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<p>The regions of the modern human genome that, despite being highly conserved among mammals, have undergone repeated <i>Homo sapien</i>-specific mutations are termed as human accelerated regions (HARs). An increased human brain size, along with the advanced cognitive faculties, is one of the most distinguishing adaptive features associated with HARs. Several studies report that majority of the HARs comprise of the cis-regulatory regions, such as enhancers and are subject to natural selection. Moreover, brain-related proteins have also been explored for their potential evolutionary implications on human cognitive advancement. In this study, we have built a parallel perspective on an already determined set of human accelerated brain enhancers (HABEs) with 34 putative target brain genes for their role in human cognitive enhancements. According to our findings, two of the HABE-associated target genes, <i>IRX3</i> and <i>MAP4K4</i><i>,</i> underwent positive selection in the human lineage. Moreover, comparative analyses with non-human primates and archaic human data, including Neanderthals and Denisovans, revealed that the <i>Homo sapiens</i>-specific mutation P422L in the IRX3 protein, linked to a positively evolving transcriptional enhancer, induces structural repercussions. By employing molecular docking studies, we established that the evolutionary mutation P422L significantly affect the binding patterns of the IRX3 protein with its interacting partner NKX6.1. In conclusion, IRX3-associated HABE and the <i>Homo sapiens</i>-specific substitution P422L in the IRX3 protein serve as examples of the accelerated evolution of human brain regulatory circuits through the combinatorial fine-tuning of coding and non-coding sequences.</p>

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Genetic Foundations of Human Brain Evolution: A Study of IRX3-Associated Human Accelerated Enhancer and the P422L Mutation

  • 期刊论文

  • 发表日期：

    2025年7月18日

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  • Rabail Zehra Raza,
  • Farah Nazir,
  • Amir Ali Abbasi

摘要

The regions of the modern human genome that, despite being highly conserved among mammals, have undergone repeated Homo sapien-specific mutations are termed as human accelerated regions (HARs). An increased human brain size, along with the advanced cognitive faculties, is one of the most distinguishing adaptive features associated with HARs. Several studies report that majority of the HARs comprise of the cis-regulatory regions, such as enhancers and are subject to natural selection. Moreover, brain-related proteins have also been explored for their potential evolutionary implications on human cognitive advancement. In this study, we have built a parallel perspective on an already determined set of human accelerated brain enhancers (HABEs) with 34 putative target brain genes for their role in human cognitive enhancements. According to our findings, two of the HABE-associated target genes, IRX3 and MAP4K4, underwent positive selection in the human lineage. Moreover, comparative analyses with non-human primates and archaic human data, including Neanderthals and Denisovans, revealed that the Homo sapiens-specific mutation P422L in the IRX3 protein, linked to a positively evolving transcriptional enhancer, induces structural repercussions. By employing molecular docking studies, we established that the evolutionary mutation P422L significantly affect the binding patterns of the IRX3 protein with its interacting partner NKX6.1. In conclusion, IRX3-associated HABE and the Homo sapiens-specific substitution P422L in the IRX3 protein serve as examples of the accelerated evolution of human brain regulatory circuits through the combinatorial fine-tuning of coding and non-coding sequences.