Sex determination can be robustly genetic, strongly environmental, or genetic subject to environmental perturbation. The genetic basis of sex determination is unknown for zebrafish (Danio rerio), a model for development and human health. We used RADtag population genomics to identify sex-linked polymorphisms. After verifying this "RAD-sex" method on medaka (Oryzias latipes), we studied two domesticated zebrafish strains (AB and TU), two natural laboratory strains (WIK and EKW), and two recent isolates from nature (NA and CB). All four natural strains had a single sex-linked region at the right tip of chromosome 4, enabling sex genotyping by PCR. Genotypes for the single nucleotide polymorphism (SNP) with the strongest statistical association to sex suggested that wild zebrafish have WZ/ZZ sex chromosomes. In natural strains, "male genotypes" became males and some "female genotypes" also became males, suggesting that the environment or genetic background can cause female-to-male sex reversal. Surprisingly, TU and AB lacked detectable sex-linked loci. Phylogenomics rooted on D. nigrofasciatus verified that all strains are monophyletic. Because AB and TU branched as a monophyletic clade, we could not rule out shared loss of the wild sex locus in a common ancestor despite their independent domestication. Mitochondrial DNA sequences showed that investigated strains represent only one of the three identified zebrafish haplogroups. Results suggest that zebrafish in nature possess a WZ/ZZ sex-determination mechanism with a major determinant lying near the right telomere of chromosome 4 that was modified during domestication. Strains providing the zebrafish reference genome lack key components of the natural sex-determination system but may have evolved variant sex-determining mechanisms during two decades in laboratory culture.. . .researchers using standard lines of zebrafish that have long been maintained in laboratories are often plagued by severe sex ratio distortions. . .. C. Lawrence, J. P. Ebersole, and R. V. Kesseli (2008) C ONSIDERING the fundamental importance of sex for species propagation, it is surprising that primary sexdetermining mechanisms are not strongly conserved among animal taxa (Bull 1983;Charlesworth 1996;Ming et al. 2011;Bachtrog et al. 2014). Closely related species or even populations of the same species can have different sexdetermining mechanisms (Takehana et al. 2007;Ross et al. 2009;Kobayashi et al. 2013;Heule et al. 2014;Larney et al. 2014). Zebrafish (Danio rerio) is a popular model for studies of vertebrate development, behavior, physiology, evolution, disease, and human health (Mills et al. 2007;Seth et al. 2013;Braasch et al. 2014;Ota and Kawahara 2014;Wilkinson et al. 2014), but researchers struggle with highly variable and distorted sex ratios, and investigations into the genetic nature of zebrafish sex determination are conflicting. To help understand these issues, we conducted a population genomic study of sex determination in multiple zebrafish strains. Zebrafish exhibit...

Background Aberrant signaling between germ cells and somatic cells can lead to reproductive disease and depends on diffusible signals, including TGFB-family proteins. The TGFB-family protein Gsdf (gonadal soma derived factor) controls sex determination in some fish and is a candidate for mediating germ cell/soma signaling. Results Zebrafish expressed gsdf in somatic cells of bipotential gonads and expression continued in ovarian granulosa cells and testicular Sertoli cells. Homozygous gsdf knockout mutants delayed leaving the bipotential gonad state, but then became a male or a female. Mutant females ovulated a few oocytes, then became sterile, accumulating immature follicles. Female mutants stored excess lipid and down-regulated aromatase, gata4, insulin receptor, estrogen receptor, and genes for lipid metabolism, vitellogenin, and steroid biosynthesis. Mutant females contained less estrogen and more androgen than wild types. Mutant males were fertile. Genomic analysis suggests that Gsdf, Bmp15, and Gdf9, originated as paralogs in vertebrate genome duplication events. Conclusions In zebrafish, gsdf regulates ovarian follicle maturation and expression of genes for steroid biosynthesis, obesity, diabetes, and female fertility, leading to ovarian and extra-ovarian phenotypes that mimic human polycystic ovarian syndrome (PCOS), suggesting a role for a related TGFB signaling molecule in the etiology of PCOS.

Wnt4 is a key regulator of ovary development in mammals, but its role in other vertebrates is unknown. Here, Kossack et al. show that zebrafish wnt4a is the ortholog of mammalian Wnt4 and is expressed....

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