The haplolethality paradox of the wupA gene in Drosophila

Haplolethals (HL) are regions of diploid genomes that in one dose fatal for the organism. Their biological meaning is obscure because heterozygous loss-of-function mutations result dominant lethality (DL) and, consequently, should be under strong negative selection. We report an depth study HL associated to gene wings up A ( wupA ). It encodes 13 transcripts (A-M) yield 11 protein isoforms (A-K) Troponin I (TnI). They functionally diverse their control muscle contraction, cell polarity and proliferation. Isoform K transfers nucleus where it increases transcription proliferation related genes CDK2 , CDK4 Rap Rab5 . The nuclear translocation isoform prevented by co-expression or B isoforms, which illustrates interactions. corresponding DL are, either DNA rearrangements clustered towards 3’ end, thus affecting genomic organization all transcripts, CRISPR-induced two ATG sites eliminate a subset products. joint elimination C, F, G H, however, do not cause phenotypes. Genetically driven expression single rescue neither nor any mutants known gene, suggesting normal function requires properly regulated specific combinations, rather than single, TnI isoforms. conclude results from combined haploinsufficiency large set qualitative quantitative which, chromosomal integrity region. Since fly encoded same its condition becomes unavoidable. These features comparable those dpp only other studied some extent, reveal scenario strict dosage dependence with implications regulation splitting.