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Need of X or Y chromosome protein after meiosis

Need of X or Y chromosome protein after meiosis



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After meiosis each spermatid get either the X chromosome or the Y chromosome. I know that the 4 spermatids formed from 1 spermatogonia are connected by cytoplasm and so the proteins made by X or Y chromosome can be shared by all the 4 cells.

I want to know what proteins made by X or Y chromosome are exclusive to the X or Y chromosome and are needed to convert spermatids to sperms.


X chromosome has many important genes required for general housekeeping. So we need not really talk about X-chromosome genes. Here is a list of genes present on the X-chromosome.

@Armatus, if all those genes were on autosomes then presence of Y wont be mandatory for male development. There are autosomal genes that are involved in sexual development for e.g. Anti-Mullerian Hormone gene is present on chromosome 19. However, there must be a master regulator that is male specific and since sex determination is chromosomal in mammals, the Y-chromosome must encode that master regulator.

Sry, encoded in Y-chromosome, is one such protein that is absolutely essential for male sexual development. Having said that, it could be very well possible that the basic genes required in the process of spermatogenesis are autosomally encoded. In fact it is so. I just took the list of genes that were associated with sepermatogenesis in KEGG and checked their chromosomal locations. They are all autosomal.

Gene --- position SPATA1 --- 1p22.3 SPATA25 --- 20q13.12 SPATA32 --- 17q21.31 SPATA9 --- 5q15 SPATA19 --- 11q25 SOHLH1 --- 9q34.3 SPATC1L --- 21q22.3 SPATA18 --- 4q12 SPATA2 --- 20q13.13 SPATA21 --- 1p36.13 SPATA2L --- 16q24.3 GMCL1 --- 2p13.3 SPATA7 --- 14q31.3 SPATA5 --- 4q28.1 SPATA6L --- 9p24.2 SPATA4 --- 4q34.2 SPATA24 --- 5q31.2 SPATS2L --- 2q33.1 SPATA16 --- 3q26.31 SPATA6 --- 1p33 SPATA12 --- 3p14.3 SPATS1 --- 6p21.1 SPATC1 --- 8q24.3 SPATA22 --- 17p13.3 SOHLH2 --- 13q13.3 SPATA13 --- 13q12.12 SPATS2 --- 12q13.12 SPATA20 --- 17q21.33 ASUN --- 12p11.23 SPATA8 --- 15q26.2 SPATA17 --- 1q41 SPATA3 --- 2q37.1 SPATA5L1 --- 15q21.1 GMCL1P1 --- 5q35.3 SPATA41 --- 15q26.3 SPATA42 --- 1p13.3 SPATA33 --- 16q24.3

Introduction and Goals

Gregor Mendel (Figure 1) concluded from his experiments that "hereditary units" transmitted traits from one generation to the next, but at the time of his work (1850-1860's) chromosomes had not yet been observed. Around the turn of the century, two events firmly placed Mendel's name in history. First, three botanists independently rediscovered Mendel's research after conducting studies similar to his. Second, scientists began to notice differences between the behavior of chromosomes (only recently observed) during mitosis and meiosis. For example, they saw that organisms had pairs of homologous chromosomes that separated during meiosis, and that the fusion of two gametes resulted in a zygote with the normal diploid number of chromosomes.

These facts meshed well with Mendel's Laws of Segregation and Independent Assortment, demonstrating that chromosomes contained the "hereditary units" proposed by Mendel. Mendel's work and the discovery of chromosomes and their behavior laid the groundwork for studies which revealed that genes are found in specific locations on chromosomes, and that homologous chromosomes segregate and non-homologous chromosomes independently assort during meiosis. This tutorial will more closely examine the role that chromosomes play in allele segregation. You will learn that genes (and their alleles) on different chromosomes segregate (or assort) independently. If they are on the same chromosome, however, they may or may not exhibit independent segregation.

By the end of this tutorial you should have a basic understanding of:

  • How chromosome behavior explains allele segregation
  • Gender determination in humans and other organisms
  • Inheritance of other sex-linked genes
  • Role of X-inactivation in gene expression


Figure 1. Gregor Mendel. (Click image to enlarge)


Mechanism

There are 2 parts to the cell cycle: interphase and mitosis/meiosis. Interphase can be further subdivided into growth 1 (G1), synthesis (S), and growth 2 (G2). During the G phases, the cell grows by producing various proteins, and during the S phase, the DNA is replicated so that each chromosome includes 2 identical sister chromatids.

Mitosis contains 4 phases: prophase, metaphase, anaphase, and telophase. In prophase, the nuclear envelope breaks down and chromatin condenses. In metaphase, the chromosomes line up along the metaphase plate, and microtubules attach to the kinetochores of each chromosome. In anaphase, the chromatids separate and are pulled by the microtubules to opposite ends of the cell. Finally, in telophase, the nuclear envelopes reappear, the chromosomes unwind into chromatin, and the cell undergoes cytokinesis, which splits the cell into 2 identical daughter cells.

Meiosis goes through all 4 phases of mitosis twice, with modified mechanisms that ultimately create haploid cells instead of diploid. One modification is in meiosis I. Homologous chromosomes are separated instead of sister chromatids, creating haploid cells. It is during this process where we see crossing over and independent assortment leading to the increased genetic diversity of the progeny. Meiosis II progresses the same way as mitosis, but with the haploid number of chromosomes, ultimately creating 4 daughter cells all genetically distinct from the original cell.

Nondisjunction can occur during anaphase of mitosis, meiosis I, or meiosis II. During anaphase, sister chromatids (or homologous chromosomes for meiosis I), will separate and move to opposite poles of the cell, pulled by microtubules. In nondisjunction, the separation fails to occur causing both sister chromatids or homologous chromosomes to be pulled to one pole of the cell.

Mitotic nondisjunction can occur਍ue to the inactivation of either topoisomerase II, condensin, or separase. This will result in 2 aneuploid daughter cells, one with 47 chromosomes (2n+1) and the other with 45 chromosomes (2n-1).

Nondisjunction in meiosis I occurs when the tetrads fail to separate during anaphase I. At the end of meiosis I, there will be 2 haploid daughter cells, one with n+1 and the other with n-1. Both of these daughter cells will then go on to divide once more in meiosis II, producing 4 daughter cells, 2 with n+1 and 2 with n-1.

Nondisjunction in meiosis II results from the failure of the sister chromatids to separate during anaphase II. Since meiosis I proceeded without error, 2 of the 4 daughter cells will have a normal complement of 23 chromosomes. The other 2 daughter cells will be aneuploid, one with n+1 and the other with n-1. 


Meiosis

Sexual reproduction requires fertilization, the union of two cells from two individual organisms. If those two cells each contain one set of chromosomes, then the resulting cell contains two sets of chromosomes. Haploid cells contain one set of chromosomes, diploid cells contain two sets of chromosomes. The number of sets of chromosomes in a cell is called its ploidy level. If the reproductive cycle is to continue, then the diploid cell must somehow reduce its number of chromosome sets before fertilization can occur again, or there will be a continual doubling in the number of chromosome sets in every generation. So, in addition to fertilization, sexual reproduction includes a nuclear division that reduces the number of chromosome sets.

