The mole genome reveals regulatory rearrangements associated with adaptive intersexuality (RNA-Seq)

Linking genomic variation to phenotypical traits remains a major challenge in evolutionary genetics. In this study, we use phylogenomic strategies to investigate a distinctive trait among mammals: the development of masculinizing ovotestes in female moles. By combining a chromosome-scale genome assembly of the Iberian mole, Talpa occidentalis, with transcriptomic, epigenetic, and chromatin interaction datasets, we identify rearrangements altering the regulatory landscape of genes with distinct gonadal expression patterns. These include a tandem triplication involving CYP17A1, a gene controlling androgen synthesis, and an intrachromosomal inversion involving the pro-testicular growth factor FGF9, which is heterochronically expressed in mole ovotestes. Transgenic mice with a knock-in mole CYP17A1 enhancer or overexpressing FGF9 showed phenotypes recapitulating mole sexual features. Our results highlight how integrative genomic approaches can reveal the phenotypic impact of noncoding sequence changes. We perform transcriptome analysis on different developmental stages in gonads from moles and mouse to find candidates genes responsible for the formation of the ovotestis in female moles.将基因组变异与表型性状关联起来，仍是进化遗传学领域的重大挑战之一。本研究采用系统基因组学（phylogenomic）策略，对哺乳动物的一种独特性状展开探究：雌性鼹鼠体内男性化卵睾的发育过程。本研究结合伊比利亚鼹鼠（Talpa occidentalis）的染色体级基因组组装结果，与转录组学、表观基因组学及染色质互作数据集，鉴定出了能够改变具有独特性腺表达模式的基因调控景观的基因组重排事件。这些重排事件包括涉及调控雄激素合成的基因CYP17A1的串联三倍化，以及涉及促睾丸生长因子FGF9的染色体内倒位；FGF9在鼹鼠卵睾中呈现异时表达特征。携带敲入的鼹鼠CYP17A1增强子，或过表达FGF9的转基因小鼠，其表型重现了鼹鼠的性别特征相关表型。本研究结果证实，整合式基因组学方法能够揭示非编码序列变异的表型效应。我们还对鼹鼠与小鼠性腺的不同发育阶段开展转录组分析，以筛选出与雌性鼹鼠卵睾形成相关的候选基因。