Rad21L at centromeres If genetic recombination is required to stabilize
are protected from cleavage and continue to hold the homologous chromosomes at the metaphase plate in
792 SECTION X n Cell Cycle

recombination enzymes or if the assembly of the syn-


A C aptonemal complex (required for the completion of
recombination) is defective. When such problems are
X 2 detected, cells arrest in meiotic prophase I. In yeast, this
Y
9 has been called the pachytene checkpoint, as cells arrest
late in meiotic prophase with nuclear morphology remi-
B niscent of the pachytene stage. Apoptosis eliminates
mammalian germ cells that arrest owing to defects in
recombination.
Synapsed pseudoautosomal region
Suppression of DNA Replication Between
Y Meiosis I and Meiosis II
X Meiosis is unique in that it involves two M phases with
no intervening S phase. On exit from meiosis I, Cdk1
Condensed unpaired portion
of X and Y chromosomes kinase is reactivated immediately. This blocks assembly
of prereplication complexes (see Fig. 42.8), thereby
FIGURE 45.13 SEX CHROMOSOMES OF A CHINESE
HAMSTER AT PACHYTENE. AB, The X and Y chromosomes are
blocking DNA replication. At least two pathways contrib-
synapsed at the pseudoautosomal region. Elsewhere, the unpaired ute to reactivation of Cdk1.
chromatin adopts a highly condensed morphology. C, In the same The first involves downregulation of translation of
preparation, autosomes are completely synapsed and show a lesser Wee1 protein kinase in meiosis. Wee1 is a mitotic inhibi-
degree of condensation. (From Dresser ME, Moses MJ. Synaptonemal tor (see Fig. 43.3) that inactivates Cdk1 by phosphoryla-
complex karyotyping in spermatocytes of the Chinese hamster (Crice-
tulus griseus). IV. Light and electron microscopy of synapsis and
tion at Tyr15. The absence of Wee1 in meiosis I was first
nucleolar development by silver staining. Chromosoma. 1980;76: observed in Xenopus laevis but this seems to be a uni-
122.) versally conserved way of reactivating Cdk1 without an
S phase. Ectopic expression of Wee1 in mature X. laevis
oocytes prevents reactivation of Cdk1 immediately after
meiosis I, how is this accomplished for the X and Y the meiosis I division. As a result, the oocytes reenter
chromosomes? The answer in most mammals is that the interphase and replicate their DNA. Meiotic cells also
X and Y chromosomes have a short region of homolo- express a specialized isoform of Cdc25, the phosphatase
gous sequence (approximately 2.6 million base pairs in that counteracts Wee1 (see Fig. 43.1).
humans) that does pair and undergo genetic recombina-
tion during meiosis. This pseudoautosomal region Metaphase II Arrest and
must undergo genetic recombination in every meiosis I the Mitogen-Activated Protein
cell for the X and Y chromosomes to be partitioned
correctly. Thus, the X and Y chromosomes act like short
Kinase Pathway
homologous chromosomes with large regions of unre- Following their activation and release from the ovary
lated DNA attached (Fig. 45.13). Unpaired regions of (ovulation), oocytes of many vertebrates arrest in meta-
the X and Y chromosomes acquire a distinct chromatin phase II of meiosis until they are fertilized. The activity
structure during late pachytene. that is responsible for this arrest was discovered in
X. laevis eggs arrested in metaphase of meiosis II and is
called cytostatic factor (CSF). Injection of cytoplasm
Cell-Cycle Regulation of Meiotic Events containing CSF into one blastomere of a two-cell frog
Meiosis employs the full set of functions that regulate embryo blocks the next cell cycle at metaphase, just
the division of somatic cells (see Chapters 40 to 43). like the egg (Fig. 45.14). Therefore, CSF can even
However, the peculiarities of the meiotic cell cycle block somatic cells indefinitely in mitotic metaphase.
require additional regulation. One major difference from CSF activity appears in meiosis II and disappears after
somatic cells is that meiotic chromosomes must undergo fertilization.
recombination and form chiasmata to segregate properly One active component of CSF is the X. laevis homolog
at the first meiotic division. Like somatic cells, meiotic of a well-known viral oncogene, v-mos, the transforming
cells have a DNA damage response that arrests cell-cycle gene of the Moloney murine sarcoma virus, which causes
progression in the presence of DNA breaks (see Fig. solid tumors in mice. The v-mos gene is a mutated
43.11). In addition, they have a crossover assurance form of the cellular c-mos gene. Vertebrates express
checkpoint that can detect the presence of stalled or c-mos (a mitogen-activated protein [MAP] kinase kinase
abnormal recombination intermediates. Such intermedi- kinase; see Fig. 27.5) exclusively in oocytes and eggs.
ates accumulate if there are problems with the core Injection of either v-Mos or c-Mos proteins into dividing
CHAPTER 45 n Meiosis 793