The nuclear division that forms haploid cells, which is called meiosis, is related to mitosis. In mitosis, both the parent and the daughter nuclei are at the same ploidy level&mdashdiploid for most plants and animals. Meiosis employs many of the same mechanisms as mitosis. However, the starting nucleus is always diploid and the nuclei that result at the end of a meiotic cell division are haploid. To achieve this reduction in chromosome number, a meiotic cell cycle consists of one round of chromosome duplication and two rounds of nuclear division. Because the events that occur during each of the division stages are analogous to the events of mitosis, the same stage names are assigned. However, because there are two rounds of division, the major process and the stages are designated with a &ldquoI&rdquo or a &ldquoII.&rdquo Thus, meiosis I is the first round of meiotic division and consists of prophase I, prometaphase I, and so on. Meiosis II, in which the second round of meiotic division takes place, includes prophase II, prometaphase II, and so on.

Meiosis I

Meiosis is preceded by an interphase consisting of the G1, S, and G2 phases, which are nearly identical to the phases preceding mitosis.

Prophase I

Early in prophase I, before the chromosomes can be seen clearly microscopically, homologous chromosomes are attached at their tips (their telomeres) to the nuclear envelope by proteins. Homologous chromosomes are similar but not identical chromosomes. For example, chromosome 12 from your mother and chromosome 12 from your father will both be present inside each of your cells. Each chromosome 12 contains the same genes, usually in the same locations, however, each gene can be a different allele. Gene A on chromosome 12 from your mother may be allele R' and gene A on chromosome 12 from your father may be allele r. In species such as humans, even though the X and Y sex chromosomes are not homologous (most of their genes differ), they have a small region of homology that allows the X and Y chromosomes to pair up during prophase I. It will be very important to understand what homologous chromosomes are when following the process of meiosis.

Two homologous chromosomes are shown prior to DNA replication. Each chromosome has three genes with their loci (locations on the chromosome) marked. Homologous chromosomes contain the same genes but are not identical. They each can contain different alleles of each gene.
Source: http://mrphome.net/mrp/Homologous_Chromosome.html

Remember that the meiotic M phase, like mitotic M phase, begins with a replicated, diploid genome. Early in meiotic prophase, DNA double strand breaks (DSBs) - hundreds of them- are intentionally induced by the cell, at somewhat random positions on all chromosomes. We will discuss repair of DSBs in more detail in a later module, but suffice it to say that one mode of repair for DSBs is to search for an unbroken copy that sequence, essentially taking the DSB on a hunt through the genome, in search of the lost information (which can then be copied). Normally, in a G2 cell, this information is easily located on the sister chromatid, which is very near to its recently replicated sister (thanks to the slow diffusion of DNA, and the actions of cohesins). In meiosis, however, the sister chromatid is excluded as a template for repair, forcing the break to go on a hunt for its homolog, which of course carries the identical, or near-identical, sequence. As the breaks find their homologous sequences, the homologous chromosomes are thereby aligned. Thus meiosis takes advantage of an existing repair pathway to force homologs to find each other and align- by intentionally inducing DNA damage! A protein complex called the synaptonemal complex than zips the homologs together (see figure below). At the same time, virtually all the breaks are repaired by copying information from the unbroken homolog, and then using this information to seal both ends of the break together without any loss of information at the break site.

In prophase I, homologous chromosomes synapse. The homologs (one red, one blue) are bound tightly together and in alignment by a protein lattice called a synaptonemal complex, while the sisters are held together by cohesins along their length (not shown!). Please note that the chromatin is still very condensed, and forms large loops emanating from the synaptonemal complex. Also note that the synaptonemal complex, having helped to align the homologs will disappear soon- its job is done.

A question about the illustration above: note that the kinetochores of the sister chromatids are both pointing in the same direction. You might recall that in mitosis we discussed how important it is that they face in opposite directions. Why was this important? Is this an error in the diagram? Defend your answer.

Many are called, but few are chosen

A very small minority of the breaks- about 1 per chromosome arm- are repaired by a different mechanism, in which the two ends of the DSB are repaired in a way that causes them to join with the homolog (at exactly the right position), rather than rejoin with each other. This "crossing over" can be observed visually after the exchange as chiasmata (singular = chiasma) (see figure below).

A very few DSBs are chosen to become chiasmata. I'm guessing you can read the Italian for "kinetochore" and maybe even "brother (!) chromatids". The synaptonemal complex is gone now. Not shown here, but very important to the mechanism of separation of homologs, is the fact that cohesins are holding the sister chromatids together along their entire length. Think of the two sisters as being glued together. What would happen when you pull the homologous centromeres (the centromere for pink vs. the centromere for blue) away from each other?

At the end of prophase I, the homologs are held together only at the chiasmata (figure below) and are called tetrads because the four sister chromatids of each pair of homologous chromosomes are now visible. The sisters are bound to each other throughout their length by cohesins.

The crossover events are the first source of genetic variation in the nuclei produced by meiosis. A single crossover event between homologous non-sister chromatids leads to a reciprocal exchange of equivalent DNA between a maternal chromosome and a paternal chromosome. Now, when that sister chromatid is moved into a gamete cell it will carry some DNA from one parent of the individual and some DNA from the other parent. The recombinant chromatid has a combination of maternal and paternal genes that did not exist before the crossover. Multiple crossovers in an arm of the chromosome have the same effect, exchanging segments of DNA to create recombinant chromosomes.

Crossover occurs between non-sister chromatids of homologous chromosomes. The result is an exchange of genetic material between homologous chromosomes. This diagram clarifies the novel genetic content found at the end of meiosis I after homologs separate. It is not a good illustration of the process of crossing over.

What are the major differences between Prophase I of Meiosis and Prophase of Mitosis?

Prometaphase I

The key event in prometaphase I is the attachment of the spindle fiber microtubules to the kinetochore proteins at the centromeres. Kinetochore proteins are multiprotein complexes that bind the centromeres of a chromosome to the microtubules of the mitotic spindle. Microtubules grow from centrosomes placed at opposite poles of the cell. The microtubules move toward the middle of the cell and attach to one of the two fused homologous chromosomes. The microtubules attach at each chromosomes' kinetochores. With each member of the homologous pair attached to opposite poles of the cell, in the next phase, the microtubules can pull the homologous pair apart. A spindle fiber that has attached to a kinetochore is called a kinetochore microtubule. At the end of prometaphase I, each tetrad is attached to microtubules from both poles, with one homologous chromosome facing each pole. The homologous chromosomes are still held together at chiasmata. In addition, the nuclear membrane has broken down entirely.

