Research Overview

Genomic changes at the ends of chromosomes are a major source of both human diversity and human disease. We are interested in the structure and function of subtelomeres: regions at the ends of chromosomes adjacent to telomere repeats. Subtelomeres are a particularly dynamic part of the human genome, subject to rampant double-strand breaks (DSBs) and DNA transfers. The Rudd lab investigates the mechanism of breakage at chromosome ends, in search of DNA sequence motifs that promote genomic instability.

Between 3-6% of patients with idiopathic intellectual disability have a detectable subtelomeric rearrangement in the form of deletions, duplications, or unbalanced translocations. Subtelomeric rearrangements are a heterogeneous collection of structural changes, occurring on all chromosome ends at different locations per end. To understand the mechanisms of breakage at chromosome ends, we must first identify the precise breakage sites. To this end, we have developed a high-resolution microarray to fine-map these subtelomeric breakpoints.

Subtelomeric DNA: Where the
double-strand breaks happen!

Array comparative genomic hybridization (CGH) allows us to quickly identify breakage sites in subtelomeres. We hybridize patient DNA samples vs. a reference DNA sample to detect copy number imbalances. Gains or losses relative to the reference genome appear as shifts in ratios of signal intensities (see array figure). For example, a terminal deletion is detected as a copy number loss (green) at the end of a chromosome. In the case of an unbalanced translocation, one chromosome end is lost (green) and replaced by a gain (red) of another chromosome end. Our array CGH experiments pinpoint breakpoint junctions in a diverse collection of subtelomeric rearrangements at a resolution previously unattainable. We are now cloning and sequencing breakpoint junctions to identify the genomic regions underlying DSBs. Given the repeat content of subtelomeres, we hypothesize that certain repetitive sequences mediate breakage at chromosome ends. Thus, we analyze breakpoint regions for motifs capable of assembling stable secondary structures that may interfere with DNA replication. Functional studies of breakage motifs promise to reveal the mechanisms of subtelomeric breaks, with broader implications for factors that mediate instability throughout the genome.