精神分裂症在一个人的脑海中唤起了许多图像。流行文化已经描绘了“搏击俱乐部”和“美丽的思想”等电影中的疾病人物。但是这种疾病到底是什么？
由于至少出现书面字母，有记录描述了今天称为精神分裂症的体征和症状。
For starters, schizophrenia is extremely complex and manifests itself in myriad ways. It is a psychiatric disorder that primarily affects one of the most, if not the most, important organs in our body: the brain. In the clinic, a presentation of the so-called positive symptoms: hallucinations and delusions along with negative symptoms: apathy and depression for a period lasting anywhere from one to six months tends to be classified under the category of Schizophrenia.
由于至少出现书面字母，有记录描述了今天称为精神分裂症的体征和症状。Furthermore, these records exist in cultures that have been separated by geography and time. This is one of the defining features of the disease – a global lifetime prevalence of 1% that does not depend on where or when one is born.
稳定的全球流行
Manifestation of this disease across cultures and millenia makes one wonder why natural selection, seems to neither eliminate nor reduce the prevalance of the disease. The disease usually manifests in late adolescence to early 20’s, the prime period of reproduction. Yet despite the observation of reduced fecundity amongst patients, the disease persists.
While many hypotheses have been suggested to explain the persistence of the disease, the most prominent is Timothy J. Crow’s ‘evolutionary hypothesis’, put forward more than twenty years ago. This hypothesis stipulates that the disease is a by-product of the evolution of the human mind –that language and psychosis are connected。最初，这很难测试，因为无法确定人类血统中首先表现出语言或精神病。
However, the sequencing of the entire human genome opened many frontiers, including the possibility of tracing evolutionary events that shaped humans.最近的工作自从尼安德特人和丹尼索沃人的共同祖先差异以来，已经追溯了人类基因组上DNA甲基化的演变。人类，尼安德特人和丹尼索牛群之间具有可变甲基化的人类基因组的这样的区域被称为差异甲基化区域或DMR。
检查精神分裂症相关SNP的DMR
In our work, published inBMC Evolutionary Biology, we build upon the results of these DMRs. We systematically investigated whether these regions are enriched for individual nucleotides on the human genome, otherwise known as single nucleotide polymorphisms (SNPs). These SNPs have been associated with Schizophrenia and twelve other traits through previous genome-wide association studies (GWAS). Our findings indicate that the human DMRs but not Neanderthal or Denisovan DMRs harbour more SNPs associated with Schizophrenia than can be expected by chance alone.
要记住的一个重要警告是，GWAS研究仅有助于确定人类基因组（SNP）的区域associated具有性状/疾病，很少有变体causative。More often than not, the results from GWAS instead point to markers involved in various developmental pathways or regions that regulate the complex orchestra of protein formation in the human body. Thus even when we say schizophrenia associated SNPs, the SNPs in and of themselves are merely associated and not causative of the disease.
The lack of enrichment of Neanderthal or Denisovan DMRs for SNPs associated with Schizophrenia could be interpreted in at least two different ways. The first and obvious interpretation is that the regions delineating methylation differences in our evolutionarily extinct cousins did not harbour more genetic variants associated with schizophrenia than expected by chance. This might make us tempted to believe that they may have been devoid of symptoms classified as schizophrenia.
我们表明，人类基因组的区域在人类谱系中特异性变化，在进化时期，与精神分裂症相关的SNP富含。
但是，由于方法论和分析材料的局限性，这种解释可能误导性。我们分析的遗传变异已映射到人类基因组。但是，我们不知道尼安德特人和丹尼索支持的基因组是否具有与精神分裂症相关的任何遗传变异。解决此问题的一种粗略方法是尝试对人类，尼安德特人和丹尼索沃斯人的基因组序列进行比对，并确定与精神分裂症相关的地区的序列相似性，但这更容易说起来难。
第二种解释是，自从尼安德特人和丹尼索沃斯的差异以来，人类谱系中发生的甲基化变化至少在具有精神分裂症风险变异的基因组区域中，至少是部分的。这种解释得到了其他遗传研究的支持，该研究仅查看基本的人类基因组序列，即DNA，一直在选择压力for enrichment of Schizophrenia associated SNPs.
我们对这些DMR的结果以及其他遗传研究现在开始支持TJ Crow提出的精神分裂症的进化假设。我们表明，人类基因组的区域在人类谱系中特异性变化，在进化时期，与精神分裂症相关的SNP富含。
由于甲基化通常受环境的影响，我们的结果也可能表明我们祖先所经历的环境可能导致与精神分裂症相关的基因组区域的可变甲基化。我们距离证明语言还有很长的路要走，精神病已联系在一起。但是，我们和其他现在已经表明，在群体层面上，最近的进化可能部分使我们容易受到精神分裂症的影响。
注释