With the complete sequence of the human genome being available, systematic mapping of regions of transcription, transcription factor binding, chromatin structure and histone modification has revealed that 80% of the genome outside of the protein-coding regions performs essential biochemical functions [ENCODE, 2012]. The ‘remainder’ of the human genome contains repeat elements, such as LINEs, SINEs, alpha satellites, and low-copy repeats (LCRs), also known as segmental duplications [Ji et al., 2000; Bailey et al., 2002]. These LCRs are at least 1 kbp in size, show more than 98% homology and predispose the intervening sequences to recombination. Such recombination events produce DNA copy number variations (CNVs), e.g. deletions and duplications, and inversions, which may manifest as genomic disorders [Sharp et al., 2006a]. Such genomic disorders occur with a frequency of 0.7-1.0 per 1,000 live births, often share neurodevelopmental phenotypes and are detected by genome-wide segmental aneuploidy screening [Ji et al., 2000; Hochstenbach et al., 2009, 2011]. CNVs flanked by 2 LCRs are termed recurrent CNVs, since they occur relatively often in cohorts of patients with genomic disorders [Koolen et al., 2006; Sharp et al., 2006b; Mefford et al., 2008; Hannes et al., 2009]. However, since recurrent CNVs also occur in healthy individuals, they themselves are not necessarily pathogenic [Poot et al., 2010]. Indeed, in some patients, 2 recurrent CNVs were found such that concomitant changes in the dosage of genes in both CNVs may account for the clinical phenotype [Girirajan et al., 2010; Poot et al., 2010]. These findings may explain some of the phenotypic variability among patients with genomic disorders and prompted a 2-hit hypothesis for developmental disorders [Girirajan and Eichler, 2010; Girirajan et al., 2011; Poot et al., 2011].
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机译：有了人类基因组的完整序列，转录区域，转录因子结合，染色质结构和组蛋白修饰的系统作图表明，蛋白质编码区域之外的基因组有80％发挥着重要的生化功能[ENCODE，2012 ]。人类基因组的“剩余部分”包含重复元素，例如LINE，SINE，α卫星和低拷贝重复（LCR），也称为片段重复[Ji等，2000; Bailey等，2002]。这些LCR的大小至少为1 kbp，具有超过98％的同源性，并且易于插入中间序列进行重组。此类重组事件产生DNA拷贝数变异（CNV），例如缺失，重复和倒位，可能表现为基因组疾病[Sharp等，2006a]。此类基因组疾病的发生频率为每1000例活产中0.7-1.0，通常具有神经发育表型，并通过全基因组分段非整倍性筛查得以检测[Ji et al。，2000; Hochstenbach等，2009，2011]。两侧有2个LCR的CNV被称为复发性CNV，因为它们在基因组疾病患者队列中相对频繁地出现[Koolen et al。，2006; Sharp et al。，2006b; Mefford等，2008; Hannes等，2009]。但是，由于CNV的复发也发生在健康个体中，因此它们本身不一定具有致病性[Poot等，2010]。确实，在一些患者中，发现了2例复发的CNV，因此两个CNV中基因剂量的伴随变化可能是临床表型的原因[Girirajan et al。，2010; Poot et al。，2010]。这些发现可能解释了基因组疾病患者的某些表型变异性，并提示了发育障碍的两命假说[Girirajan and Eichler，2010; Girirajan等，2011; Poot等，2011]。
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