A novel factor modulating X chromosome dosage compensation in Anopheles
Elzbieta Krzywińska, Paolo Ribeca, Luca Ferretti, Andrew Hammond, Jaroslaw Krzywinski
Abstract
Dosage compensation (DC), a process countering chromosomal imbalance in individuals with heteromorphic sex chromosomes, has been molecularly characterized only in mammals, Caenorhabditis elegans , and fruit flies. 1 In Drosophila melanogaster males, it is achieved by an approximately 2-fold hypertranscription of the monosomic X chromosome mediated by the MSL complex. 2 , 3 The complex is not assembled on female X chromosomes because production of its key protein MSL-2 is prevented due to intron retention and inhibition of translation by Sex-lethal, a female-specific protein operating at the top of the sex determination pathway. 4 It remains unclear how DC is mechanistically regulated in other insects. In the malaria mosquito Anopheles gambiae , an approximately 2-fold hypertranscription of the male X also occurs 5 by a yet-unknown molecular mechanism distinct from that in D . melanogaster . 6 Here we show that a male-specifically spliced gene we call 007 , which arose by a tandem duplication in the Anopheles ancestral lineage, is involved in the control of DC in males. Homozygous 007 knockouts lead to a global downregulation of the male X, phenotypically manifested by a slower development compared to wild-type mosquitoes or mutant females—however, without loss of viability or fertility. In females, a 007 intron retention promoted by the sex determination protein Femaleless, known to prevent hypertranscription from both X chromosomes, 7 introduces a premature termination codon apparently rendering the female transcripts non-productive. In addition to providing a unique perspective on DC evolution, the 007 , with its conserved properties, may represent an important addition to a genetic toolbox for malaria vector control.