The Epigenome of Evolving Drosophila Neo-Sex Chromosomes: Dosage Compensation and Heterochromatin Formation

Sex chromosomes originated from autosomes but have evolved a highly specialized chromatin structure. Drosophila Y chromosomes are composed entirely of silent heterochromatin, while male X chromosomes have highly accessible chromatin and are hypertranscribed as a result of dosage compensation. Here, we dissect the molecular mechanisms and functional pressures driving heterochromatin formation and dosage compensation of the recently formed neo-sex chromosomes of Drosophila miranda. We show that the onset of heterochromatin formation on the neo-Y is triggered by an accumulation of repetitive DNA. The neo-X has evolved partial dosage compensation and we find that diverse mutational paths have been utilized to establish several dozen novel binding consensus motifs for the dosage compensation complex on the neo-X, including simple point mutations at pre-binding sites, insertion and deletion mutations, microsatellite expansions, or tandem amplification of weak binding sites. Spreading of these silencing or activating chromatin modifications to adjacent regions results in massive mis-expression of neo-sex linked genes, and little correspondence between functionality of genes and their silencing on the neo-Y or dosage compensation on the neo-X. Intriguingly, the genomic regions being targeted by the dosage compensation complex on the neo-X and those becoming heterochromatic on the neo-Y show little overlap, possibly reflecting different propensities along the ancestral chromosome that formed the sex chromosome to adopt active or repressive chromatin configurations. Our findings have broad implications for current models of sex chromosome evolution, and demonstrate how mechanistic constraints can limit evolutionary adaptations. Our study also highlights how evolution can follow predictable genetic trajectories, by repeatedly acquiring the same 21-bp consensus motif for recruitment of the dosage compensation complex, yet utilizing a diverse array of random mutational changes to attain the same phenotypic outcome.性染色体（sex chromosomes）源自常染色体（autosomes），但已演化出高度特化的染色质结构。果蝇（Drosophila）的Y染色体完全由沉默型异染色质（heterochromatin）组成，而雄性X染色体则拥有高度开放的染色质，并因剂量补偿（dosage compensation）作用发生超转录。本研究针对米兰达果蝇（Drosophila miranda）新近形成的新性染色体（neo-sex chromosomes），解析了驱动其异染色质形成与剂量补偿的分子机制及功能选择压力。研究表明，新Y染色体上异染色质形成的起始由重复DNA的积累所触发。新X染色体已演化出部分剂量补偿能力，我们发现已通过多种突变路径在新X染色体上确立了数十个剂量补偿复合物（dosage compensation complex）的全新结合共有基序（binding consensus motifs），包括预结合位点处的简单点突变、插入缺失突变、微卫星扩增（microsatellite expansions）或是弱结合位点的串联扩增。这些沉默或激活型染色质修饰向邻近区域的扩散，会导致新性染色体连锁基因出现大规模表达紊乱，且新Y染色体上的基因沉默与新X染色体上的剂量补偿，均与基因自身功能几乎不存在关联。值得注意的是，新X染色体上被剂量补偿复合物靶向的基因组区域，与新Y染色体上发生异染色质化的区域几乎没有重叠，这或许反映了作为该性染色体起源的祖先染色体，在形成激活型或抑制型染色质构象方面存在不同倾向。本研究结果对当前的性染色体演化模型具有广泛启示，并阐明了机制约束如何限制演化适应性。本研究同时揭示了演化如何遵循可预测的遗传轨迹：通过反复获得相同的21碱基对共有基序来招募剂量补偿复合物，同时利用多样化的随机突变变化实现相同的表型结果。