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<p>Human-specific traits arise from a confluence of genomic and ecological innovations. A unique telomere-to-telomere fusion of ancestral ape chromosomes produced human chromosome 2 (HSA2), reorganizing the genome and its regulatory landscape. In parallel, hundreds of Human Accelerated Regions (HARs), conserved elements with human-specific sequence changes, became developmental enhancers, and ancient retroviral insertions, namely, endogenous retroviruses (ERVs), were co-opted into promoters and enhancers. Here, we integrate comparative genomics, epigenomics, and host-microbiome co-evolution to propose a unified framework linking these factors to human evolution. We posit that the chromosome 2 fusion reshaped 3D genome architecture and gene regulation. HAR and endogenous retroviral sequences formed composite regulatory modules that drove innovations in cortex development, limb patterning, and immune function. Moreover, host-microbiome co-evolution is woven into this framework, with examples of microbiota-responsive HAR-ERV circuits influencing mucosal immunity, gut-brain signaling, and inflammation.</p> Graphical abstract <p>An integrative model from HSA2 fusion to tunable ERV-HAR circuits and microbiome-conditioned outputs. Ideogram of HSA2 marking the fusion junction and conserved TAD scaffold, with local loop retargeting near the break, anchored by the classic hallmarks of the 2q13 telomere-to-telomere fusion and the remnant inactivated centromere framing a substrate for regulatory rewiring. An ERV LTR as a stimulus-responsive input (IFN/IL-1β, SCFAs, lipids), a HAR as a human-specific tuner (amplitude/timing), and a 3D loop to a target promoter. Right, three chr-2 vignettes (2q32.3 mucosal immunity; 2p21 CAMKMT; 2q22.3 TEX41) summarize predicted pathways. Microbial co-diversification and selection pulses motivating Micro-Capture-C/HiChIP enhancer-promoter maps, organoid co-culture challenges, CRISPRi/a and base editing of HAR/LTR motifs, and optogenetic loop tethering (LADL), culminating in a therapeutic dial to modulate inducible ERV-HAR modules in infection and autoimmunity</p> <p></p>

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Genomic-microbial coevolution in human development: chromosome 2 fusion, and human accelerated regions

  • 期刊论文

  • 发表日期：

    2026年4月21日

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  • Siddharth Singh,
  • Md Shahadab,
  • Kumar Sachin,
  • Rajan Kumar Pandey,
  • Pankaj Trivedi,
  • Amit Kumar Mishra,
  • Hem Chandra Jha

摘要

Human-specific traits arise from a confluence of genomic and ecological innovations. A unique telomere-to-telomere fusion of ancestral ape chromosomes produced human chromosome 2 (HSA2), reorganizing the genome and its regulatory landscape. In parallel, hundreds of Human Accelerated Regions (HARs), conserved elements with human-specific sequence changes, became developmental enhancers, and ancient retroviral insertions, namely, endogenous retroviruses (ERVs), were co-opted into promoters and enhancers. Here, we integrate comparative genomics, epigenomics, and host-microbiome co-evolution to propose a unified framework linking these factors to human evolution. We posit that the chromosome 2 fusion reshaped 3D genome architecture and gene regulation. HAR and endogenous retroviral sequences formed composite regulatory modules that drove innovations in cortex development, limb patterning, and immune function. Moreover, host-microbiome co-evolution is woven into this framework, with examples of microbiota-responsive HAR-ERV circuits influencing mucosal immunity, gut-brain signaling, and inflammation.

Graphical abstract

An integrative model from HSA2 fusion to tunable ERV-HAR circuits and microbiome-conditioned outputs. Ideogram of HSA2 marking the fusion junction and conserved TAD scaffold, with local loop retargeting near the break, anchored by the classic hallmarks of the 2q13 telomere-to-telomere fusion and the remnant inactivated centromere framing a substrate for regulatory rewiring. An ERV LTR as a stimulus-responsive input (IFN/IL-1β, SCFAs, lipids), a HAR as a human-specific tuner (amplitude/timing), and a 3D loop to a target promoter. Right, three chr-2 vignettes (2q32.3 mucosal immunity; 2p21 CAMKMT; 2q22.3 TEX41) summarize predicted pathways. Microbial co-diversification and selection pulses motivating Micro-Capture-C/HiChIP enhancer-promoter maps, organoid co-culture challenges, CRISPRi/a and base editing of HAR/LTR motifs, and optogenetic loop tethering (LADL), culminating in a therapeutic dial to modulate inducible ERV-HAR modules in infection and autoimmunity