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Meiotic Drive, Mouse
M e i o t i c D r i ve , M o u s e 1165 has very few genes other than the sex-determining region (SRY). However, development is not entirely normal in these cases. Unfortunately, the SRY of humans is close to the pseudoautosomal region so that occasionally, by accident, there is a crossover at meiosis that transfers the SRY to the X chromosome. The result is an XXy individual who expresses male characteristics. By contrast, in mice, the SRY is far away from the pseudoautosomal region, so these accidents are less frequent. There are many forms of sex determination that are entirely different from the XX/ XY type, but they are beyond the scope of this article.
Roeder SG (1997) Meiotic chromosomes: it takes two to tango. Genes and Development 11: 2600±2621.
See also: Chiasma; Chromosome Pairing, Synapsis; Crossing-Over; Genetic Recombination; Sex Linkage; Synaptonemal Complex
Meiotic Drive, Mouse K Ardlie Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0809
Male versus Female Meiosis In general, males produce large numbers of gametes while females produce relatively few. The male gametes tend to be little more than a nucleus with a minimum number of cellular components, while the female cells may contain large amounts of resources for the early development of the embryo, as is evident from the size of the eggs of a wide variety of organisms. The process of meiosis reflects these different requirements of the sexes. For example, in human males, meiosis is a continuing process in the testes from puberty to advanced age, and hundreds of thousands of spermatozoa are formed every day. In females, on the other hand, only a few hundred thousand cells of the ovaries enter meiotic prophase sometime before birth and they stay arrested at that stage for up to 50 years, unless recruited for ovulation. The arrest of female meiosis is not only a common phenomenon in animals, but also in numerous plant species where the flower buds overwinter. The selective advantage of large numbers of male gametes is not certain, but it is often attributed to between-male gamete competition in outbreeding species. In males, all four products of meiosis usually become gametes capable of fertilization. In females, on the other hand, only one of the four products will function in reproduction. The other three products degenerate or may contribute to accessory tissues or, in rare instances, may reenter the oocyte and fuse with the oocyte nucleus and thereby simulate fertilization, a process known as parthenogenesis. For complex reasons, this does not lead to viable offspring in mammals but can produce viable offspring in other vertebrates and in invertebrates.
Further Reading
Moens PB (ed.) (1987) Meiosis. San Diego, CA: Academic Press. Moens PB, Pearlman RE, Heng HHQ and Traut W (1998) Chromosome cores and chromatin at meiotic prophase. Current Topics in Developmental Biology 37: 241±262.
Mendelism is a magnificent invention for fairly testing genes in many combinations, like an elegant factorial experimental design. Yet it is vulnerable at many points and is in constant danger of subversion by cheaters that seem particularly adept at finding such points. (J. Crow, 1988)
Richard Dawkins popularized the `selfish gene' with the notion that the gene, as the unit of selection, is inherently selfish and that the individual is simply the vehicle in which genes propagate themselves. There exists a class of genes, however, which take this passive selfishness a step further and which are capable of their own active self-propagation. That is, they possess characteristics which allow them to enhance their own transmission relative to the rest of the individuals. Such genes, which actively interfere with, or destroy, other genes in the same nucleus have been referred to as the `ultraselfish genes.' One class of ultraselfish genes are the meiotic drive genes, which attracted the attention of geneticists because they `cheat' during meiosis. Meiotic drive was the term first used by Sandler and Novitski in 1957 to refer to segregation distortion resulting from an event, or events, associated with meiotic divisions per se. It has now come to encompass broadly all examples of segregation distortion, regardless of mechanism and including examples that we now know to occur postmeiotically. Meiotic drive is generally restricted to one sex (usually the male) and is broadly defined as an excess recovery of one allelic alternative in the functional gametes of a heterozygous parent. Drive systems rarely have phenotypic markers, and can be difficult to study, thus known incidences of meiotic drive are restricted to organisms that are well characterized genetically. Nevertheless, they are taxonomically widespread and the number of examples described continues to grow. Because meiotic drive genes often actively destroy their homologs to increase their own representation in the gene pool, this has earned them colorful names such as `spore
1166
M e i o ti c D r i ve , M o u s e
killer' and `gamete eliminator.' The best-described examples of drive come from Drosophila (such as Sex-Ratio (SR), a meiotic drive system on the X chromosome of D. pseudoobscura, and Segregation Distorter (SD), an autosomal drive system on the second chromosome of D. melanogaster) and the house mouse, Mus musculus, where at least two examples have been described. In every system that has been analyzed, meiotic drive involves interactions among several loci of a gene complex, encompassing large chromosomal regions. The molecular mechanisms and evolutionary consequences of meiotic drive are still not well understood, although such deviations from Mendelism can have profound effects from an evolutionary perspective. Simple models of meiotic drive generally predict rapid fixation of the driven allele, yet all known examples are maintained in natural populations as polymorphisms. Genomes may respond to meiotic drive genes in a variety of ways, and strong counterbalancing selection to prevent their fixation may result in the evolution of suppressers, enhancers, sterility, and lethal alleles.
