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GENDER AND SEX CHROMOSOMES
BACTERIA

     Although bacteria (pictured above) do not reproduce through sexual reproduction, there are several mechanisms which allow an exchange of genes between individuals.  Prokaryotes continue to exchange genes with other organisms today (through processes such as transformation, transduction, and conjugation).  The amount of DNA thought to have originated through lateral transfer ranges from 0% in Mycoplasma genitalium to 16.6% in Synechocystis (Han, 2001). This certainly does not approach the frequency with which it occurs in eukaryotes, although eukaryotes are much more choosy about the individuals they exchange genes with (typically members of their own species).  While sexual reproduction offers an incredible potential for variation in sexually reproducing organisms, this lateral gene transfer is a source of variation and evolution in prokaryotes (Levin, 2000).  Sexual reproduction, whether practiced by plants or animals, requires the genetic distinction between male and female mating types which produce haploid cells which fuse to form diploid zygotes. 

Models predict that diploid organisms have advantages over haploid under certain conditions, such as when parasites are present (Nuismer, 2004; Turzel, 2001).

     Eukaryotes, whose diversity includes humans, fish, plants, fungi, amoebae, and algae, utilize homologous molecular mechanisms to reproduce sexually.

IRIS THYME
SPIDER MILLIPEDE

     In animals, gender may be determined through a variety of mechanisms.  Although the downstream genetic mechanisms which control gender differentiation in amniotes are highly conserved, the initial triggers of gender differ widely (Water, 2007). In Drosophila, the number of X chromosomes determine gender (one X chromosome causes male development; two or more result in female development).  Caenorhabditis elegans uses an XX:XO mechanism for gender determination (Vallender, 2006). Changes in steroid hormones (even externally applied) and temperature can determine gender in fish, amphibians, and reptiles.  Birds possess the ZZ/ZW system (in which the females are the heterogametic gender with two different chromosomes); mammals XX/XY (in which males are heterogametic); while fish, amphibians, and reptiles can possess both systems (Uguz, 2003).

     In most fish, the sex chromosomes are not differentiated from each other.  A number of heteromorphic sex chromosome patterns are known in fish such as XX/XY, ZZ/ZW, XO/XX, and multiple sex chromosomes (such as X1X2Y/X1X1X2X2 ).  The XY/XX system is known in 4 species of Bathylagidae, 2 species of Salmonidae, 1 species of Ictaluridae, 2 species of Erythrinidae, 1 species of Anostomidae, 1 species of Myctophidae, 2 species of Cyprinodontidae, 1 species of Gasterosteidae, and 3 species of Melamphaeicae.  The ZZ/ZW system is known in 1 species of Bagridae, 4 species of Anostomatidae, 1 species of Characidae, 1 species of Anguillidae, 1 species of Congridae, 1 species of Synodontidae, 1 species of Cyprinodontidae, 4 species of Poeciliidae, 1 species of Gasterosteidae, and 2 species of Belontiidae (Solari, 1994).    

 

     In most amphibians, there are no differences between the chromosomes of males and females (they are homomorphic).  Of 350 studied species of amphibians, there are only 41 (12%) cases of heteromorphic sex chromosomes.  Both XY and ZX systems are known.  In heteromorphic cases, the differences between male and female chromosomes may be differences in size, differences in banding patterns (small or extensive), and the presence of inversions.  In some species of amphibian, there are homomorphic sex chromosomes in some races but heteromorphic sex chromosomes in others (such as in two species of the newt Triturus).   In the marsupial frog Gastrotheca walkeri the X chromosome is larger than the Y while in the closely related species G. ovifera, the Y chromosome is larger than the X and is composed primarily of heterochromatin.  Extra female chromosomes are known in some species.  Temperature can affect the gender of tadpoles, although different amphibians vary in whether warmer temperatures increases the number of males or females (Solari, 1994).

Like birds, snakes utilize a ZZ:ZW chromosomal mechanism for gender determination.The Z and W chromosomes are the same structure in primitive snakes such as boids while higher snakes (vipers and elapids) have a small W chromosome with a great percentage of heterochromatin. The genes located on the autosomes and sex chromosomes differ in these two groups, indicating that this mechanism evolved independently twice. In contrast, crocodiles and many lizards determine gender using nest temperature which is presumed to be the ancestral amniote mechanism (Vallender, 2006; Matsubara, 2006).

