Singh, SiddharthMd ShahadabSachin, Kumar et al2026-07-152026-04-24Singh, S., Shahadab, M., Sachin, K. et al. Genomic-microbial coevolution in human development: chromosome 2 fusion, and human accelerated regions. Mamm Genome 37, 59 (2026). https://doi.org/10.1007/s00335-026-10228-1http://10.0.2.71/handle/123456789/431Human-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.enChromosome-2 (HSA2)Human accelerated regions (HARs)Endogenous retroviruses (ERVs)Host-microbiome co-evolutionGut-brain axisArticle