The Genom of Homo sapiens.pdf

HUMAN SUBTELOMERIC SEQUENCES 45Figure 3. Human subterminal sequence organization. The shaded region is low-copy subtelomeric repeat (Srpt) DNA; unshaded issingle-copy DNA. The terminal (TTAGGG)n tracts are depicted by the arrows, with a 3´-end overhang as shown. The cross-hatchedportion of the Srpt regions in b and c are the TelBam11 and TelBam3.4 segments, respectively. The subterminal regions from whichsingle-copy and low-copy hybridization probes can be derived are shown, as are regions from which allele-specific primers (A_sp)can be selected.telomere-specific and allele-specifc primers. The Tel-Bam3.4 class of subterminal low-copy repeat sequence(Brown et al. 1990) has properties similar to the Tel-Bam11 class, including a low-copy DNA hybridizationprobe specific for this subtelomeric repeat and sufficientdivergence for development of single-telomere-specificand allele-specific telomere-oriented primers (Fig. 3c).Completed reference telomeres that include TelBam3.4family members are those for 9ptel, 15qtel, 16ptel, andXq/Yqtel.Individual-specific telomere-length typing of all 92telomeres in a given genome would have a dramatic impacton basic studies of human telomere capping/uncapping,end-resection and 3´-overhang processing, andtelomere replication and maintenance. In addition, thiscapability may reveal inborn individual-specific differencesin telomere lengths that could affect susceptibilityto aging and cancer phenotypes. The completion of thehuman genome telomere regions and the ongoing analysisof variation in human subtelomeric regions will enableprogress toward this goal.CONCLUSIONSAs shown in Table 1 and Figure 2, there are still verylarge gaps in our understanding of human subtelomericDNA sequence content, organization, and structure. Thecomplete sequencing of these regions is absolutely essentialfor an accurate picture of the human genome. Evenfrom the little that is currently known, it is clear thatlarge-scale subtelomeric variation can have importantfunctional consequences in terms of mutations that causehuman disease (van Deutekom et al. 1996), relative susceptibilityof telomere regions to chromosome rearrangement/instability(Bailey et al. 2002), and subtelomericgene dosage, gene variation, and gene evolution (Trask etal. 1998; Mah et al. 2001; Bailey et al. 2002). It is verylikely that the specific sequence content and organizationof subtelomere regions will have an impact on telomereposition effects, telomeric chromatin/heterochromatinstructure, and DNA replication near telomeres. Telomeremaintenance pathways, particularly those influenced byrecombination, may likewise be affected by differentialsubtelomeric structure and sequence organization. Littleis currently known of possible recombination within andadjacent to large variant regions, and how the haplotypestructure of subtelomeric regions might be affected byspecific subtelomeric sequence content and organizationduring human evolution.Current “finished” reference sequences for most subtelomericregions are amalgams of sequenced BAC,PAC, and half-YAC clones from separate alleles, and theonly cases where some certainty exists with respect to thesequence organization of single, specific subtelomeric al-