Department of Psychiatry, University of Oxford, SANE-POWIC, Warneford Hospital, Oxford, UK.
Clin Genet. 2012 Apr;81(4):319-24. doi: 10.1111/j.1399-0004.2012.01830.x. Epub 2012 Jan 17.
The psychoses (schizophrenia and bipolar disorder) occur in all populations with approximately uniform incidence and sex-dependent age of onset. Core symptoms involve aspects of language; brain structural deviations are sex and hemisphere-related. Genetic predisposition is unaccounted for by linkage or association. The hypothesis is proposed that the 'missing heritability' is epigenetic in form and generated in meiosis on a species-specific XY chromosomal template. A duplication from Xq21.3 to Yp11.2 that occurred 6 million years ago is proposed as critical to hominin evolution. Within this block of homology the Protocadherin11XY gene pair is expressed as a cell surface adhesion factor in both X and Y forms; it has undergone a series of coding changes (16 in the Y sequence and 5 in the X including two to cysteines) in the hominin lineage. According to the hypothesis these sequence changes, together with one or more deletions and a paracentric inversion in the Y block, were successively selected; late events in this series established cerebral asymmetry (the 'torque') as the defining characteristic of the human brain. Built around this reference frame, an epigenetic message channels early development of the embryo in a sapiens-specific format. Diversity in meiotic pairing is postulated as the basis for species-specific deviations in development associated with psychosis.
精神疾病（精神分裂症和双相情感障碍）发生在所有人群中，其发病率大致相同，且与性别相关的发病年龄也不同。核心症状涉及语言方面；大脑结构偏差与性别和大脑半球有关。遗传易感性不能用连锁或关联来解释。提出了这样的假设，即“缺失的遗传性”在形式上是表观遗传的，并且在减数分裂过程中，在特定于物种的 XY 染色体模板上产生。据推测，600 万年前从 Xq21.3 到 Yp11.2 的重复对于人类进化至关重要。在这个同源性块中，原钙粘蛋白 11XY 基因对以 X 和 Y 形式表达为细胞表面粘附因子；在人类谱系中，它经历了一系列编码变化（Y 序列中有 16 个，X 序列中有 5 个，包括两个变为半胱氨酸）。根据该假设，这些序列变化，以及 Y 块中的一个或多个缺失和旁中心化倒位，被相继选择；该系列的晚期事件确立了大脑的不对称性（“扭矩”）作为人类大脑的特征。以这个参考框架为基础，一个表观遗传信息通道以智人特异性的格式引导胚胎的早期发育。假设减数分裂配对的多样性是与精神疾病相关的特定物种发育偏差的基础。
