The Genom of Homo sapiens.pdf

CENTROMERE ANNOTATION 147CONCLUSIONSCurrent studies of the genomic organization of the centromericregions of human chromosomes reveal severalfeatures, despite the large gaps that are apparent in thecurrent genome sequence assemblies (e.g., Fig. 2). Themost proximal contigs on several chromosome arms inthe genome have reached α-satellite DNA, includingthose on chromosomes 7 (Hillier et al. 2003; Scherer et al.2003), 16 (Horvath et al. 2000), 21 (Brun et al. 2003), 22(Dunham et al. 1999), and the Y chromosome (Skaletskyet al. 2003), in addition to our work on the X chromosomeand chromosome 17, as summarized here. Other fully sequencedcontigs (chromosome 10, Guy et al. 2003) terminatein other types of satellite DNA, short of connectingto α satellite at the centromere. However, only thecontigs on Xp and 17p span from euchromatin of thechromosome arm to higher-order α-satellite repeat arraysthat have been annotated functionally with centromereassays (Fig. 7). Others (like the chromosome 21q junctionillustrated in Fig. 7) terminate in monomeric α satellite,but are separated by a gap of undetermined size from thehigher-order sequences of the functional centromere.Thus, chromosome arm/centromere junctions remain importantgoals for future research, requiring a combinationof directed efforts to extend existing contigs and suitablefunctional assays to provide validation and functional annotation.As we move toward an understanding of the organization,function, and evolution of the human genome, anyclaims of a “complete” sequence will need to include fullanalysis of the pericentromeric and other heterochromaticregions of our chromosomes. The data presented here andelsewhere (Schueler et al. 2001) suggest that, notwithstandingtheir repetitive content, the satellite-containingcentromeric regions of human chromosomes can beFigure 7. Genome assembly of the centromeric regions of the Xchromosome, and chromosomes 17 and 21. Both the X and 17centromeres have contiguous sequence on the short-arm sides,connecting euchromatin to monomeric α satellite (green) tohigher-order repeat α satellite (red). Orange indicates othersatellite sequences. A chromosome 21q contig has reachedmonomeric α satellite but has not connected to higher-order αsatellite (gap indicated by question marks). For these three humanchromosomes, the centromere activity of their respectivehigher-order repeat α satellites has been functionally annotatedusing a human artificial chromosome assay (Harrington et al.1997; Ikeno et al. 1998; Schueler et al. 2001).mapped, sequenced, assembled, and annotated functionally.Complete assembly of centromere contigs should,therefore, be feasible and will provide an importantsource of genomic and functional data for studies of chromosomebiology, as well as genome evolution.Scientific arguments aside, there is also a strong historicaland philosophical imperative for including centromeresin the final stages of gap closure in the archival,truly complete sequence of the genome of Homo sapiens.After all, which part of the Rosetta Stone would onechoose to omit?ACKNOWLEDGMENTSWe thank Evan Eichler, Jeff Bailey, Devin Locke, andEric Green for helpful discussions and assistance. 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