t Haplotypes The best studied example of meiotic drive in the house mouse is the t haplotype, which biases DNA transmission by disrupting spermatogenesis. t haplotypes are a selfish form of chromosome 17 that are found in natural populations of all subspecies of the house mouse. They comprise a large 20 cM (centimorgan) region, which is approximately the proximal third of the chromosome. Within this region are a series of four major nonoverlapping inversions which suppress recombination across the region in /t heterozygotes so that t haplotypes are inherited as a single genetic unit. t haplotypes show segregation bias in male mice only. In /t females, segregation is normal and offspring are produced in the expected Mendelian ratios. In contrast, in /t males, the t haplotype is transmitted to over 90 % of the offspring. This is known as transmission ratio distortion (TRD) and is a consequence of the production of wild type sperm that are functionally inactivated due to motility defects. Multiple independent loci are involved in drive. Three to five t complex distorter loci (Tcds) have been described. These vary in strength and act additively on a single, centrally located t complex responder (Tcr) locus to produce the high transmission bias in favor of the t haplotype. The mechanism by which this occurs is still unclear and investigations are ongoing. t haplotypes have not become fixed in natural populations owing to several, strong counterbalancing forces. All males that inherit two t haplotypes are
unconditionally sterile, due to the inactivation of all of their sperm. Additionally, most t haplotypes carry recessive lethal mutations, which results in homozygous lethality during early embryogenesis. The overall frequency of t haplotypes in wild populations is very low, around 10±15 %, and additional forces have also been demonstrated to be acting against t haplotypes to maintain such a low frequency. These include selection against /t heterozygotes, reduced TRD due to multiple mating, and the social and population behavior of mice, which can result in loss of t haplotypes through genetic drift.
HSR Inverted Duplication ± In Most well-known instances of meiotic drive have typically been confined to males; however, an example of drive has been described in the Eastern European subspecies of Mus musculus, in which an aberrant form of chromosome 1, known as In, causes segregation distortion during oogenesis. Unlike the t haplotype, this is an example of meiotic drive that actually does occur during meiosis, as all interactions are known to occur during the second meiotic division. In contains two large insertions held together in an inversion and behaves strangely during oogenesis. Chromatid segregation in heterozygous (/In) females depends on which sperm enters the oocyte before the second meiotic division, such that drive in favor of the In chromosome happens from heterozygous females if they are mated to a / homozygote male. However, if the male himself carries an In chromosome (/In), then drive is ameliorated and the female's offspring inherit her two chromosomes in Mendelian ratios. Genetic analysis has identified a two component system consisting of a postulated distorter and responder loci, where the distorter is on chromosome 1, distal to the responder, and acts on the responder when in trans. The organizational features of this system are very similar to other drive systems, such as the t haplotype, including a two-component system and inversions, and there is considerable parallelism in the way meiotic drive affects various steps in the formation of gametes and zygotes in the two sexes. In is also found at low, variable frequencies in natural populations, and studies of the population dynamics of this chromosome show that selection again acts against homozygous carriers. The viability of homozygotes of both sexes is reduced to 55 % and the fertility of homozygous females is as low as 10%. There are at least three meiotic drive levels (ranging from 50% to 85%) determined by different allelic variants of distorter, and population structure and small population sizes may also contribute to the loss of the chromosome, particularly at lower levels of drive.
