Abstract
Human nucleolar organizer regions (NORs), containing ribosomal gene (rDNA) arrays, are located on the p-arms of acrocentric chromosomes (HSA13-15, 21, and 22). Absence of these p-arms from genome references has hampered research on nucleolar formation. Previously, we assembled a distal junction (DJ) DNA sequence contig that abuts rDNA arrays on their telomeric side, revealing that it is shared among the acrocentrics and impacts nucleolar organization. To facilitate inclusion into genome references, we describe sequencing the DJ from all acrocentrics, including three versions of HSA21, ∼3 Mb of novel sequence. This was achieved by exploiting monochromosomal somatic cell hybrids containing single human acrocentric chromosomes with NORs that retain functional potential. Analyses revealed remarkable DJ sequence and functional conservation among human acrocentrics. Exploring chimpanzee acrocentrics, we show that "DJ-like" sequences and abutting rDNA arrays are inverted as a unit in comparison to humans. Thus, rDNA arrays and linked DJs represent a conserved functional locus. We provide direct evidence for exchanges between heterologous human acrocentric p-arms, and uncover extensive structural variation between chromosomes and among individuals. These findings lead us to revaluate the molecular definition of NORs, identify novel genomic structural variation, and provide a rationale for the distinctive chromosomal organization of NORs.
Highlights
Nucleolar organizer regions (NORs), comprising ribosomal gene repeat arrays, are the most heavily expressed regions of eukaryotic genomes
To isolate individual human chromosomes, we exploited a panel of monochromosomal somatic cell hybrids A9-13, A9-14, A9-15, A921, and A9-22 (Cuthbert et al 1995; Sullivan et al 2001)
The additional advantage gained from using GM10063 is that we could be certain that the sequences obtained are distal to rDNA
Summary
Nucleolar organizer regions (NORs), comprising ribosomal gene (rDNA) repeat arrays, are the most heavily expressed regions of eukaryotic genomes. RDNA arrays ranging from 50 kb (∼1 rDNA repeat) to 6 Mb (∼140 repeats) are located on the p-arms of the five acrocentric chromosomes, HSA13–15, HSA21, and HSA22 (Fig. 1A; Henderson et al 1972; Stults et al.2008, 2009). E unplaced or misplaced on the human genome Hybridization of these BACs to normal human metaphase spreads revealed that these sequences are shared between all five acrocentric chromosomes. We identified a large (∼40 kb) block of 48-bp satellite repeats, CERs, at the distal end of the DJ and showed that CER blocks are found distal to the rDNA on all acrocentric chromosomes, with additional pericentromeric blocks on HSA14 and HSA22
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