The insect sex determination and the intimately linked dosage compensation pathways represent a challenging evolutionary puzzle that has been solved only in Drosophila melanogaster. Analyses of orthologs of the Drosophila genes identified in non-drosophilid taxa^1,2 revealed that evolution of sex determination pathways is consistent with a bottom-up mode,³ where only the terminal genes within the pathway are well conserved. doublesex (dsx), occupying a bottom-most position and encoding sex-specific proteins orchestrating downstream sexual differentiation processes, is an ancient sex-determining gene present in all studied species.^2,4,5 With the exception of lepidopterans, its female-specific splicing is known to be regulated by transformer (tra) and its co-factor transformer-2 (tra2).6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 Here we show that in the African malaria mosquito Anopheles gambiae, a gene, which likely arose in the Anopheles lineage and which we call femaleless (fle), controls sex determination in females by regulating splicing of dsx and fruitless (fru; another terminal gene within a branch of the sex determination pathway). Moreover, fle represents a novel molecular link between the sex determination and dosage compensation pathways. It is necessary to suppress activation of dosage compensation in females, as demonstrated by the significant upregulation of the female X chromosome genes and a correlated female-specific lethality, but no negative effect on males, in response to fle knockdown. This unexpected property, combined with a high level of conservation in sequence and function in anopheline mosquitoes, makes fle an excellent target for genetic control of all major vectors of human malaria.

昆虫性别决定和密切相关的剂量补偿途径代表了一个具有挑战性的进化难题，该难题仅在黑腹果蝇中得到解决。对在非果蝇类群^{1、2中鉴定的}果蝇基因的直系同源物的分析表明，性别决定途径的进化与自下而上的模式一致，^3其中只有途径内的末端基因得到很好的保守。doublesex ( dsx ) 占据最底部位置并编码协调下游性分化过程的性别特异性蛋白质，是一种古老的性别决定基因，存在于所有研究物种中。^{2 、4 , 5}除鳞翅目动物外，已知其雌性特异性剪接受变压器( tra ) 及其辅因子变压器-2 ( tra2 ) 调节。6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 在这里，我们展示了在非洲疟疾蚊子冈比亚按蚊中，一个可能出现在按蚊谱系中的基因，我们称之为无雌性（fle），控制着性别决定雌性通过调节dsx和无果( fru ) 的剪接; 性别决定途径分支中的另一个末端基因）。此外，fle代表了性别决定和剂量补偿途径之间的新分子联系。有必要抑制女性剂量补偿的激活，正如女性 X 染色体基因的显着上调和相关的女性特异性致死率所证明的那样，但对男性没有负面影响，以响应fle击倒。这种出人意料的特性，再加上按蚊的序列和功能的高度保守性，使蚊子成为人类疟疾所有主要媒介的遗传控制的极好目标。