Melanoma, Cytogenetic Studies 1167
Deviation from Mendelian Inheritance (DMI) While no other meiotic drive systems are known for the mouse at present, several instances of deviations from Mendelian inheritance (DMI) have been described. Modest DMI has been described from linkage test crosses on chromosomes 2, 4, and 10, but these may be the result of sampling fluctuations from small numbers of test mice. These findings are often not replicated. Strong and replicated DMI (of 70±90 %) has been described favoring Mus spretus-derived alleles at several X-linked loci in four mouse interspecific crosses. The mechanism for this deviation, however, appears most likely to be due to lethality of embryos carrying particular combinations of alleles, rather than to true segregation distortion during oogenesis in F1 hybrid females.
diploid individual (sporophyte). Certain cells of this individual undergo meiosis to produce spores, which, in turn, divide mitotically to give rise to multicellular haploid individuals (gametophytes). These gametophytes eventually generate gametes, which fuse to produce zygotes. See also: Tetrad Analysis
Melanoma, Cytogenetic Studies J Limon Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1593
References
Sandler and Novitski (1957) American Naturalist 41: 105±110.
See also: Segregation Distortion, Mouse
Meiotic Product I Ruvinsky Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0810
Meiotic product is a general term that refers to any of the four haploid cells resulting from a meiotic division. The specific names and eventual fates of these cells differ between organisms with distinct life cycles. The haploid products of a gametic meiosis, characteristic of animals and some protists, are gametes which are formed by meiosis in a diploid individual. These gametes fuse to produce a zygote. As a variation on the theme, gametogenesis in females of many animal species proceeds in such a way that only one gamete is produced per diploid cell entering meiosis. The other three by-products, known as polar bodies, simply remain as a nuclei with a small amount of cytoplasm. Fungi and some algae undergo zygotic meiosis. In this type of life cycle, a diploid zygote formed by syngamy of two gametes immediately enters meiosis. This results in production of four haploid cells, which divide mitotically and eventually produce multicellular haploid organisms (or many single-cell organisms). These individuals give rise to gametes by differentiation of their cells. In sporic meiosis, seen in plants and some algae, a diploid zygote differentiates into a multicellular
The majority of cytogenetic studies of malignant melanoma have been performed on human tumors; a few studies have also been performed on transplantable melanomas in rodents. Cytogenetic studies on the human malignant melanoma have revealed that, as in most human cancers, melanoma cells display acquired, clonal chromosome aberrations. The most consistently observed numerical changes have been losses of chromosomes 10 and 9, and gain of chromosome 7. Among structural aberrations, the most common have been del(6q) or other rearrangements, including i(6)(p10), that lead to loss of 6q. Results from chromosome transfer experiments have provided functional evidence for the presence of a tumor suppressor gene on chromosome 6, which may be acting early in the pathway of tumor formation. All aberrations mentioned above may play an important role in the tumorigenesis and development of malignant melanoma. In addition, various abnormalities of chromosome 1, often resulting in loss of 1p material, and, with a lower frequency, abnormalities of chromosomes 7, 9 (mostly affecting 9p), 11, and 17 were observed. However, the cytogenetic pattern of cutaneous malignant melanoma outlined above concerns predominantly metastatic tumors, since only approximately 20% of all abnormal malignant melanoma karyotypes have been obtained from primary tumors. In general, the karyotypes of metastatic melanoma are more complex, with higher modal chromosomal numbers and higher numbers of structural chromosome abnormalities. It seems that rearrangements of chromosome 11 are later events in tumor progression, and may represent an indicator for a less favorable clinical outcome. An increase in number of chromosome 7, often accompanied by enhanced expression
Roeder SG (1997) Meiotic chromosomes: it takes two to tango. Genes and Development 11: 2600±2621.