     Only four examples of heteromorphic sex chromosomes are known in turtles and the differences between male and female chromosomes are slight.   In the lizard family Iguanidae, many species utilize an XY system of gender determination although some possess multiple sex chromosomes (for example, males may possess a diploid count of 36 while females possess 35 chromosomes).  Among primitive snakes, there is one species of boa which determines gender through a ZW system in which the sex chromosomes differ in an inverted region.  Most advanced snakes utilize a ZW system with 8 species known in which multiple sex chromosomes are utilized (Solari, 1994).

TURTLE

     Temperature dependent sex determination has been shown in 28 turtle species, several lizards, and all crocodilians.  Temperature can also control gender in amphibians.  Some fish are synchronous hermaphrodites in that they possess both ovarian and testicular tissue simultaneously.  Others are sequential hermaphrodites in which the individuals change their gender (Uguz, 2003).   

Tilapia mossambicus and T.niloticus females are homogametic (XX) and the males are heterogametic (XY) while the opposite is true of the males (ZZ) and females (ZW) of T. hornorum and T. aureus (Uguz, 2003).   Temperature can determine gender in some fish.  Cold temperatures induce female development in some Atherinids, Poecilids, cichlids and high temperatures induce female development in Dicentrarchus labrax and Ictalurus punctatus (Uguz, 2003). 

     In different species of the lizard Anolis, males and females may have the same karyotype, an XY/XX system, or an X1X2Y/X1X1X2X2 system.  Individuals of the species Anolis grahami vary in possessing heteromorphic sex chromosomes.  In the live bearing species Lacerta vivipara, some females possess one chromosome fewer than males.  In the snake Bungarus caeruleus, females possess one chromosome fewer than males. (Chiarelli, 1973).  Sex chromosomes arose separately in birds and mammals.  In ratites, the Z and W chromosomes are less dimorphic than in all other birds, supporting other evidence that they were one of the first bird lineages to evolve (Fridolfsson, 1988; Solari, 1994). In birds, the DMRT1 gene appears to determine gender in a dosage-dependent manner (Water, 2007).

     Although most mammals determine gender using an XY/XX system including most marsupials, there are variations which have arisen in some mammalian groups (Whitworth, 2001).  Monotremes possess X and Y chromosomes although the Y is not much smaller than the X.  In echidnas, females are X1X1X2X2  while males are X1X2Y (Solari, 1994).  In the marsupial family Macropodidae, some species use and XY/XX gender determiantion system while others use XY1Y2/XX, X1X2Y/X1X1X2/X2, --/XX, and XY/-- systems.  In Macropodidae, the nucleolus is organized around the X chromosome in all but one species but its position varies greatly.  In some species, male diploid chromosome numbers are 15 while those of the females 16.  There are also variations in the genetic mechanisms of gender in Permelidae and Petauridae (Stonehouse, 1977; Rofe, 1985; Solari, 1994).    Differences in the number of chromosomes between males and females of the insectivore Sorex araneus have been observed.  Males and females possess different numbers of chromosomes in 5 different genera of the rodent family Muridae while all other species in the genera have the typical XX/XY system.  The deer Muntiacus reevsi possesses a diploid count of 46 while that of M. muntjac can be 6 or 7 (there are two Y chromosomes which result in males having an additional chromosome).  In one species of cattle (Tragelaphus spekei strepsiceros), males have one fewer chromosome than females. In the bat family Phyllostomatidae, an XY1Y2 system seems to have evolved separately in 3 separate genera in three separate subfamilies.  Males have one fewer chromosomes than females in 2 genera of viverrids (Chiarelli, 1973).

