Double, Double Toil and Trouble

摘要

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].