Metaphase I

During metaphase I, the homologous chromosomes are arranged in the center of the cell with the kinetochores facing opposite poles. The homologous pairs orient themselves randomly at the equator. For example, if the two homologous members of chromosome 1 are labeled a and b, then the chromosomes could line up a-b, or b-a. This is important in determining the genes carried by a gamete, as each will only receive one of the two homologous chromosomes. This is called Independent Assortment. Recall that homologous chromosomes are not identical, they contain slight differences in their genetic information, causing each gamete to have a unique genetic makeup.

This randomness is the physical basis for the creation of the second form of genetic variation in offspring. Consider that the homologous chromosomes of a sexually reproducing organism are originally inherited as two separate sets, one from each parent. Using humans as an example, one set of 23 chromosomes is present in the egg donated by the mother. The father provides the other set of 23 chromosomes in the sperm that fertilizes the egg. Every cell of the multicellular offspring has copies of the original two sets of homologous chromosomes. In prophase I of meiosis, the homologous chromosomes form the tetrads. In metaphase I, these pairs line up at the midway point between the two poles of the cell to form the metaphase plate. Because there is an equal chance that a microtubule fiber will encounter a maternally or paternally inherited chromosome, the arrangement of the tetrads at the metaphase plate is random. Any maternally inherited chromosome may face either pole. Any paternally inherited chromosome may also face either pole. The orientation of each tetrad is independent of the orientation of the other 22 tetrads. There are two possibilities for orientation at the metaphase plate the possible number of alignments therefore equals 2n, where n is the number of chromosomes per set. Humans have 23 chromosome pairs, which results in over eight million (2 23 ) possible genetically-distinct gametes. This number does not include the variability that was previously created in the sister chromatids by crossover. Given these two mechanisms, it is highly unlikely that any two haploid cells resulting from meiosis will have the same genetic composition (see figure below). And this is without even considering the first type of variation generated by crossing over!

How does the cell ensure that the homologs are oriented in opposite directions?

You may recall from mitosis that kinetochores were oriented to opposite poles by holding the sisters together with cohesins, and then tugging on the kinetochores. If each sister's kinetochore is pointed a different way, and this is true for every chromosome, the cell will be able to detect that tension is present at every kinetochore- none are "relaxed". The absence of this "relaxed" signal will induce cleavage of the cohesins, and the chromatids can now separate and head to opposite poles.

In meiosis, the cell has not only glued the sisters together, it has also covalently bound the homologs together, at just a few spots, via the formation of chiasma. When the centromeres of each homolog are oriented in opposite directions, and the motor proteins of the kinetochores attempt to creep along the microtubules, tension will be established. Once all kinetochores are experiencing tension, the cohesins present on the chromosome arms will be cleaved, allowing the homologous centromeres to separate. The cohesins very near the centromere will remain, for use in the establishment of tension between sister kinetochores, in metaphase of meiosis II.

To summarize the genetic consequences of meiosis I, the maternal and paternal genes are recombined by crossover events that occur between each homologous pair during prophase I. In addition, the random assortment of tetrads on the metaphase plate produces a unique combination of maternal and paternal chromosomes that will make their way into the gametes.

Random, independent assortment during metaphase I can be demonstrated by considering a simple cell with a set of only two chromosomes (n = 2). In this case, there are two possible arrangements at the equatorial plane in metaphase I. The total possible number of different gametes is 2 n , where n equals the number of chromosomes in a set. In this example, there are four possible genetic combinations for the gametes. With n = 23 in human cells, there are over 8 million possible combinations of paternal and maternal chromosomes. Note that this figure- and this discussion- doesn't including the diversity generated by crossing over.

Anaphase I

Anaphase I is triggered by the cleavage of cohesins along the length of the chromosome arms. The kinetochore motor proteins are now free walk along the spindle and pull the homologous chromosomes apart. The spindle itself falls apart behind the progressing kinetochores. The sister centromeres remain tightly bound together via cohesins at the centromere.

What major difference occurs in Anaphase I of Meiosis compared to Anaphase of Mitosis?

Telophase I and Cytokinesis

In telophase, the separated chromosomes arrive at opposite poles. The remainder of the typical telophase events may or may not occur, depending on the species. In some organisms, the chromosomes decondense and nuclear envelopes form around the chromosomes in telophase I. In other organisms, cytokinesis&mdashthe physical separation of the cytoplasmic components into two daughter cells&mdashoccurs without reformation of the nuclei (considering that another round of chromosome migration is about to occur (Mitosis II) this failure to reform a nuclear membrane makes a certain amount of sense. In nearly all species of animals and some fungi, cytokinesis separates the cell contents via a cleavage furrow (constriction of the actin ring that leads to cytoplasmic division) after Meiosis I. In plants, cytokinesis might or might not occur at this stage, depending on the species. In Arabidopsis, a popular plant model system, cytokinesis does not occur until Meiosis II is complete.

Two haploid cells are the end result of the first meiotic division. The cells are haploid because at each pole, there is just one homolog for each chromosome. Each homolog still consists of two sister chromatids. Recall that sister chromatids are almost duplicates- don't forget that they might carry information from one of the homologs somewhere along their arms due to exchanges that occurred during crossing over, and these crossover positions will be different for each sister.

Meiosis II

In meiosis II, these two sister chromatids will separate. Thus the net result of meiosis I and II will be 4 haploid cells, with chromosomes that only have 1 chromatid.

The two cells produced in meiosis I go through the events of meiosis II in synchrony. During meiosis II, the sister chromatids within the two daughter cells separate, forming a total of four new haploid gametes. The mechanics of meiosis II is similar to mitosis.

Prophase II

If the chromosomes decondensed in telophase I, they condense again. If nuclear envelopes were formed, they fragment into vesicles. The centrosomes that were duplicated between Meiosis I and II move away from each other toward opposite poles, and new spindles are formed.

Prometaphase II

The nuclear envelopes are now completely broken down, and the spindle is fully formed. Each sister chromatid's kinetochore attaches to microtubules.

Metaphase II

The sister chromatids are maximally condensed and aligned at the equator of the cell. Cohesins prevent the kinetochores from pulling apart, establishing tension and telling the cell that the kinetochores are properly aligned for every chromosome.

Anaphase II

The sister chromatids are pulled apart by the kinetochore microtubules and move toward opposite poles. Non-kinetochore microtubules elongate the cell.

The process of chromosome alignment differs between meiosis I and meiosis II. In prometaphase I, microtubules attach to the fused kinetochores of homologous chromosomes, and the homologous chromosomes are arranged at the midpoint of the cell in metaphase I. In anaphase I, the homologous chromosomes are separated. In prometaphase II, microtubules attach to the kinetochores of sister chromatids, and the sister chromatids are arranged at the midpoint of the cells in metaphase II. In anaphase II, the sister chromatids are separated.