    The XY1Y2/XX system is known in marsupials (Macrotis lagotis in Peramelidae and Wallabia bicolor and Potorous tridactylus in Macropodidae), insectivores (Echinops telfairi in Centetidae and 6 species of Sorex in Sorcidae), bats (12 species of Phyllostomatidae), rodents (3 species of Cricetidae), and deer (Muntgacus muntjak).  The X1X2Y/X1X1X2X2 sex determination system is known in marsupials (Lagorchestes conspicillatus in Macropodidae), rodents (Leggada minutoides in Muridae), carnivores (8 species of Viverridae) and antelopes (2 species of Tragelaphus in Antilopidae).  Some bats and gerbils use an XY1Y2  system while some insectivores use X1X2Y.  Variations from the XY determination system are also known in lemmings and voles. An XX/XO system is known in bats (Mesophylla macconelli) and primates (Callimico goeldii in Callithricidae) (Chiarelli, 1973; Solari, 1994).  Two groups of rodents (the mole voles of Europe and the Japanese country rat) determine gender without a Y chromosome or the SRY gene (Water, 2007).

  There are three mechanisms to inactivate X chromosomes known in mammals. Marsupials exclusively inactivate the X chromosome inherited from the male parent. In placental mammals, inactivation is random in most tissues (although the placenta may preferentially inactivate the paternal X chromosome as in rodents and artiodactyls). The paternal X inactivation observed in marsupials may have been the ancestral condition for this placental pattern. Also in placental mammals, all sex chromosomes are inactivated during the early meiosis (Namekawa, 2007).

 THE Y CHROMOSOME

     

The ancestral Y chromosome possessed all the genes located on the X chromosome, most of which have been lost.  This loss was not complete by the diversification of mammalian lineages.  UBE1X is a pseudoautosomal gene is monotremes located on the Y chromosome which has reduced to functionless fragments in primates.  Rodent Y chromosomes lack an RPS4X gene which is present on the Y chromosomes of other placental mammals and primates lack a Y copy of STS which is present in rodents (Pask, 2000).  Of monotremes, only the sexual determination of the platypus is known and it is complex: males possess a  X1Y1X2Y2X3Y3X4Y4X5Y5 karyotype (Rens, 2004).  Although the X and Y chromosomes have a common therian ancestry, some genes on the X and Y chromosomes in eutherians are autosomal in marsupials (such as ZFY/X, AMELY/X, STS/STSP, and the pseudoautosomal genes).  Thus, chromosomal regions were added to the X and Y chromosomes at the base of the eutherian lineage (Pask, 2000).  The X-Y homologous gene ubiquitin activating enzyme (UBE1) has been lost from the Y chromosome in the primate lineage.  This is predicted in the model that the X and Y chromosomes were derived from autosomes and that selection favors the loss of homologous genes to discourage crossing over between them (Mitchell, 1998).   Fish, amphibians, and reptiles possess homologs of Y chromosomal genes (such as ZFY) and SOX genes involved in the determination of gender in mammals.(Spotila, 1994) but they are not limited to one gender (Uguz, 2003; Tiersh, 1992). 

      The development of the reproductive system is under genetic control.  Mutations in several genes can cause the absence of gonads in mice, including Lim1, SF-1, WT1, EMX2, and LHX9 (Clarkson, 2002).  The genes which are required for the development of gonads include steroidogenic factor 1 (Sf11), Wilms tumor 1 (Wt1), Lim1, Lhx9, and Emx2; mutations in any of genes can cause the absence of gonads in mice.  Sf1 is a member of the nuclear hormone receptor family which is required for the development of gonads and Leydig cells in testis.  Lim1 and Lhx9 are homeodomain genes.  Emx2 is the homolog of a head gap gene in Drosophila.  Desert hedgehog and its receptor Patched are expressed in the developing testis but not the developing ovary (Tilmann, 2002).  Wnt4 inhibits the formation of Leydig cells in ovaries (Tilmann, 2002).  One family of DNA binding proteins which share a DM domain are involved in the development of the male reproductive system in nematodes, insects, and mammals (in mammals Dmrt1) maintains the seminiferous tubules (Colvin, 2001).

