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Cell-in-cell, a phenomenon characterized by one or more viable cells entering actively into another cell, was observed more than a century and has only attracted more attention in recent years and is becoming a new hot topic in the biological field, owing its biological significance in evolutionary as well as physiological and pathological relevance in development, homeostasis and diseases. In this paper we focus on the diversity, evolutionary conservatism and clinical implication of cell-in-cell as well as latest opinions on the research strategies. Based on the findings from our laboratory and other research groups three working models of cell-in-cell are also proposed.

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Structural variants (SVs) can be important drivers of human adaptation with strong effects, but previous studies have focused primarily on common variants with weak effects. Here, we used large-scale single-molecule long-read sequencing of 320 Tibetan and Han samples, to show that SVs are key drivers of selection under high-altitude adaptation. We expand the landscape of global SVs, apply robust models of selection and population differentiation combining SVs, SNPs and InDels, and use epigenomic analyses to predict driver enhancers, target genes, upstream regulators, and biological functions, which we validate using enhancer reporter and DNA pull-down assays. We reveal diverse Tibetan-specific SVs affecting the cis- and trans-regulatory circuitry of diverse biological functions, including hypoxia response, energy metabolism, lung function, etc. Our study greatly expands the global SV landscape, reveals the central role of gene-regulatory circuitry rewiring in human adaptation, and illustrates the diverse functional roles that SVs can play in human biology.