Telophase II and Cytokinesis

The chromosomes arrive at opposite poles and begin to decondense. Nuclear envelopes form around the chromosomes. Cytokinesis separates the two cells into four unique haploid cells. At this point, the newly formed nuclei are both haploid. The cells produced are genetically unique because of the random assortment of paternal and maternal homologs and because of the recombination of maternal and paternal segments of chromosomes (with their sets of genes) that occurs during crossing over. The entire process of meiosis is outlined in the figure below.

An animal cell with a diploid number of four (2n = 4) proceeds through the stages of meiosis to form four haploid daughter cells.

Comparing Mitosis and Meiosis

Mitosis and meiosis are both forms of division of the nucleus in eukaryotic cells. They share some similarities, but also exhibit distinct differences that lead to very different outcomes. Mitosis is a single nuclear division that results in two nuclei that are usually partitioned into two new cells. The nuclei resulting from a mitotic division are genetically identical to the original nucleus. They have the same number of sets of chromosomes, one set in the case of haploid cells and two sets in the case of diploid cells. In most plants and all animal species, it is typically diploid cells that undergo mitosis to form new diploid cells. In contrast, meiosis consists of two nuclear divisions resulting in four nuclei that are usually partitioned into four new cells. The nuclei resulting from meiosis are not genetically identical and they contain one chromosome set only. This is half the number of chromosome sets in the original cell, which is diploid.

The main differences between mitosis and meiosis occur in meiosis I, which is a very different nuclear division than mitosis. In meiosis I, the homologous chromosome pairs become associated with each other, are bound together with the synaptonemal complex, develop chiasmata and undergo crossover between sister chromatids, and line up along the metaphase plate in tetrads with kinetochore fibers from opposite spindle poles attached to each kinetochore of a homolog in a tetrad. All of these events occur only in meiosis I.

When the chiasmata resolve and the tetrad is broken up with the homologs moving to one pole or another, the ploidy level&mdashthe number of sets of chromosomes in each future nucleus&mdashhas been reduced from two to one. For this reason, meiosis I is referred to as a reduction division. There is no such reduction in ploidy level during mitosis.

Meiosis II is much more analogous to a mitotic division. In this case, the duplicated chromosomes (only one set of them) line up on the metaphase plate with divided kinetochores attached to kinetochore fibers from opposite poles. During anaphase II, as in mitotic anaphase, the kinetochores divide and one sister chromatid&mdashnow referred to as a chromosome&mdashis pulled to one pole while the other sister chromatid is pulled to the other pole. If it were not for the fact that there had been crossover, the two products of each individual meiosis II division would be identical (like in mitosis). Instead, they are different because there has always been at least one crossover per chromosome. Meiosis II is not a reduction division because although there are fewer copies of the genome in the resulting cells, there is still one set of chromosomes, as there was at the end of meiosis I.

Meiosis and mitosis are both preceded by one round of DNA replication however, meiosis includes two nuclear divisions. The four daughter cells resulting from meiosis are haploid and genetically distinct. The daughter cells resulting from mitosis are diploid and identical to the parent cell.

The Mystery of the Evolution of Meiosis

Meiosis is such an extraordinarily complex series of cellular events that biologists have had trouble hypothesizing and testing how it may have evolved. Although meiosis is inextricably entwined with sexual reproduction and its advantages and disadvantages, it is important to separate the questions of the evolution of meiosis and the evolution of sex, because early meiosis may have been advantageous for different reasons than it is now. Thinking outside the box and imagining what the early benefits from meiosis might have been is one approach to uncovering how it may have evolved.

Meiosis and mitosis share obvious cellular processes and it makes sense that meiosis evolved from mitosis. The difficulty lies in the clear differences between meiosis I and mitosis. Adam Wilkins and Robin Holliday 2 summarized the unique events that needed to occur for the evolution of meiosis from mitosis. These steps are homologous chromosome pairing, crossover exchanges, sister chromatids remaining attached during anaphase, and suppression of DNA replication in interphase. They argue that the first step is the hardest and most important, and that understanding how it evolved would make the evolutionary process clearer. They suggest genetic experiments that might shed light on the evolution of synapsis.

There are other approaches to understanding the evolution of meiosis in progress. Different forms of meiosis exist in single-celled protists. Some appear to be simpler or more &ldquoprimitive&rdquo forms of meiosis. Comparing the meiotic divisions of different protists may shed light on the evolution of meiosis. Marilee Ramesh and colleagues 3 compared the genes involved in meiosis in protists to understand when and where meiosis might have evolved. Although research is still ongoing, recent scholarship into meiosis in protists suggests that some aspects of meiosis may have evolved later than others. This kind of genetic comparison can tell us what aspects of meiosis are the oldest and what cellular processes they may have borrowed from in earlier cells.

Click through the steps of this interactive animation to compare the meiotic process of cell division to that of mitosis: How Cells Divide.


Evolutionary History of the Y Chromosome

About 310 million years ago, there was no Y chromosome as we know it. At that time, when mammals were evolving from their common ancestors with reptiles and birds, what are now the X and Y chromosomes were a pair of autosomes similar to today's X chromosome. Sex in these ancestors was probably determined by the temperature at which the egg is incubated, as it is in many reptiles today. This can occur only in ectotherms, animals that do not maintain a constant body temperature. Otherwise, only males or only females would be produced, not a situation conducive to long-term reproductive success.

Sometime between 165 and 310 million years ago, SRY (sex-determining region Y) evolved in the ancestral lineage of mammals. SRY is the gene on the mammalian Y chromosome that determines that the organism will be male. Once SRY evolved, endothermy could also evolve since both males and females could develop at the same temperature. The evolution of chromosomally based ZW sex determination in birds enabled them to independently evolve endothermy and its associated characteristics - insulated skin covering made of keratin (feathers or fur) and a four-chambered heart.

Further evidence that X and Y were once a pair of autosomes comes from DNA sequences of the human X and chicken autosomes (Ross et al., 2005). Figure 2 shows a dotter plot comparing the human X chromosome with parts of the chicken ##1 and ##4 chromosomes. The human Xp (the shorter arm) is nearly identical to part of the chicken ##1 chromosome, whereas the human Xq (the longer arm) has large chunks of similarity with parts of the chicken ##4 chromosome. The autosome that became X and Y in mammals lives on as autosomes in chickens.

This dotter plot compares the human X chromosome with portions of the ##1 and ##4 chromosomes of the chicken. The human X chromosome is horizontal. Notice the similarities between the human Xp on the left with part of the chicken ##1, and between the human Xq on the right with parts of the chicken ##4. A dotter plot is created by a program that compares nucleotide sequences of two DNA molecules. Where the sequences are the same, it places a dot on a graph. If you were to compare two identical chromosomes, you would get a straight line going from the upper left corner of the graph to the lower right corner. If the two DNA molecules are similar but not identical, you get a dotted line if they are very different, there is no line. The more similar the sequences, the darker the dotted line. (Adapted by permission from Macmillan Publishers Ltd: Ross et al., 2005.)