See also: Chiasma; Chromosome Pairing, Synapsis; Crossing-Over; Genetic Recombination; Sex Linkage; Synaptonemal Complex
Meiotic Drive, Mouse K Ardlie Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0809
Male versus Female Meiosis In general, males produce large numbers of gametes while females produce relatively few. The male gametes tend to be little more than a nucleus with a minimum number of cellular components, while the female cells may contain large amounts of resources for the early development of the embryo, as is evident from the size of the eggs of a wide variety of organisms. The process of meiosis reflects these different requirements of the sexes. For example, in human males, meiosis is a continuing process in the testes from puberty to advanced age, and hundreds of thousands of spermatozoa are formed every day. In females, on the other hand, only a few hundred thousand cells of the ovaries enter meiotic prophase sometime before birth and they stay arrested at that stage for up to 50 years, unless recruited for ovulation. The arrest of female meiosis is not only a common phenomenon in animals, but also in numerous plant species where the flower buds overwinter. The selective advantage of large numbers of male gametes is not certain, but it is often attributed to between-male gamete competition in outbreeding species. In males, all four products of meiosis usually become gametes capable of fertilization. In females, on the other hand, only one of the four products will function in reproduction. The other three products degenerate or may contribute to accessory tissues or, in rare instances, may reenter the oocyte and fuse with the oocyte nucleus and thereby simulate fertilization, a process known as parthenogenesis. For complex reasons, this does not lead to viable offspring in mammals but can produce viable offspring in other vertebrates and in invertebrates.
Further Reading
Moens PB (ed.) (1987) Meiosis. San Diego, CA: Academic Press. Moens PB, Pearlman RE, Heng HHQ and Traut W (1998) Chromosome cores and chromatin at meiotic prophase. Current Topics in Developmental Biology 37: 241±262.
Mendelism is a magnificent invention for fairly testing genes in many combinations, like an elegant factorial experimental design. Yet it is vulnerable at many points and is in constant danger of subversion by cheaters that seem particularly adept at finding such points. (J. Crow, 1988)
Richard Dawkins popularized the `selfish gene' with the notion that the gene, as the unit of selection, is inherently selfish and that the individual is simply the vehicle in which genes propagate themselves. There exists a class of genes, however, which take this passive selfishness a step further and which are capable of their own active self-propagation. That is, they possess characteristics which allow them to enhance their own transmission relative to the rest of the individuals. Such genes, which actively interfere with, or destroy, other genes in the same nucleus have been referred to as the `ultraselfish genes.' One class of ultraselfish genes are the meiotic drive genes, which attracted the attention of geneticists because they `cheat' during meiosis. Meiotic drive was the term first used by Sandler and Novitski in 1957 to refer to segregation distortion resulting from an event, or events, associated with meiotic divisions per se. It has now come to encompass broadly all examples of segregation distortion, regardless of mechanism and including examples that we now know to occur postmeiotically. Meiotic drive is generally restricted to one sex (usually the male) and is broadly defined as an excess recovery of one allelic alternative in the functional gametes of a heterozygous parent. Drive systems rarely have phenotypic markers, and can be difficult to study, thus known incidences of meiotic drive are restricted to organisms that are well characterized genetically. Nevertheless, they are taxonomically widespread and the number of examples described continues to grow. Because meiotic drive genes often actively destroy their homologs to increase their own representation in the gene pool, this has earned them colorful names such as `spore
1166
M e i o ti c D r i ve , M o u s e
killer' and `gamete eliminator.' The best-described examples of drive come from Drosophila (such as Sex-Ratio (SR), a meiotic drive system on the X chromosome of D. pseudoobscura, and Segregation Distorter (SD), an autosomal drive system on the second chromosome of D. melanogaster) and the house mouse, Mus musculus, where at least two examples have been described. In every system that has been analyzed, meiotic drive involves interactions among several loci of a gene complex, encompassing large chromosomal regions. The molecular mechanisms and evolutionary consequences of meiotic drive are still not well understood, although such deviations from Mendelism can have profound effects from an evolutionary perspective. Simple models of meiotic drive generally predict rapid fixation of the driven allele, yet all known examples are maintained in natural populations as polymorphisms. Genomes may respond to meiotic drive genes in a variety of ways, and strong counterbalancing selection to prevent their fixation may result in the evolution of suppressers, enhancers, sterility, and lethal alleles.
