Molecular patterns of sex determination in the animal kingdom: a comparative study of the biology of reproduction

Abstract

Determining sexual fate is an integral part of reproduction, used as a means to enrich the genome. A variety of such regulatory mechanisms have been described so far and some of the more extensively studied ones are being discussed. For the insect order of Hymenoptera, the choice lies between uniparental haploid males and biparental diploid females, originating from unfertilized and fertilized eggs accordingly. This mechanism is also known as single-locus complementary sex determination (slCSD). On the other hand, for Dipterans and Drosophila melanogaster, sex is determined by the ratio of X chromosomes to autosomes and the sex switching gene, sxl. Another model organism whose sex depends on the X:A ratio, Caenorhabditis elegans, has furthermore to provide for the brief period of spermatogenesis in hermaphrodites (XX) without the benefit of the "male" genes of the sex determination pathway. Many reptiles have no discernible sex determining genes. Their sexual fate is determined by the temperature of the environment during the thermosensitive period (TSP) of incubation, which regulates aromatase activity. Variable patterns of sex determination apply in fish and amphibians. In birds, while sex chromosomes do exist, females are the heterogametic (ZW) and males the homogametic sex (ZZ). However, we have yet to decipher which of the two (Z or W) is responsible for the choice between males and females. In mammals, sex determination is based on the presence of two identical (XX) or distinct (XY) gonosomes. This is believed to be the result of a lengthy evolutionary process, emerging from a common ancestral autosomal pair. Indeed, X and Y present different levels of homology in various mammals, supporting the argument of a gradual structural differentiation starting around the SRY region. The latter initiates a gene cascade that results in the formation of a male. Regulation of sex steroid production is also a major result of these genetic interactions. Similar observations have been described not only in mammals, but also in other vertebrates, emphasizing the need for further study of both normal hormonal regulators of sexual phenotype and patterns of epigenetic/environmental disruption.

Figure 1

Haplodiploid reproduction. In Hymenoptera, unfertilized eggs develop into uniparental haploid males whereas fertilized eggs into biparental diploid females.

Figure 2

Single-locus complementary sex determination (sl-CSD). In single-locus complementary sex determination (sl-CSD), heterozygotes at a single sex locus develop as females whereas hemizygotes and homozygous diploids develop as males. However, homozygous diploid males are generally sterile, unable to mate or not viable.

Figure 3

Matched matings in sl-CSD. In matched matings, half the diploid offspring are homozygous at the sex locus and turn into diploid males, which are unable to contribute to reproduction.

Figure 4

The X:A ratio determines sex in Drosophila melanogaster. In Drosophila melanogaster sex is determined by the X:A ratio, which is communicated through the balance between the X numerator elements and the autosomal denominators in the presence of several maternally derived proteins. An X:A ratio of 0.5 leads to a non-functional SXL and male development, whereas an X:A ratio of 1 maintains SXL in its active state and is conducive to female development.

Figure 5

Sex-specific splicing of the sxl mRNA. Early activation of the sxl gene through a different primer (P_E) in females allows the appearance of an early SXL protein that guides the splicing of the mRNA originating from the 'standard' primer (P_M). This alternative splicing leads to a functional 'mature' SXL protein that then takes up the role of retaining its active state. In males, where no early transcripts can be found, a male-specific exon is included which contains many early stop codons thus leading to the creation of a truncated and non functional protein.

Figure 6

Genes involved in sex determination in Drosophila melanogaster. The SXL protein regulates the female-specific splicing of the tra mRNA. The TRA protein then forms dimers with TRA-2 which regulate the sex-specific splicing of dsx mRNA. DSX^F is the result of said sex-specific splicing in females, whereas DSX^M is present in males. All of the above also interact with other genes in turn, in order to mediate sexual development.

Figure 7

The currently known X-signal elements in C.elegans. In C.elegans, the X-signal elements, such as the SEX-1 and FOX-1 proteins, control the levels of XOL-1 and help determine sex.

Figure 8

Sex gene pathway in C.elegans. A simple depiction of the sex determination gene pathway as it is known today in the soma of C.elegans. The interactions between several groups of gene products that have been observed to have an inhibitory effect on each other follow the switch of xol-1. The result is that several of these proteins remain active only in males only and others only in hermaphrodites.