This dotter plot compares the human X chromosome with portions of the ##1 and ##4 chromosomes of the chicken. The human X chromosome is horizontal. Notice the similarities between the human Xp on the left with part of the chicken ##1, and between the human Xq on the right with parts of the chicken ##4. A dotter plot is created by a program that compares nucleotide sequences of two DNA molecules. Where the sequences are the same, it places a dot on a graph. If you were to compare two identical chromosomes, you would get a straight line going from the upper left corner of the graph to the lower right corner. If the two DNA molecules are similar but not identical, you get a dotted line if they are very different, there is no line. The more similar the sequences, the darker the dotted line. (Adapted by permission from Macmillan Publishers Ltd: Ross et al., 2005.)

After the evolution of SRY, X and Y continued to be very similar until a large inversion occurred on the Y chromosome. At this point, there could be no recombination between X and Y along the entire length of this inversion. Additional alterations to the Y chromosome further inhibited its ability to recombine with the X. Genes on this stretch of DNA could be maintained on the X chromosome, because X chromosomes recombine when they are in females. But because these genes on the Y could never recombine, over 1000 of them have been lost. These genes, and their associated ‘‘sex-linked traits,’’ such as red and green cone proteins (color-blindness) and Factors VIII and IX (hemophilia), are found on the X chromosome but not on the Y and were presumably on the original pair of autosomes. Small pseudoautosomal regions exist at both ends of the X and Y chromosomes in humans and at one end in other mammals. Here, X and Y remain homologous, recombine, and pair during meiosis. You might ask why a non-recombining Y chromosome was selected for. It is likely that not crossing over with the X is an advantage, so SRY does not regularly get transferred to the X chromosome. Since there are an average of two to three crossovers per chromosome during meiosis, this is a very real concern.

There are 76 protein-coding genes on the human Y they code for 26 distinct proteins, because several genes code for the same protein. These genes are almost exclusively concerned with male fertility: men with deletions in them have no associated health problems except infertility. These genes have probably migrated to the Y chromosome from various autosomes in the last few hundred million years. Since these genes do not recombine, how are they preserved over evolutionary time?


MSCI: a consequence of synaptic failure

Over recent years it has become apparent that MSCI is in fact a manifestation of MSUC, a more general meiotic-silencing mechanism(Schimenti, 2005) (see Table 1). In meiotic cells,homologues synapse via a proteinaceous scaffold called the synaptonemal complex (SC). The SC consists of two axial elements, which form during leptotene between the sister chromatids, and of a central component, which forms as synapsis takes place (de Boer and Heyting, 2006). Meiotic DNA is arranged in loops that attach at their base to these axial elements (see Fig. 2C). As the X and Y chromosomes only synapse via a homologous distal segment, such that much of the X and Y axial elements are unsynapsed during pachytene, the proteins involved in MSCI might be expected to localise to the chromatin of the arms of the DNA loops, surrounding the axial element, where most genes reside. Indeed,this is exactly where γH2AX is found(Turner et al., 2004). However, prior to MSCI initiation, both BRCA1 and ATR associate exclusively with the axial element of the X and Y chromosomes(Turner et al., 2004)(Fig. 2C). Shortly after, ATR translocates from the axial element to the chromatin loops, concomitant with the appearance of γH2AX at those sites(Fig. 2D). Based on the association of BRCA1 and ATR with the unsynapsed X and Y chromosome axial element, and on their absence from the distal regions of synapsed sex chromosomes, it was proposed that MSCI and a lack of synapsis were intimately linked (Turner et al., 2004). It became apparent that BRCA1 and ATR were recognizing the axial elements of the X and Y chromosomes simply because they were unsynapsed, rather than because of some special feature of these chromosomes.

Schematic representation of MSCI. (A) During leptotene,widespread ATM-dependent H2AX phosphorylation occurs in response to meiotic-DNA DSB formation. BRCA1 and ATR form foci on newly forming axial element (AEs). (B) During zygotene, synapsis coincides with the loss of BRCA1, ATR and γH2AX from autosomal AEs. BRCA1, ATR and γH2AX remain as foci on the AEs of autosomes that have not yet synapsed and on the AE of the X chromosome. (C) Zygotene-pachytene transition. Autosomal synapsis is complete and recombination-related γH2AX disappears. BRCA1-and ATR-staining becomes linear on the X and Y AEs. Meiotic DNA is arranged in loops attached at their bases to the AEs. (D) Early pachytene. ATR translocates along DNA loops, where it phosphorylates H2AX, resulting in MSCI and in the formation of the sex body. (E) Mid-to-late pachytene. Other histone modifications [e.g. the production of H3K9me2, uH2A and histone variants (e.g. H2AFY)] ensure the maintenance of MSCI. (F)Diplotene-to-diakinesis. The X and Y chromosomes migrate to the centre of the nucleus. BRCA1, ATR and γH2AX are lost from the X and Y chromosomes, but the other modifications remain. These modifications ensure the maintenance of MSCI throughout the meiotic divisions (G) and into spermatids(H), and is termed post-meiotic sex chromosome repression (PSCR).

Schematic representation of MSCI. (A) During leptotene,widespread ATM-dependent H2AX phosphorylation occurs in response to meiotic-DNA DSB formation. BRCA1 and ATR form foci on newly forming axial element (AEs). (B) During zygotene, synapsis coincides with the loss of BRCA1, ATR and γH2AX from autosomal AEs. BRCA1, ATR and γH2AX remain as foci on the AEs of autosomes that have not yet synapsed and on the AE of the X chromosome. (C) Zygotene-pachytene transition. Autosomal synapsis is complete and recombination-related γH2AX disappears. BRCA1-and ATR-staining becomes linear on the X and Y AEs. Meiotic DNA is arranged in loops attached at their bases to the AEs. (D) Early pachytene. ATR translocates along DNA loops, where it phosphorylates H2AX, resulting in MSCI and in the formation of the sex body. (E) Mid-to-late pachytene. Other histone modifications [e.g. the production of H3K9me2, uH2A and histone variants (e.g. H2AFY)] ensure the maintenance of MSCI. (F)Diplotene-to-diakinesis. The X and Y chromosomes migrate to the centre of the nucleus. BRCA1, ATR and γH2AX are lost from the X and Y chromosomes, but the other modifications remain. These modifications ensure the maintenance of MSCI throughout the meiotic divisions (G) and into spermatids(H), and is termed post-meiotic sex chromosome repression (PSCR).