     Reptilian homologs of AMH, DAX1, SF1, SOX9, and WT1 seem to function similarly to those proteins in mammals (Pleau, 1999; Shimada, 1998).  The enzyme 3β-hydroxysteroid dehydrogenase-5-ene-4-ene isomerase (3β HSD) is important in steroid synthesis and has a temperature sensitive activity (Pleau, 1999).  The activity of aromatase which converts androgen to estrogen seems to be an important feature of temperature sensitive sex determination in reptiles.  Aromatase is also temperature sensitive.  Both these enzymes vary in their activity at male vs. female-producing incubation temperatures (Pleau, 1999)..

     A number of genes determine the differentiation of reproductive tissues into male or female specific patterns.  Mutations in these genes can cause sex reversal or the development of some type of intersex phenotype.  Intersex individuals have been described in goats, llamas, sheep, pigs, pandas, dogs, cats, raccoon dogs, whales, moles, rabbits, kangaroos, wallabies, opossums, horses, mice, voles, lemmings, and humans (Vaiman, 2000).  The females of several species of the mole genus Talpa possess ovotestes, gonads with both ovarian and testicular tissue (Barrionuevo, 2004).

 

    A number of genes are known to be involved in the differentiation of gonads.  SF1 and WT1 are required for the genital ridge to become a bipotential gonad.  SRY and SOX9 are required for this gonad to become a testis, after which point SF1 is required for testosterone production (and thus the maturation of male structures) and SF1 and AMH are required for the regression of Muellerian ducts.   DAX1 is required for the production of the ovary and SF1 promotes the production of follicular cells (Ramikissoon, 1996).

 

SRY

     The SRY gene on the Y chromosome is the testis determining factor which initiates male development.  To date, the SRY gene has not been identified in monotremes.  It is present in marsupials, although it has not been demonstrated to function in sex determination.  Genes other than SRY can determine gender, given that some placental mammals lack SRY and that most human XY females do not have mutations in the SRY gene (Pask, 2000).

     SRY is a gene of the SOX gene family which had already produced multiple members by the divergence of the coelomate lineages.  By the origin of the mammalian lineage, three additional genes (Sry, Sox15, and Sox30) had evolved in the SOX family. (Koopman, 2004).  SRY lacks introns, as does SOX3, the gene to which it is most similar and may have evolved. 

     Interestingly, SRY has been modified or lost in some mammalian groups.  An intron has been inserted in the SRY gene of dasyurid marsupials, apparently without altering its function (O’Neill, 1998).  Mole voles do not use SRY or SOX9 to determine gender.  There must be an additional testis determining factor as yet unknown in them (Baumstark, 2001).  Males and females of the rodent Tokudaia osimensis have the same karyotype, lacking a Y chromosome.  This species does not involve the gene Sry in sex determination as does the rest of its subfamily (Murniae, Family Muridae).  Similarly, two species of the rodent genus Ellobius do not use Sry in sex determination, have identical karyotypes in males and females, and thus are unlike the other members of their subfamily (Arvicolinae, Family Muridae) (Soullier, 1998; Just, 1995). Two groups of rodents (the mole voles of Europe and the Japanese country rat) determine gender without a Y chromosome or the SRY gene (Water, 2007).

SOX9

     SOX9 mutations cause feminization of XY individuals and autosomal sex reversal (Jordan, 2001, Vaiman, 2000) and may be a vestige of an older dosage-dependent mechanism for sex determination (Foster, 1994). In birds and mammals, SOX9 is preferentially expressed in males and functions in testis differentiation.  In frogs, it is expressed in both genders, seemingly involved in the development of both ovaries and testes (Takase, 2000). 

     SOX9 is expressed in the brain, heart, and testes.  Sox9 is needed for the endochondral skull elements formed by cranial neural crest cells but not for intermembranous bone and that formed from mesoderm.  Sox9 is involved in both chondrogenesis and sex determination.  Mutations cause skeletal dysplasia (Mori-Akiyama, 2003; OMIM).  SOX9 is essential for chondrocyte development and targets the enhancer of chondrocyte specific genes, such as collagen Col2a1 (Lefebvre, 1997/8).