modification creates a binding site for polo kinase, which


A. Two-cell embryo B then also phosphorylates Emi2. Emi2 phosphorylated by
polo kinase is recognized by SCFTrCP, which ubiquitylates
Inject egg cytosol, it, marking it for destruction. This results in activation of
with activated
c-Mos, into one the APC/C (see Fig. 40.15), termination of the CSF meta-
blastomere phase arrest, and completion of meiosis II.

Timing of Meiosis in Humans


C The fate of cells undergoing meiosis, as well as the timing
of meiotic events, differs significantly between human
c-Mos removed
by antibody males and females.
before injection Males produce approximately 100 million sperm a day
in a process called spermatogenesis. This process
continues throughout adult life. Spermatogenesis starts
with the division of stem cells called spermatogonia
and involves eight divisions prior to meiosis. These
D. The MAP kinase cascade that arrests eggs
in metaphase of meiosis II: divisions are unusual in that cytokinesis is incomplete,
c-Mos MEK MAPK p90Rsk [Emi2] CSF and the cells remain connected by intercellular bridges.
The process could produce up to 256 cells, but usually
some cells die and others fail to divide, so a more typical
FIGURE 45.14 ROLE OF C-MOS IN THE CYTOSTATIC
FACTOR PATHWAY. A, Diagram of the experiment that identified number is around 200 cells arising from the initial
c-Mos as an essential component of cytostatic factor (CSF) required stem cell division. When these cells pass through
for arrest of eggs in meiotic metaphase. One blastomere of an Xenopus meiosis (they are then referred to as spermatocytes) the
laevis embryo at the two-cell stage was injected with cytoplasm from final result is approximately 800 postmeiotic sperma-
a metaphase-arrested egg containing CSF activity. B, This blastomere
tids. Spermatids then undergo a complex program of
(right half of the embryo) remained blocked in metaphase while the left
blastomere divided many times. C, The same experiment was per- differentiation, resulting in the production of highly
formed, but prior to injection, the c-Mos was removed from the egg specialized spermatozoa. The entire process of sper-
cytoplasm by absorption with a specific antibody. Both the injected matogenesis takes approximately 64 days, the bulk of
and uninjected blastomeres continued to divide normally. D, The which is spent in meiosis I. Approximately 16 days are
mitogen-activated protein (MAP) kinase (MAPK) pathway leading to
spent in pachytene, the longest stage of the meiosis I
metaphase II arrest in vertebrate eggs. (BC, Micrographs courtesy
George Vande Woude, NCI, Frederick, MD. Modified from Sagata N, prophase. In contrast, only about 8 hours are spent in
Watanabe N, Vande Woude GF, etal. The c-Mos proto-oncogene meiosis II.
product is a cytostatic factor responsible for meiotic arrest in vertebrate By the twentieth week of fetal life each ovary of a
eggs. Nature. 1989;342:512518.) human female contains approximately 3 106 primordial
follicles, each with an oocyte arrested in the diplotene
stage of meiosis. This lengthy arrested stage is referred
blastomeres of early frog embryos arrests the cells at to as dictyate. Thereafter, arrested primordial follicles
metaphase (Fig. 45.14). These experiments led to a are recruited continuously to mature into growing
proposal that c-Mos is CSF. primary follicles. However, successful follicular growth
CSF arrest requires the MAP kinase (MAPK) signal depends on follicle-stimulating hormone (FSH), so before
transduction pathway (see Fig. 27.5). Mos activates the pubertywhen the hypothalamus-pituitary-ovarian axis
pathway by phosphorylating mitogen activated protein/ maturesall activated oocytes undergo programmed
extracellular signal-related kinase kinase (MEK), which cell death and degenerate in a process known as atresia.
then activates MAPK. MAPK then activates a downstream At birth, the ovary contains approximately 1,000,000
kinase called p90Rsk (Fig. 45.14D). Introduction of germ cells of which approximately 300,000 to 400,000
constitutively active c-Mos or p90Rsk into X. laevis eggs remain at puberty. Following puberty and in response to
induces metaphase arrest like CSF. However, this is not high levels of FSH each month, a cohort of follicles with
the whole story, because metaphase arrest is maintained their dictyate-arrested oocytes is activated to complete
in extracts depleted of p90Rsk. Thus the pathway must meiosis and grow. Only one of these activated oocytes
include at least one unidentified step beyond p90Rsk. matures fully and is shed from the ovary in response to
The extra component of CSF is an anaphase-promoting a surge of luteinizing hormone. The other follicles degen-
complex/cyclosome (APC/C) inhibitor called Emi2. A erate by atresia. As the successful oocyte is shed from
burst of cytoplasmic Ca2+ released at fertilization (see Fig. the ovary, it completes meiosis I and is arrested at meta-
26.15) activates Ca2+/calmodulin-dependent protein phase of meiosis II by CSF. It remains arrested at this
kinase II (CaMKII), which phosphorylates Emi2. This stage until fertilization occurs. By the time of menopause
794 SECTION X n Cell Cycle