Figure 9

Sex determining interactions on a cellular level. Suggested protein interactions in the later stages of the sex determination pathway in C.elegans. While the SDC proteins have also been known to serve as part of the dosage compensation mechanism in C.elegans, HER-1 has been pictured as capable of binding to the TRA-2 receptor, which then releases the FEM molecules in males. Those in turn bind to the TRA-1 transcription factors rendering them inactive. In hermaphrodites, the TRA-2 receptors retain their hold on FEM, and TRA-1 is free to act as a transcription factor on the genome.

Figure 10

Gene interactions that allow spermatogenesis and oogenesis in the hermaphrodite C.elegans, as opposed to the gene pathway in the soma. The top half of each frame displays the gene pathway for sex determination in the C.elegans soma and the bottom half the changes that concern the hermaphrodite germline. During the fourth larval stage (L4), a special set of genes expressed in the germline (fog-2, gld-1, laf-1) allows spermatogenesis to occur in hermaphrodites by interfering with the original sex determination pathway (inhibition of tra-2 that leads to the activation of the fem gene products and others such as fog-1 and fog-3). Once spermatogenesis is over and the hermaphrodite enters its mature stage (M), the original sex determination pathway is re-established (tra-2 becomes active again) in the germline of adult hermaphrodites and makes the switch to oogenesis (by inactivating the genes fem, fog-1 and fog-3 gene products that allowed spermatogenesis).

Figure 11

Aromatase. Aromatase is a cytP450 enzyme that allows the conversion of androgens into estrogens.

Figure 12

Temperature-dependent sex determination. Aromatase activity levels during the thermosensitive period (TSP) are regulated by the temperature of the environment and control gonadal differentiation. Changes in the environment temperature before and after TSP do not seem to affect sex.

Figure 13

Sex determination in the medaka. Although many details for the molecular model of sex determination in the medaka are still missing, the mechanism is known to be based on the presence of XX/XY sex chromosomes. Following a stage of undifferentiated gonads, males exclusively express DMY, a gene bearing a DM domain, which is a genetic feature that considered central in sex determination pathways of various species. Among the genes induced downstream is DMRT1, which participates in gonadal development and differentiation in fish, birds and mammals. In XX females, the exact genetic cascade triggered in the absence of DMY is unclear, but it supposed to involve sex-specific gene expression, such as FIGa and sex steroid/aromatase regulation.

Figure 14

The role of ZPKCI and ASW (WPKCI) in ZW sex determination. According to one theory, the ZPKCI proteins form homodimers in ZZ males that stimulate a factor required for the differentiation of the testes. Whereas in ZW females, the ASW (also known as WPKCI) proteins form heterodimers with ZPKCI that may prevent the activation of that factor or stimulate directly the differentiation of ovaries.

Figure 15

The multistage model of sex chromosome evolution. The mammalian X and Y chromosomes are thought to derive from a common initial autosomal pair. By a gradual process of genetic instability, which may have been related to failure in the recombination process, the chromosomes have begun to differ from each other. The first area to acquire a sex-specific role is considered to be the locus around the major sex determinant gene, i.e. SRY. Thus, in evolutionary lower mammals with a more conserved chromosomal content, such as monotremes, X and Y retain homology in all their length but for the SRY region. Subsequent stages of X-Y recombination failure have led to other, transient forms of X-Y structure, such as those observed in marsupials and primates. The greatest level of heterogeny is considered to be that found in modern humans.

Figure 16

Genetic model of sex determination in humans. The formation of the undifferentiated/bipotential gonad is controlled by several genes acting simultaneously, such as WT1, SF1 and Lim1. Primary sex determination is based on the presence of the Y chromosome and its main sex-determining gene, SRY. In this case, SOX9, FtzF1/SF1 and AMH expression divert the gonad and the reproductive tract towards the male phenotype. This differentiation process is regulated by several other genes, including DAX1, GATA4, FOXL2 and, possibly, DMRT1 and 2 (not shown in the figure). In females, SRY absence allows gonadal development towards a female phenotype, mediated by genes such as DAX1, Wnt4 and SF1, resulting in aromatase upregulation. The exact role of stra8 (not shown) in this process remains to be clarified.