 

 

DAZ

     The DAZ genes on the Y chromosome are important for fertility and deletions here are a common cause of male infertility.  This Y specific chromosome cluster is thought to be derived from and ancestral gene on human chromosome 3 (DAZL) which is required for both male and female fertility in other organisms.  Another autosomal gene  (BOULE) may be the ancestor of DAZL and it is homologous to genes which regulate meiosis in invertebrates.  BOULE was present in early bilateran animals, DAZL evolved early in the vertebrate lineage, and the Y-specific DAZ cluster evolved since the divergence of new world monkeys and human lineages (Xu, 2001).

 

DAX

There is an X-linked gene DAX-1 which, when present in two copies, can cause XY individuals with SRY to develop as females.  It is a nuclear hormone receptor that binds to retinoic acid and regulates transcription.  DAX-1 is not required for normal male development (Zanaria, 1994). DAX and SRY are thus antagonistic in their function. (Jordan, 2001).  DAX inhibits Sertoli cell development (Clarkson, 2002).

 

FGF9

Mutations in FGF9 in mice can cause a number of defects ranging from the underdevelopment of testes to sex reversal (in addition to effects in other tissues such as underdevelopment of lungs) (Colvin, 2001).

 

WT1

Mammalian WT1 can produce 24 different proteins through alternate splicing, alternate translational initiation sites, and RNA editing (Clarkson, 2002).

WT1 upregulates SRY expression and can also activate BCL2, CDKN1A, and DAX1.  WT1 mutations can cause complete sex reversal.  (Clarkson, 2002).

WT1 and SF1 are upstream of SRY (Magararit, 1998).  WT1 possess four zinc finger domains and mutations are involved in four types of disorders: Wilms tumor, WAGR syndrome, Frasier Syndrome, and Denys-Drash Syndrome.  All of these syndromes may include some aspects of sex reversal (Vaiman, 2000).

Wt1 is required for the production of both kidneys and gonads (Tilmann, 2002).  Wnt family members act through Frizzled receptors (Jordan, 2001).  Wnt-4 expression is maintained in developing ovaries but not developing testes.  XX mice without Wnt-4 masculinization and persistence of rudimentary male ducts, and degeneration of female ducts.  Overexpression of Wnt-4 in XY individuals results in female development   (Jordan, 2001).

 

SF-1

SF-1 is a orphan nuclear hormone receptor.  Mutations can result in sex reversal and agenesis of the adrenal glands and gonads.  Sex reversal can occur in heterozygous humans (Vaiman, 2000; (Jordan, 2001).  SF1 functions upstream of SRY (Magararit, 1998). Some turtles have a gender specific SF1 expression pattern similar to mammals.  SF1 has a similar pattern of expression in marsupials and placental mammals.  It is involved in the development of the adrenal glands, anterior pituitary, and hypothalamus.  It also regulates cytochrome 450 genes which are involved in steroid metabolism in ovaries and testes (Whitworth, 2001).

 

AMH

In mammals, the first step in sex determination is the differentiation of the gonads controlled by genes followed by a second step of phenotypic changes induced by hormones.  Anti-Muellerian hormone is a member of the TGFβ family which is required for male development (without which they develop as pseudphermaphrodites).   Females exposed to AMH undergo partial sex reversal.  Four transcription factors are known to bind to the AMH promoter: SF-1, WT1, SOX-9, and GATA-4 (Vaiman, 2000).  Mullerian inhibiting substance is a member of the TGFβ family which is expressed by Sertoli cells in developing testis (Tilmann, 2002).

      In birds, androgens and Anti-Muellerian hormone are required for testicular development while estrogen is important for ovarian development.  Sox9 may be the transcription factor which initiates the transcription of male genes and AMH (Shimada, 1998). 

 

 

ATRX

ATRX is a member of the helicase superfamily that is only found on the X chromosome.  Mutations in humans can cause thalassemia, mental retardation, and sex reversal.  An ATRY gene (on the Y chromosome) is known in marsupials and it expressed in the testes.  ATRX is involved in gonadal development downstream of SRY, SOX9, and AMH.  ATRX is not expressed in the marsupial testis (Pask, 2000).

 

 

M33, a homolog of Drosophila polycomb, can also cause sex reversal (Tilmann, 2002).