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Autism and the question of the human

机译：自闭症和人类问题

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Large-scale sequencing has characterized an enormous number of genetic variations (GVs), and the functional analysis of GVs is fundamental to understanding differences in disease susceptibility and therapeutic response among and within populations. Using a combination of a sequence-based predictor with known phosphorylation and protein-protein interaction information, we computationally detected 9606 potential phosSNPs (phosphorylation-related single nucleotide polymorphisms), including 720 known, disease-associated SNPs that dramatically modify the human phosSNP-associated kinase-substrate network. Further analyses demonstrated that the proteins in the network are heavily associated in various signaling and cancer pathways, while cancer genes and drug targets are significantly enriched. We re-constructed four population-specific kinase-substrate networks and found that several inherited disease or cancer genes, such as IRS1, RAF1, and EGFR, were differentially regulated by phosSNPs. Thus, phosSNPs may influence disease susceptibility and be involved in cancer development by reconfiguring phosphorylation networks in different populations. Moreover, by systematically characterizing potential phosphorylation-related cancer mutations (phosCMs) in 12 types of cancers, we observed that both types of GVs preferentially occur in the known cancer genes, while a considerable number of phosphorylated proteins, especially those over-representing cancer genes, contain both phosSNPs and phosCMs. Furthermore, it was observed that phosSNPs were significantly enriched in amplification genes identified from breast cancers and tyrosine kinase circuits of lung cancers. Taken together, these results should prove helpful for further elucidation of the functional impacts of disease-associated SNPs.
机译：大规模测序已表征了众多的遗传变异（GV），并且GV的功能分析对于了解人群之间和人群之间疾病易感性和治疗反应的差异至关重要。使用基于序列的预测子与已知的磷酸化和蛋白质-蛋白质相互作用信息的组合，我们通过计算检测了9606种潜在的phosSNP（磷酸化相关的单核苷酸多态性），包括720种与疾病相关的已知SNP，它们极大地修饰了与phosSNP相关的人类激酶-底物网络。进一步的分析表明，网络中的蛋白质与各种信号传导和癌症途径密切相关，而癌症基因和药物靶标则显着富集。我们重建了四个特定于人群的激酶-底物网络，发现几种遗传的疾病或癌症基因（例如IRS1，RAF1和EGFR）受到phosSNP的差异调节。因此，phosSNPs可能会影响疾病的易感性，并通过在不同人群中重新配置磷酸化网络来参与癌症的发展。此外，通过系统地表征12种类型癌症中潜在的磷酸化相关癌症突变（phosCMs），我们观察到两种类型的GV都优先出现在已知的癌症基因中，而相当数量的磷酸化蛋白（尤其是那些过度代表癌症基因的蛋白） ，同时包含phosSNP和phosCM。此外，已观察到，phosSNPs在从乳腺癌和肺癌的酪氨酸激酶回路鉴定的扩增基因中显着富集。综上所述，这些结果将证明有助于进一步阐明与疾病相关的SNP的功能影响。

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