t Haplotypes The best studied example of meiotic drive in the house mouse is the t haplotype, which biases DNA transmission by disrupting spermatogenesis. t haplotypes are a selfish form of chromosome 17 that are found in natural populations of all subspecies of the house mouse. They comprise a large 20 cM (centimorgan) region, which is approximately the proximal third of the chromosome. Within this region are a series of four major nonoverlapping inversions which suppress recombination across the region in /t heterozygotes so that t haplotypes are inherited as a single genetic unit. t haplotypes show segregation bias in male mice only. In /t females, segregation is normal and offspring are produced in the expected Mendelian ratios. In contrast, in /t males, the t haplotype is transmitted to over 90 % of the offspring. This is known as transmission ratio distortion (TRD) and is a consequence of the production of wild type sperm that are functionally inactivated due to motility defects. Multiple independent loci are involved in drive. Three to five t complex distorter loci (Tcds) have been described. These vary in strength and act additively on a single, centrally located t complex responder (Tcr) locus to produce the high transmission bias in favor of the t haplotype. The mechanism by which this occurs is still unclear and investigations are ongoing. t haplotypes have not become fixed in natural populations owing to several, strong counterbalancing forces. All males that inherit two t haplotypes are
unconditionally sterile, due to the inactivation of all of their sperm. Additionally, most t haplotypes carry recessive lethal mutations, which results in homozygous lethality during early embryogenesis. The overall frequency of t haplotypes in wild populations is very low, around 10±15 %, and additional forces have also been demonstrated to be acting against t haplotypes to maintain such a low frequency. These include selection against /t heterozygotes, reduced TRD due to multiple mating, and the social and population behavior of mice, which can result in loss of t haplotypes through genetic drift.
HSR Inverted Duplication ± In Most well-known instances of meiotic drive have typically been confined to males; however, an example of drive has been described in the Eastern European subspecies of Mus musculus, in which an aberrant form of chromosome 1, known as In, causes segregation distortion during oogenesis. Unlike the t haplotype, this is an example of meiotic drive that actually does occur during meiosis, as all interactions are known to occur during the second meiotic division. In contains two large insertions held together in an inversion and behaves strangely during oogenesis. Chromatid segregation in heterozygous (/In) females depends on which sperm enters the oocyte before the second meiotic division, such that drive in favor of the In chromosome happens from heterozygous females if they are mated to a / homozygote male. However, if the male himself carries an In chromosome (/In), then drive is ameliorated and the female's offspring inherit her two chromosomes in Mendelian ratios. Genetic analysis has identified a two component system consisting of a postulated distorter and responder loci, where the distorter is on chromosome 1, distal to the responder, and acts on the responder when in trans. The organizational features of this system are very similar to other drive systems, such as the t haplotype, including a two-component system and inversions, and there is considerable parallelism in the way meiotic drive affects various steps in the formation of gametes and zygotes in the two sexes. In is also found at low, variable frequencies in natural populations, and studies of the population dynamics of this chromosome show that selection again acts against homozygous carriers. The viability of homozygotes of both sexes is reduced to 55 % and the fertility of homozygous females is as low as 10%. There are at least three meiotic drive levels (ranging from 50% to 85%) determined by different allelic variants of distorter, and population structure and small population sizes may also contribute to the loss of the chromosome, particularly at lower levels of drive.
