The one-to-four rule and paralogues of sex-determining genes.

Because of two successive rounds of tetraploidization at their inception, the vertebrates contain four times more protein-coding genes in their genome than the invertebrates: 60,000 versus 15,000. Consequently, each invertebrate gene has been amplified to the maximum of four paralogous genes in vertebrates: the one-to-four rule. When this rule is applied to genes pertinent to gonadal development and differentiation, the following emerged: (i) Two closely related zinc-finger transcription factor genes in invertebrates have been amplified to two paralogous groups in vertebrates. One consisted of EGR1, EGR2, EGR3 and EGR4, whereas the only known paralogue of the other is WT1, which controls the developmental fate of the entire nephric system, and therefore of gonads. Interestingly, EGR1 and WT1 act as antagonists of each other in nephroblastic cells. (ii) SF-1, which controls the fate of two steroid hormone-producing organs, adrenals and gonads, is descended from the invertebrate Ftz-F1 gene, and its only known paralogue is GCNF-1. (iii) The Y-linked SRY, the mammalian testis-determining gene, is a paralogue neither of SOX3 (SRX) nor of SOX9. Its ancient origin suggests that SRY once became extinct in earlier vertebrates, only to revive itself in the mammalian ancestor. (iv) Inasmuch as four paralogues of one invertebrate nuclear receptor gene have differentiated to receptors of androgen, mineralocoticoid, glucocorticoid and progesterone, there should at most be four paralogous estrogen-receptor genes in the vertebrate genome. It is likely that one of them plays a pivotal role in the estrogen-dependent sex-determining mechanism so commonly found among reptiles, amphibians and fish.