Department of Biochemistry and Molecular Genetics and Human Medical Genetics and Neuroscience Programs, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Am J Hum Genet. 2012 Sep 7;91(3):444-54. doi: 10.1016/j.ajhg.2012.07.016. Epub 2012 Aug 16.
DUF1220 domains show the largest human-lineage-specific increase in copy number of any protein-coding region in the human genome and map primarily to 1q21, where deletions and reciprocal duplications have been associated with microcephaly and macrocephaly, respectively. Given these findings and the high correlation between DUF1220 copy number and brain size across primate lineages (R(2) = 0.98; p = 1.8 × 10(-6)), DUF1220 sequences represent plausible candidates for underlying 1q21-associated brain-size pathologies. To investigate this possibility, we used specialized bioinformatics tools developed for scoring highly duplicated DUF1220 sequences to implement targeted 1q21 array comparative genomic hybridization on individuals (n = 42) with 1q21-associated microcephaly and macrocephaly. We show that of all the 1q21 genes examined (n = 53), DUF1220 copy number shows the strongest association with brain size among individuals with 1q21-associated microcephaly, particularly with respect to the three evolutionarily conserved DUF1220 clades CON1(p = 0.0079), CON2 (p = 0.0134), and CON3 (p = 0.0116). Interestingly, all 1q21 DUF1220-encoding genes belonging to the NBPF family show significant correlations with frontal-occipital-circumference Z scores in the deletion group. In a similar survey of a nondisease population, we show that DUF1220 copy number exhibits the strongest correlation with brain gray-matter volume (CON1, p = 0.0246; and CON2, p = 0.0334). Notably, only DUF1220 sequences are consistently significant in both disease and nondisease populations. Taken together, these data strongly implicate the loss of DUF1220 copy number in the etiology of 1q21-associated microcephaly and support the view that DUF1220 domains function as general effectors of evolutionary, pathological, and normal variation in brain size.
DUF1220 结构域是人类基因组中蛋白编码区域中具有最大种系特异性拷贝数增加的区域，主要定位于 1q21，该区域的缺失和相互重复分别与小头畸形和大头畸形有关。鉴于这些发现以及 DUF1220 拷贝数与灵长类动物谱系中大脑大小之间的高度相关性（R(2) = 0.98；p = 1.8 × 10(-6))，DUF1220 序列是潜在的与 1q21 相关的大脑大小病理相关的候选物。为了研究这种可能性，我们使用专门为高重复 DUF1220 序列评分而开发的特殊生物信息学工具，对具有 1q21 相关小头畸形和大头畸形的个体（n = 42）实施靶向 1q21 阵列比较基因组杂交。我们表明，在所检查的所有 1q21 基因（n = 53）中，DUF1220 拷贝数与 1q21 相关的小头畸形个体的大脑大小之间具有最强的关联，特别是对于三个进化上保守的 DUF1220 进化枝 CON1(p = 0.0079)、CON2(p = 0.0134) 和 CON3(p = 0.0116)。有趣的是，属于 NBPF 家族的所有 1q21 DUF1220 编码基因与缺失组的额枕周径 Z 评分均呈显著相关性。在对非疾病人群的类似调查中，我们表明 DUF1220 拷贝数与大脑灰质体积具有最强的相关性（CON1，p = 0.0246；CON2，p = 0.0334）。值得注意的是，只有 DUF1220 序列在疾病和非疾病人群中均具有一致性的显著意义。综上所述，这些数据强烈暗示 1q21 相关小头畸形的病因是 DUF1220 拷贝数的缺失，并支持 DUF1220 结构域作为大脑大小的进化、病理和正常变异的普遍效应子的观点。