Melanoma, Cytogenetic Studies 1167
Deviation from Mendelian Inheritance (DMI) While no other meiotic drive systems are known for the mouse at present, several instances of deviations from Mendelian inheritance (DMI) have been described. Modest DMI has been described from linkage test crosses on chromosomes 2, 4, and 10, but these may be the result of sampling fluctuations from small numbers of test mice. These findings are often not replicated. Strong and replicated DMI (of 70±90 %) has been described favoring Mus spretus-derived alleles at several X-linked loci in four mouse interspecific crosses. The mechanism for this deviation, however, appears most likely to be due to lethality of embryos carrying particular combinations of alleles, rather than to true segregation distortion during oogenesis in F1 hybrid females.
diploid individual (sporophyte). Certain cells of this individual undergo meiosis to produce spores, which, in turn, divide mitotically to give rise to multicellular haploid individuals (gametophytes). These gametophytes eventually generate gametes, which fuse to produce zygotes. See also: Tetrad Analysis
Melanoma, Cytogenetic Studies J Limon Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1593
References
Sandler and Novitski (1957) American Naturalist 41: 105±110.
See also: Segregation Distortion, Mouse
Meiotic Product I Ruvinsky Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0810
Meiotic product is a general term that refers to any of the four haploid cells resulting from a meiotic division. The specific names and eventual fates of these cells differ between organisms with distinct life cycles. The haploid products of a gametic meiosis, characteristic of animals and some protists, are gametes which are formed by meiosis in a diploid individual. These gametes fuse to produce a zygote. As a variation on the theme, gametogenesis in females of many animal species proceeds in such a way that only one gamete is produced per diploid cell entering meiosis. The other three by-products, known as polar bodies, simply remain as a nuclei with a small amount of cytoplasm. Fungi and some algae undergo zygotic meiosis. In this type of life cycle, a diploid zygote formed by syngamy of two gametes immediately enters meiosis. This results in production of four haploid cells, which divide mitotically and eventually produce multicellular haploid organisms (or many single-cell organisms). These individuals give rise to gametes by differentiation of their cells. In sporic meiosis, seen in plants and some algae, a diploid zygote differentiates into a multicellular
The majority of cytogenetic studies of malignant melanoma have been performed on human tumors; a few studies have also been performed on transplantable melanomas in rodents. Cytogenetic studies on the human malignant melanoma have revealed that, as in most human cancers, melanoma cells display acquired, clonal chromosome aberrations. The most consistently observed numerical changes have been losses of chromosomes 10 and 9, and gain of chromosome 7. Among structural aberrations, the most common have been del(6q) or other rearrangements, including i(6)(p10), that lead to loss of 6q. Results from chromosome transfer experiments have provided functional evidence for the presence of a tumor suppressor gene on chromosome 6, which may be acting early in the pathway of tumor formation. All aberrations mentioned above may play an important role in the tumorigenesis and development of malignant melanoma. In addition, various abnormalities of chromosome 1, often resulting in loss of 1p material, and, with a lower frequency, abnormalities of chromosomes 7, 9 (mostly affecting 9p), 11, and 17 were observed. However, the cytogenetic pattern of cutaneous malignant melanoma outlined above concerns predominantly metastatic tumors, since only approximately 20% of all abnormal malignant melanoma karyotypes have been obtained from primary tumors. In general, the karyotypes of metastatic melanoma are more complex, with higher modal chromosomal numbers and higher numbers of structural chromosome abnormalities. It seems that rearrangements of chromosome 11 are later events in tumor progression, and may represent an indicator for a less favorable clinical outcome. An increase in number of chromosome 7, often accompanied by enhanced expression