Sex Determination (Insects)

Sex determination depends on molecular switches that signal whether the male or the female sex-differentiating pathway will be followed during development; it can be triggered by genetic, epigenetic, or environmental cues. Insects display sexual dimorphism, in which males and female differ in form, behavior, and/or physiology. Although sex determination and developmental pathways leading to two distinct sexes are universal within insects, the primary signals that trigger sex determination are highly diverse and differ between groups. The primary signal for sex determination can entail genetic signaling, epigenetic signaling via maternally expressed genes or genomic imprinting of genes, or cytoplasmic factors like B chromosomes and bacterial infections. The primary signals can act alone or in combination. Molecular genetic details of sex determination and sex differentiation are known mainly from Drosophila , and these are described below. Comparison of sex determination of insects, nematode worms, and mammals points to a similar genetic mechanism that underlies sex determination: a cascade of gene expression, with alternative splicing of key genes and intermediate genes, leading to alternative splicing of a double-switch gene that ultimately controls differentiation of males and females. In insects, it appears that key genes and intermediate genes early in the cascade are unique to each group of insects, but genetic pathways for controlling sex differentiation after the double switch appear to be the same in all insects. Overall, sex determination in insects is highly variable among groups, and in some groups the mechanisms of sex determination differ between populations of a single species (e.g., the house fly Musca and the midge Chironomus).