during fetal development. (Any fetal death is a spontane-


ous abortion, commonly called a miscarriage.) It is now
First polar body thought that at least 30% of all conceptions result in
spontaneous abortions. Furthermore, more than 60% of
those spontaneous abortions are aneuploid. These figures
Metaphase II oocyte probably underestimate the frequency of meiotic abnor-
malities. Many spontaneous abortions occur very early
during pregnancy and many are never detected at all.
Few fetuses lost in the first 4 to 6 weeks of gestation are
tested in a laboratory, so their karyotypes are unknown.
Meiotic errors involving certain autosomes can
produce fetuses that survive to birth. Females with three
50 m or more copies of the gene-rich X chromosome survive,
because all but one X chromosome are inactivated
FIGURE 45.15 POLAR BODY FORMATION. Asymmetric cleav- (silenced) in somatic cells (see Fig. 8.6). Rare individuals
age during mouse oogenesis produces a large oocyte and small polar with three copies of chromosome 13 or chromosome18
body. (Modified from Jiao ZX, Xu M, Woodruff TK. Age-associated
alteration of oocyte-specific gene expression in polar bodies: potential
survive to birth; but those who do typically die shortly
markers of oocyte competence. Fertil Steril. 2012;98:480486.) thereafter. The exception is individuals trisomic for
chromosome 21 (a condition that is commonly known
as Down syndrome). These individuals have intellec-
the ovarian reserve is almost depleted, leaving approxi- tual disability as well as other characteristic phenotypic
mately 1000 primordial follicles in the ovary. features, including decreased life expectancy. Why do
In human females, meiosis produces only one mature individuals with Down syndrome survive whereas others
egg. Both meiotic cell divisions are asymmetrical, pro- affected by aneuploidy do not? Perhaps the very small
ducing one large and one very small and short-lived cell. number (233) of coding genes on chromosome 21
The small cells are called polar bodies (Fig. 45.15). includes none whose dosage is critical for survival.
The frequency of certain types of aneuploidy, such as
trisomy for chromosome 21, increases with the ages of
Meiotic Defects and Human Disease the mother and father. Only 0.04% of children of 20-year-
Abnormalities in meiosis are surprisingly common but are old mothers old have trisomy 21. This number rises
not widely observed in human populations because their dramatically with maternal age; nearly 5% of the concep-
consequences are extremely severe. In fact, meiotic tions in mothers 45 years old have trisomy 21 (Fig.
abnormalities are a leading cause of fetal death, particu- 45.16). This maternal age effect is a leading cause of
larly during the first trimester of pregnancy in humans. human genetic disease. Some believe that during the
The two major causes of problems are chromosome many years of arrest of oocytes in meiosis I dictyate,
nondisjunction during the meiotic divisions and the gen- chiasmata joining homologous chromosomes gradually
eration of unbalanced chromosomal rearrangements via dissociate. A mechanism to explain this might be the
faulty recombination. progressive loss of cohesion between sister chromatids