Turner et al. (Turner et al.,2005) questioned whether unsynapsed autosomes would also attract BRCA1, and whether this would ultimately lead to autosomal silencing. Using T(X16)16H male mice, in which an X-16 reciprocal translocation frequently results in errors in chromosome 16 synapsis, it was demonstrated that regions of unsynapsed chromosome 16 were indeed positive for BRCA1, ATR andγH2AX and were silenced (Turner et al., 2005). Baarends et al.(Baarends et al., 2005) also reported similar findings in mice that contained a translocation between chromosome 1 and 13, using uH2A as a marker of silencing. Both authors then studied the localization of MSCI proteins in the XO female mouse(Speed, 1986). These mice have only one X chromosome instead of two, and the single X chromosome has no homologous partner with which to synapse during meiosis. Both studies found that the unsynapsed chromosomes were also silenced during female meiosis. In a later study, Turner et al. (Turner et al.,2006) tested whether MSCI could be prevented by providing the normally unsynapsed X or Y chromosome with a synaptic partner. This proved to be the case. For example, in XYY mice, in which the Y chromosome is provided with an additional Y chromosome, fully synapsed YY bivalents were negative forγH2AX and evaded MSCI. These results are summarized in Fig. 3B,C,E.

Meiotic sterility caused by MSUC and by MSCI failure. (A) In normal (XY) males, silencing of the single X chromosome by MSCI is tolerated because essential X-encoded genes have autosomally integrated retrogene copies that are expressed during the precise time-window of MSCI-to-PSCR. (B)When autosomes fail to synapse, they are also silenced by MSUC. If unsynapsed autosomal segments contain a gene or genes crucial for meiosis, those genes will be silenced, causing meiotic arrest. (C) Allowing either the X or Y chromosome to synapse, as seen in XYY males, allows MSCI escape, with the ensuing expression of sex-linked genes causing meiotic arrest. (D) In XX females, all chromosomes have homologues and are thus completely synapsed.(E) In the XO female mouse, the single X chromosome has no synaptic partner and is therefore silenced by MSUC. Because no autosomal retrogenes are activated in the female gonad, these XO oocytes perish. (F) In approximately one-third of XO oocytes, the single X chromosome circumvents MSUC by synapsing non-homologously either with itself, to form a hairpin, or with other chromosomes.

Meiotic sterility caused by MSUC and by MSCI failure. (A) In normal (XY) males, silencing of the single X chromosome by MSCI is tolerated because essential X-encoded genes have autosomally integrated retrogene copies that are expressed during the precise time-window of MSCI-to-PSCR. (B)When autosomes fail to synapse, they are also silenced by MSUC. If unsynapsed autosomal segments contain a gene or genes crucial for meiosis, those genes will be silenced, causing meiotic arrest. (C) Allowing either the X or Y chromosome to synapse, as seen in XYY males, allows MSCI escape, with the ensuing expression of sex-linked genes causing meiotic arrest. (D) In XX females, all chromosomes have homologues and are thus completely synapsed.(E) In the XO female mouse, the single X chromosome has no synaptic partner and is therefore silenced by MSUC. Because no autosomal retrogenes are activated in the female gonad, these XO oocytes perish. (F) In approximately one-third of XO oocytes, the single X chromosome circumvents MSUC by synapsing non-homologously either with itself, to form a hairpin, or with other chromosomes.

Taken together, these findings demonstrate that unsynapsed chromosome regions are silenced during meiosis. Related meiotic-silencing mechanisms have previously been shown to operate in both Caenorhabditis elegans(Bean et al., 2004) and Neurospora crassa (Shiu et al.,2001), in which they may function in genome defence(Shiu et al., 2001). In C. elegans, the single X chromosome of male meiotic cells is enriched in H3K9me2, and, when autosomes fail to synapse, they acquire the same repressive histone mark (Bean et al.,2004). In Neurospora, DNA that is unsynapsed during meiosis is silenced but, in contrast to the situation in mammals(Okamoto et al., 2005), this silencing affects all homologous DNA sequences, whether those sequences are synapsed or not. For this reason, meiotic silencing in Neurospora has been termed meiotic silencing by unpaired DNA (MSUD) (see Table 1). MSUD is thought to function post-transcriptionally, because it uses components of the RNAi pathway, including the RNA-dependent RNA polymerase (RdRP) sad-1(suppressor of ascus dominance 1)(Shiu et al., 2001) and the argonaute-like protein Sms-2 (suppressor of meiotic silencing 2)(Lee et al., 2003). RdRPs function in RNAi by converting single-stranded RNA precursors into double-stranded RNA, which are then cleaved by Dicer to form short interfering RNAs (siRNAs). These small RNA molecules induce destruction of homologous mRNA via an argonaute-containing protein complex RISC (RNA-induced silencing complex) (Dawe, 2004). The data of Turner et al. (Turner et al.,2005) and Baarends et al.(Baarends et al., 2005)indicate that MSUC operates at the transcriptional level, but this does not preclude the possibility that RNAi is involved, because the core RNAi machinery can silence genes at the transcriptional level(Grewal and Jia, 2007). Indeed, a recent study has found that maelstrom (MAEL), whose Drosophila orthologue is implicated in RNAi(Findley et al., 2003),localises to the sex body (Costa et al.,2006).

A curious unanswered question is why does MSUC/MSCI use proteins involved in DSB repair? As already outlined, in mammals, meiotic DNA-DSB formation precedes synapsis (see Box 1). When synapsis fails, the resulting unsynapsed chromosome axes are replete with unrepaired DNA DSBs. Could it be that unsynapsed axes are recognized as such through the presence of BRCA1-bound DSBs, which act as nucleation centres for the later MSUC response? Two studies have found that mice with a mutation in Spo11, which encodes an enzyme responsible for meiotic DSB formation, have defective MSCI, indicating a requirement for DSBs in meiotic silencing(Bellani et al., 2005 Barchi et al., 2005). However,other data suggests that meiotic DSBs actually antagonize the MSCI response,possibly by sequestering the MSCI machinery and thereby preventing its relocation to the XY bivalent (Barchi et al., 2005 de Vries et al.,2005).


Sex Chromosomes and Meiosis

While there are several different systems for sex determination, for simplicity's sake we will focus on the X-Y system of sex determination to examine sex-linked inheritance. During meiosis, the two X chromosomes (found in females) or the X and Y chromosomes (found in males) pair together but undergo little crossing over. One of these chromosomes goes to each gamete, so females produce gametes with only X chromosomes, whereas males produce equal numbers of gametes with either an X or Y chromosome. If two gametes with X chromosomes undergo fertilization, the resultant offspring will be female (XX). That is, if an ovum with an X chromosome and a sperm with an X chromosome combine, the resultant offspring will be female. However, if an ovum with an X chromosome and a sperm with a Y chromosome combine, the offspring will be male (XY). While it has long been known that the X chromosome contains a substantial number of genes, researchers have only recently found genes on the Y chromosome, most of which are associated with the development of male gonads. Therefore, it appears that a gene (or genes) on the Y chromosome provides the biochemical signal that begins the development of male gonads in embryos.