SEX-DETERMINING SIGNALS

Patterns of sex determination have been explored since chromosomes were first described in the late 1800s. By the early 1900s, it was discovered that many insects have distinct chromosomes in males and females; the work is best described in the comprehensive 1973 topic by M. J. D. White, Animal Cytology and Evolution. A generality about sex-determining mechanisms is that they are tremendously variable among insect orders, although considerable variation also can be found within genera or even within species. Regardless, some broad categories of the primary signal for sex determination can be identified.
The most common pattern of chromosomal sex determination is for females to be the homogametic sex, with two copies of one sex chromosome (XX), whereas males are the heterogametic sex, with two different sex chromosomes (XY). Some insect groups (e.g., Lepidoptera, Trichoptera) have the opposite pattern, in which males are the homogametic sex (ZZ) and females are heterogametic (ZW). Y chromosomes are usually much smaller than X and do not successfully recombine with the X. Unlike mammals, few sex-determining genes are located on Y chromosomes. Thus, the Y chromosome has been lost entirely in numerous orders of insects, leading to a system in which females are XX but males are haploid for sex chromosomes (denoted XO). A molecular genetic mechanism interacting with chromosomal sex determination has been described in Drosophila, and it entails a “molecular counting” mechanism that assesses the ratio of X chromosomes to autosomes early in development. Thus, chromosomal sex determination may generally depend on this type of genic balance, but whether this mechanism is a general feature of insects or is unique to Drosophila is unknown.
Sex chromosomes vary greatly in number and size in insects. Translocations and duplications of sex chromosomes are common and fall into two general categories. First, in groups with XO males, small parts of the X chromosomes may be duplicated and form what are called “neo-Y” chromosomes. Second, entire X and Y chromosomes may be duplicated, so that some species have sexes that are homogametic or heterogametic, but contain multiple copies of the sex chromosomes. For instance, in the oriental rat flea, Xenopsylla cheopis, males are X1X2Y, whereas females are X1X1X2X2, although in other insect groups it is not uncommon for there to be up to five copies of the X chromosome. Multiple sex chromosomes like these would change the balance between sex chromosomes and autosomes and thus bring into doubt the generality of genetic balance as a sex-determining signal.
Many insects have no identifiable sex chromosomes, but still have specific genetic loci encoding genes that act as key sex-determining signals. A common pattern is to have a dominant sex-determining factor that specifies male development for individuals with an Ml+ genotype, whereas females have a +l+ genotype. In this regard, M represents a key gene in a system similar to heterogametic sex determination, but lacking sex chromosomes that differ in size. House flies (Musca domestica) demonstrate further variations of the same theme, in which intermediate genes change the sexual phenotype. Another dominant genetic factor, F, interacts with rare MlM genotypes to produce females with an MlM Fl+ genotype. Individuals with an MlM + l+ genotype develop as males. Finally, some house fly populations have epigenetic sex determination via a maternally expressed gene. Here, a gene found in females determines whether they will produce only female or only male progeny, regardless of the genotype of their male mates.
Haplodiploid sex determination (sometimes called arrhenotoky—the production of males) is found in all Hymenoptera and Thysanoptera and in some Homoptera and Coleoptera. It provides an interesting study of combinations of epigenetic and genetic sex determination. In haplodiploidy, females arise from fertilized eggs and therefore expression during development, with numerous switches in pathways that eventually lead to somatic sexual differentiation and germ-line differentiation. Here we describe the hierarchy as it is known from the careful work done on Drosophila. The sex-determining “trigger” for male development (XY) is an imbalance between genes on the X chromosome and one of the autosomes (X:A = 0.5), whereas females (XX) have an equal ratio of genes on the X chromosome and auto-somes (X:A = 1.0). A molecular counting mechanism controls early transcription of sexlethal (Sxl), the key gene in the sex-determining cascade in Drosophila that controls sex determination and dosage compensation. Intermediate genes, especially transformer (tra), interact with one another to control expression of the double-switch gene doublesex (dsx). This pathway controls somatic sexual differentiation of male and female morphology and behavior, in addition to germ-line differentiation leading to mature ovaries and testes.
In brief, the cascades work as follows (Fig. 1). In females (X: A = 1.0), the molecular counting mechanism activates the early transcription of Sxl mRNA. SXL protein produced by this mRNA regu-
A simplified diagram of heterogametic (XX:XY) sex determination in D. melanogaster. showing the main genes and proteins contributing to the cascade of gene expression leading to development of males and females. This is the best understood and most fully explored genetic system of sex determination in insects, but is probably unique to D. melanogaster and closely related species. Names of genes are in lowercase italics; names of proteins are in uppercase.
FIGURE 1 A simplified diagram of heterogametic (XX:XY) sex determination in D. melanogaster. showing the main genes and proteins contributing to the cascade of gene expression leading to development of males and females. This is the best understood and most fully explored genetic system of sex determination in insects, but is probably unique to D. melanogaster and closely related species. Names of genes are in lowercase italics; names of proteins are in uppercase.
lates the splicing of subsequent Sxl mRNAs to produce the active female-specific form of SXL (f) protein. Active SXL (f) protein regulates splicing of tra mRNA to produce female-specific TRA (f) protein. In turn, TRA (f) protein interacts with other proteins (not shown) to regulate the splicing of dsx mRNA, generating the DSX (f) form. DSX (f) protein negatively regulates the genes responsible for male somatic sexual differentiation, but allows genes responsible for somatic sexual differentiation to produce a morphologically female fly.
In male Drosophila (X:A = 0.5), the molecular counting mechanism prevents transcription of the Sxl gene early in development. In the next step, the absence of SXL protein results in unspliced Sxl ( m) mRNA. This form includes an exon with stop codons embedded in its sequence, so that Sxl (m) transcripts make no functional protein. In turn, transcripts of the tra gene also are not spliced, again resulting in nonfunctional protein because of internal stop codons. Without TRA protein, there is no alterative splicing of dsx, and DSX (m) protein is made. This pathway is the default, because of the absence of functional proteins from key and intermediate genes early in the pathway. Without these proteins, transcription of the double-switch gene dsx results in male-specific DSX (m) protein. DSX (m) negatively regulates the genes responsible for female somatic sexual differentiation, but allows genes responsible for somatic sexual differentiation to produce a morphologically male fly.
Because male and female D. melanogaster have different numbers of X chromosomes (males have one X and females have two), a mechanism is required to compensate for the difference in the number of genes present in the two genotypes. This mechanism is known as dosage compensation. In male Drosophila, a group of genes collectively known as male-specific lethal (msl) genes are active and increase transcriptionltranslation of genes on the single X chromosome. Thus, genes on the single X chromosome in males generate approximately twice the gene products, which are approximately equal to those from genes on the two X chromosomes in the female fly. In female Drosophila the SXL (f) protein prevents msl genes from acting, and there is no subsequent increase in transcription and translation of genes on the X chromosome in females.
A fairly large number of genes also control germ-line sex differentiation and the production of egg and sperm. The regulation of the genes responsible for germ-line sex differentiation is poorly understood. Although different forms of DSX protein appear to affect the morphology of the sex cells in Drosophila, which gene products comprise the “switch” that determines the fate of germ cells as either egg or sperm remain to be identified.
Insects other than Drosophila do not use exactly the same genetic pathways for sex determination. Not only are sex-determining triggers different, but for many insects that have been studied some or all of the genes described above either do not exist at all or do not perform the same function. In addition to Drosophila, the gene Sxl has been isolated from four other Diptera (the fruit fly Bactrocera, Mediterranean fruit fly Ceratitis, phorid fly Megaselia, house fly Musca), but in none of these does SXL protein differ between males and females. Thus Sxl is not involved in sex determination in these insects, and since no homolog of tra has been found in any other insects outside of Drosophila, it is unlikely that the same genetic pathway for sex determination exists in other insects. On the other hand, the gene dsx appears to be conserved in structure and function in Bactrocera, Ceratitis, Megaselia, and the silkworm Bombyx mori (Lepidoptera). Apparent homologs of dsx can also be found in the nematode Caenorhabditis (mab-3) and in mammals (DMT1), and in each they have sex-specific functions in somatic sexual differentiation andlor germ-line differentiation. The control of sex determination is highly variable in insects, but control of sex differentiation leading to somatic sexual differentiation and germ-line differentiation in males and females appears to be conserved, with the possibility that genes within pathways of sex differentiation of all metazoans have common origins.

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