When chromosomes fail to segregate properly in one as the mother ages. There appears to be no mechanism
or both meiotic divisions (nondisjunction), the daughter to replace cohesin complexes that are gradually lost in
cells lack the normal haploid complement of chromo- dictyate oocytes. Mice with a mutation in a key subunit
somes. Embryos that have gained an entire set of chro- of the cohesin complex (Fig. 45.7; see also Fig. 8.18)
mosomes are referred to as polyploid. In human exhibit a pattern of chromosome nondisjunction with
embryos, polyploidy is a common type of chromosomal increasing maternal age that looks much like that seen
abnormality. It is estimated that 1% to 3% of all concep- in aging human mothers. Another potential source of
tions are triploid (69 chromosomes; 23 from one parent errors lies in the mechanism of spindle assembly in
and 46 from the other parent). Two-thirds of these arise oocytes, which does not involve centrosomes and
from two sperm fertilizing one egg (nothing wrong with appears to be more prone to errors than in somatic cells
meiosis there). In other cases, they come from a diploid (see Chapter 44).
gamete, the result of a defective meiotic segregation. Not all cases of human aneuploidy originate from the
Very few triploid embryos survive to birth. mother. One of the most common aneuploidies, 45,X
Most chromosomal abnormalities in human embryos (see Table 45.1 for an explanation of nomenclature)
result from the loss or gain of one or more chromosomes involves the loss of the paternal X or Y chromosome 70%
during meiosis. This condition is called aneuploidy. to 80% of the time. This aneuploidy accounts for nearly
Most zygotes that arise from aneuploid gametes die 10% of spontaneous abortions. In addition, about 7% of
CHAPTER 45 n Meiosis 795

TABLE 45.1 Aneuploidies Involving the Sex Chromosomes in Newborn Humans


Karyotype Frequency Sex Comments
47,XXY* 1/1000 M Klinefelter syndrome. Increased height, sterile, a proportion may
have some learning difficulties.
47,XYY 1/1000 M Increased height, generally fertile, typically with chromosomally
normal offspring. A proportion may have some learning difficulties.
Other X or Y aneuploidy 1/1350
Total: 1 in 360 male births
47,XXX 1/900 F Increased height, generally fertile, typically with chromosomally
normal offspring. A proportion have serious learning difficulties.
45,X 1/4000 F Turner syndrome. Reduced height, infertile, normal intelligence.
Of 45,X embryos, 99% terminate as spontaneous abortions.
Other X or Y aneuploidy 1/2700
Total: 1 in 580 female births
*This number gives the total number of chromosomes, followed by the complement of sex chromosomes.
Modified from Nussbaum RL, McInnes RR, Willard HF. Genetics in Medicine. 6th ed. Philadelphia, PA: WB Saunders; 2001:150.

[Table 45.1]) reveal that spontaneous abortion is a highly


efficient protective mechanism for the elimination of
chromosomal imbalances that arise from errors in
meiosis.
Chromosome number
3.0

ACKNOWLEDGMENTS
16
We thank Abby Dernburg, Jim Haber, Scott Hawley, Amy
% Trisomies

MacQueen, Adele Marston, and Alberto Pendas for their


2.0 suggestions on revisions to this chapter.

21
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