Sperm Are Produced Continuously in Most Mammals

In mammals, there are major differences in the way in which eggs are produced (oogenesis) and the way in which sperm are produced (spermatogenesis). In human females, for example, oogonia proliferate only in the fetus, enter meiosis before birth, and become arrested as oocytes in the first meiotic prophase, in which state they may remain for up to 50 years. Individual oocytes mature from this strictly limited stock and are ovulated at intervals, generally one at a time, beginning at puberty. In human males, by contrast, meiosis and spermatogenesis do not begin in the testes until puberty and then go on continuously in the epithelial lining of very long, tightly coiled tubes, called seminiferous tubules. Immature germ cells, called spermatogonia (singular, spermatogonium), are located around the outer edge of these tubes next to the basal lamina, where they proliferate continuously by mitosis. Some of the daughter cells stop proliferating and differentiate into primary spermatocytes. These cells enter the first meiotic prophase, in which their paired homologous chromosomes participate in crossing-over, and then proceed with division I of meiosis to produce two secondary spermatocytes, each containing 22 duplicated autosomal chromosomes and either a duplicated X or a duplicated Y chromosome. The two secondary spermatocytes derived from each primary spermatocyte proceed through meiotic division II to produce four spermatids, each with a haploid number of single chromosomes. These haploid spermatids then undergo morphological differentiation into sperm (Figure 20-27), which escape into the lumen of the seminiferous tubule (Figure 20-28). The sperm subsequently pass into the epididymis, a coiled tube overlying the testis, where they undergo further maturation and are stored.

Figure 20-27

The stages of spermatogenesis. Spermatogonia develop from primordial germ cells that migrate into the testis early in embryogenesis. When the animal becomes sexually mature, the spermatogonia begin to proliferate rapidly, generating some progeny that (more. )

Figure 20-28

Highly simplified drawing of a cross section of a seminiferous tubule in a mammalian testis. (A) All of the stages of spermatogenesis shown take place while the developing gametes are in intimate association with Sertoli cells. These large cells extend (more. )

An intriguing feature of spermatogenesis is that the developing male germ cells fail to complete cytoplasmic division (cytokinesis) during mitosis and meiosis. Consequently, large clones of differentiating daughter cells that have descended from one maturing spermatogonium remain connected by cytoplasmic bridges, forming a syncytium (Figure 20-29). The cytoplasmic bridges persist until the very end of sperm differentiation, when individual sperm are released into the tubule lumen. This accounts for the observation that mature sperm arise synchronously in any given area of a seminiferous tubule. But what is the function of the syncytial arrangement?

Figure 20-29

Cytoplasmic bridges in developing sperm cells and their precursors. The progeny of a single maturing spermatogonium remain connected to one another by cytoplasmic bridges throughout their differentiation into mature sperm. For the sake of simplicity, (more. )

Unlike oocytes, sperm undergo most of their differentiation after their nuclei have completed meiosis to become haploid. The presence of cytoplasmic bridges between them, however, means that each developing haploid sperm shares a common cytoplasm with its neighbors. In this way, it can be supplied with all the products of a complete diploid genome. Developing sperm that carry a Y chromosome, for example, can be supplied with essential proteins encoded by genes on the X chromosome. Thus, the diploid genome directs sperm differentiation just as it directs egg differentiation.

Some of the genes that regulate spermatogenesis have been conserved in evolution from flies to humans. The DAZ gene, for example, which encodes an RNA-binding protein and is located on the Y chromosome, is deleted in many infertile men, many of whom cannot make sperm. Two Drosophila genes that are homologous to DAZ are essential for spermatogenesis in the fly. RNA-binding proteins are especially important in spermatogenesis, because many of the genes expressed in the sperm lineage are regulated at the level of RNA translation.


INTERACTION BETWEEN THE SPINDLE AND CHROMOSOMES

Chromosome–microtubule interactions in oocytes may be 𠇍ifferent” from those in mitosis. In mitosis, the main interaction is provided by kinetochores, which interact with dynamic microtubule ends. In the simplest model of mitosis, microtubules nucleated from centrosomes capture kinetochores and generate pulling forces (the “search and capture” model) (Kirschner and Mitchison 1986). When sister kinetochores are attached to microtubules from the opposite poles, chromosomes becomes congressed to the metaphase plate. The pulling forces acting between kinetochores and the opposite poles are resisted by cohesion among sister chromatids, and destruction of cohesin at the onset of anaphase triggers the movement of sister chromatids toward the poles. Although kinetochores are also important in meiosis, nonkinetochore interactions seem more prominent in oocytes than in mitotic cells.

In mouse, it has been shown that kinetochore-microtubule end-on attachment is not properly established until well after chromosome congression at the spindle equator (Brunet et al. 1999). Chromosomes move toward the spindle equator by sliding along the surface of the spindle without end-on attachment, leading to ring arrangement of chromosomes at the spindle equator (Kitajima et al. 2011). This congression is followed by trial-and-error establishment of bipolar end-on attachment of homologous kinetochores at the spindle equator. Full stable end-on attachment will not be achieved until several hours after nuclear envelope breakdown, and the delay of end-on attachment in oocytes appears to be caused by slow gradual increase of Cdk1 activity (Davydenko et al. 2013). An artificial premature increase of Cdk1 activity resulted in the premature establishment of attachment. As this also increased the lagging chromosomes in anaphase I, slow increase of Cdk1 activity is proposed to delay stable attachment until spindle bipolarity is established. It remains to be established how the chromosomes congress to the spindle equator without end-on microtubule attachment to kinetochores or how a gradual increase of Cdk delays the microtubule attachment to kinetochores.

Observations in C. elegans oocytes also indicated different contributions of kinetochores in meiosis to those in mitosis. First, microtubules appear to interact with chromosomes laterally during chromosome congression. This congression is at least partly mediated by the chromokinesin KLP-19, which localizes to the junction among the homologs (Wignall and Villeneuve 2009). Furthermore, inactivation of kinetochores by RNA interference (RNAi) resulted in less tight congression and misorientation of chromosomes relative to the spindle axis. Surprisingly, chromosomes without active kinetochores can separate during anaphase at a speed comparable with the wild type (Dumont et al. 2010). Anaphase chromosome movement seems to be driven by the elongation of spindle microtubules among separating homologous chromosomes. However, it should be noted that C. elegans centromeres are not restricted to small regions, as kinetochores are formed along proximal parts of chromosomes in meiosis (Dumont et al. 2010).

How do the chromosomes move without end-on attachment in oocytes? Even in mitosis, there is evidence of such forces acting on chromosomes. Polar ejection forces act on chromosome arms and are involved in chromosome congression at the metaphase plate (Rieder and Salmon 1994). When chromosomes were artificially cut, a chromosome fragment that lacked kinetochores moved toward the spindle equator (Rieder et al. 1986). Chromokinesins play a part in polar ejection forces, but interaction of chromosome arms with growing microtubule plus ends can also generate such forces. In the case of Drosophila oocytes, the chromokinesin Nod is thought to generate polar ejection forces (Theurkauf and Hawley 1992 Matthies et al. 1999). Nod is an immotile kinesin but can promote microtubule polymerization (Cui et al. 2005). In mouse oocytes, the chromokinesin Kid is dispensable for chromosome congression (Kitajima et al. 2011).


