Doan Ryan N, Bae Byoung-Il, Cubelos Beatriz, Chang Cindy, Hossain Amer A, Al-Saad Samira, Mukaddes Nahit M, Oner Ozgur, Al-Saffar Muna, Balkhy Soher, Gascon Generoso G, Nieto Marta, Walsh Christopher A
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Department of Molecular Biology, Centro de Biología Molecular 'Severo Ochoa', Universidad Autonoma de Madrid, UAM-CSIC, Nicolas Cabrera 1, 28049 Madrid, Spain; Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CNB-CSIC, Darwin 3, Campus de Cantoblanco, 28049 Madrid, Spain.
Cell. 2016 Oct 6;167(2):341-354.e12. doi: 10.1016/j.cell.2016.08.071. Epub 2016 Sep 22.
Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations-identified by whole-genome and targeted "HAR-ome" sequencing-showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases. Using chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice, we identified disease-linked, biallelic HAR mutations in active enhancers for CUX1, PTBP2, GPC4, CDKL5, and other genes implicated in neural function, ASD, or both. Our data provide genetic evidence that specific HARs are essential for normal development, consistent with suggestions that their evolutionary changes may have altered social and/or cognitive behavior. PAPERCLIP.
比较分析已确定了可能与人类进化有关的基因组区域，但并未直接评估其功能。人类加速区域（HARs）是人类中具有较高分化程度的保守基因组位点。如果某些HARs调控人类特有的社会和行为特征，那么突变可能会影响认知和社会障碍。引人注目的是，通过全基因组和靶向“HAR-ome”测序鉴定出的罕见双等位基因突变，在父母有共同祖先的自闭症谱系障碍（ASD）个体中显著多于家族对照，这表明在5%的近亲ASD病例中有此类突变的作用。通过染色质相互作用测序、大规模平行报告基因检测（MPRA）和转基因小鼠，我们在CUX1、PTBP2、GPC4、CDKL5以及其他与神经功能、ASD或两者都有关的基因的活性增强子中鉴定出了与疾病相关的双等位基因HAR突变。我们的数据提供了遗传学证据，表明特定的HARs对正常发育至关重要，这与它们的进化变化可能改变了社会和/或认知行为的观点一致。回形针。