Forensic Science

Leonor Gusmão María Brión Iva Gomes , in Handbook of Analytical Separations , 2008

30.1 Introduction

30.1.1 Y-chromosome structure

The Y chromosome is one of the smallest human chromosomes, with an estimated average size of 60 million base pairs (Mb) ( Fig. 30.1 ). During male meiosis recombination only takes place in the pseudoautosomal regions at the tips of both arms of Y and X chromosomes (PAR1, with 2.6 Mb, and PAR 2, with 0.32 Mb). Along ∼95% of its length the Y chromosome is male-specific and effectively haploid, since it is exempt from meiotic recombination. Therefore, this Y-chromosome segment where X-Y crossing over is absent has been designated as the non-recombining region of the Y chromosome or NRY. Because of the high non-homologous recombination occurring within this Y chromosome specific region, a more appropriately name of male-specific region or MSY is nowadays used to designate it [1] .

Fig. 30.1 . Y-Chromosome structure.

The MSY is a mosaic of heterochromatic and euchromatic regions. Besides the centromeric heterocromatin, a large heterochromatic region is located on the distal long arm of the Y chromosome (Yq) and constitutes more than half of the chromosome in some normal males, but is virtually undetectable in others [2] . A third heterochromatic region was recently discovered by Skaletsky et al. [1] , interrupting the euchromatic sequences of proximal Yq (see Fig. 30.1 ). These regions are composed of highly repeated sequences of non-functional DNA: DYZ1, DYZ2, DYZ3, DYZ17, DYZ18, and DYZ19.

The euchromatin is a constant size region and includes sequences homologous to the X chromosome, Y-specific repetitive sequences, and all the genes identified in the Y chromosome, which include the now identified 27 distinct protein-coding genes or gene families. Near-complete sequence of the Y-chromosome euchromatin has been recently revealed by Skaletsky et al. [1] that classifies the euchromatic sequences into three categories. First, the X-transposed, consisting in a stretch recently transposed from the X chromosome – ∼3–4 million years ago, that still presents 99% homology to their X-chromosome counterparts. Second, the X-degenerate, consisting of a class of sequences more distantly related to the X chromosome – remnants of ancient autosomal sequences from which the modern X and Y derive. And at last, the ampliconic class composed largely of sequences that exhibit as much as 99.9% identity to other sequences in the MSY, maintained by frequent Y–Y gene conversion events. These sequences are located in seven segments scattered across the long and proximal short arms, and the most striking structural feature are eight massive palindromes located in the ampliconic regions of Yq, six of which carry testis genes.

30.1.2 The evolution of sex chromosomes

The similarities between the X and Y chromosome sequences are consistent with the hypothesis of a common origin. The mammalian advanced sex chromosome systems originated 300 million years ago from systems in which the X and Y were initially largely genetically homologous [3,4] . The evolution of sex chromosomes involved mechanisms of restriction of gene recombination, transposition, and translocation. The sequence of events that induced the morphological and genetic differentiation of the X and Y chromosomes and the genetic inactivation of the Y-chromosome genes is still not completely understood. The presently accepted explanation of the differentiation of the initially morphologically homogeneous X and Y chromosomes invokes successive processes where alternated steps of mutation and restriction of recombination were involved ( Fig. 30.2 ).

Fig. 30.2 . Differentiation of the initially morphologically homogeneous X and Y chromosomes.

In time, the Y chromosome comes to carry genes that are beneficial to the male but not to the female sex. If linked to the sex-determining region of the Y chromosome, those genes, favored in males and selected negatively in females, will tend to spread through the population. In order to keep this genetic heterogeneity between X and Y chromosomes, restriction of recombination involves sex determination genes and loci controlling secondary sexual characteristics being promoted by selection mechanisms. In a process referred to as “Muller ratchet,” the lack of exchange through all or part of the originally homologous X and Y chromosomes will accumulate deleterious recessive mutations, since they are not restricted by selection. If there is no recombination, some mutations are more liable to be lost from the population and spread of a favorable Y-linked mutant allele through a population that would allow for the fixation of deleterious alleles at other loci. The accumulation of recessive deleterious alleles on the Y chromosome favors a selection for increased activity of the homologous loci on the X chromosome. On the other hand, with the reduction of Y chromosome genetic activity, there will be weak selection against insertions into the Y chromosome. In the absence of gene exchange and selective pressures, transposable elements and tandem repeat sequences are expected to accumulate, leading to a step-by-step reduction of the Y activity.

Sequencing of the MSY provided the opportunity to reexamine the model of evolution of the human sex chromosomes, showing that it is a consequence of two opposed evolutionary dynamics acting on the Y chromosome: gene decay versus gene acquisition and conservation [1,5] .

Because of the presence of MSY gene pairs in the ampliconic sequences of the euchromatin which are subject to frequent gene conversion [1,5] , and of the little or no X-degenerate gene loss or decay observed during the last 6 million years of human evolution [6] , the predictions that the Y chromosome would be vanished completely in the next 10 million years seem to no longer have support.

30.1.3 The Y-chromosome inheritance

As a result of the evolutionary process, exchange between X and Y chromosomes is limited to two small regions of the X-Y pair and, consequently, to a great extent, the Y chromosome is paternally inherited and haploid. Along generations, the MSY is transmitted from father to son unchanged unless a mutational event takes place. For this reason, the Y chromosome contains a record of all the mutational events that occurred among his ancestors, reflecting the history of paternal lineage. Therefore, all modern Y chromosomes have a single paternal ancestor, on their male-specific region.

30.1.4 Y-chromosome-specific polymorphisms

In 1985, Casanova et al. [7] undertook the first search for Y-linked restriction fragment length polymorphisms (RFLPs) in humans, with the report of two Y-specific polymorphisms. This and latter surveys on Y-specific markers by RFLP studies [8–10] and sequence analysis [11,12] emphasized the low level of polymorphism of this chromosome, compared with other chromosomes [13] . The attempt to identify new Y-specific polymorphisms in different population samples, mainly in Caucasians [8,9] and Africans [10] , showed that the Y chromosome is apparently devoid of polymorphic genetic markers. Jakubiczka et al. [8] estimated a frequency of less than 1 point mutation in 18,000 nucleotides, and Malaspina et al. [9] calculated less than 1 per 46,515 nucleotides. Spurdle and Jenkins [10] screened a 20,808 bp segment for Y-specific RFLPs and did not detect any new polymorphism.

The low variation found in the Y chromosome was unexpected in view of its origin and is best explained, simply, by its presence at one quarter of the frequency of the autosomes, in diploid populations. Therefore, it is especially subject to drift that will be reflected in a corresponding reduced diversity [14] . The effective population size of the Y chromosome can also be reduced by a particular pattern of mating behavior found in specific populations. The lack of recombination also explains the low Y chromosome variation found, due to the effect of selective pressure in which a whole haplotype is involved instead of a specific allele [15] .


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