The hidden role of acrocentric short arms in genome instability

Department: Institute of Genetics and Cancer

Number of current Students: 4 (1 in 3rd year, 3 in 4th year) - 2 of these 4 are planned to finish in December 2026

Completed Supervisor training: Completed

Co Supervisors: Aneta Mikulasova PhD, Institute of Genetics and Cancer, University of Edinburgh CMVM, amikulas@ed.ac.uk

The short arms of acrocentric chromosomes 13, 14, 15, 21 and 22 are among the least understood regions of the human genome. They consist of highly repetitive DNA (rDNA arrays, satellite repeats and segmental duplications), meaning much of their sequence is missing from canonical references like hg38. Genome-sequencing reads originating from these regions therefore remain unmapped or mis-mapped. The Telomere-to-Telomere (T2T) consortium added 66.1Mb of acrocentric short-arm sequence (PMID:35357919), and studies using this new sequence are now beginning to show how dynamic these regions are in the germline. They undergo recombination between heterologous chromosomes (PMID:37165241) and show elevated de novo mutation rates (PMID:42561914). Their somatic instability, however, remains uncharacterised. Pre-T2T studies reported acquired Robertsonian translocations in blood cancer (PMID:15120908) and rDNA rearrangements in solid tumours (PMID:19920195), but captured only selected features of acrocentric instability and at limited resolution.

We hypothesise that acrocentric short arms represent an overlooked source of somatic structural variation and that their rearrangement can alter the regulatory environment of partner loci. Multiple myeloma provides a useful model because its genome contains frequent, traceable chromosomal rearrangements without the extreme structural complexity of many solid cancers.

Our preliminary data support this idea. Using a repeat-aware computational approach, we identified acrocentric short-arm rearrangements in 6/23 CoMMpass (PMID:39160255) myeloma genomes. In patient-derived xenografts (PDXs), we found a case with a chromosome 14 p-q inversion associated with >500 kb of DNA-methylation remodelling and formation of a neo-topologically-associating domain. In another PDX, a beta-satellite region on 14p was classified by ChromHMM as a super-enhancer state, despite beta-satellite DNA being associated with H3K9me3-rich constitutive heterochromatin (PMID:18648073). These observations suggest that acrocentric rearrangements may have consequences beyond simply marking genome instability.

Aims:

Aim 1: Define the frequency, sequence context and genomic architecture of acrocentric short-arm rearrangements using T2T-aligned genome sequencing from ~1,000 CoMMpass cases.

Aim 2: Determine how acrocentric instability changes during somatic evolution using 65 cases with longitudinal genome sequencing, asking whether these rearrangements are stable or accumulate further complexity during clonal evolution.

Aim 3: Study how acrocentric rearrangements affect partner loci using multiomic data from 13 PDXs, integrating DNA methylation, histone modifications, RNA-seq and Micro-C to reveal changes in chromatin state, gene regulation and 3D genome organisation.

The student will train in genome biology, structural-variant analysis, repeat-aware T2T genome analysis, and integration of epigenomic and 3D-genome data. The project will establish how repetitive genome architecture influences somatic chromosome stability and genome organisation.

BBSRC Remit Area: Understanding the Rules of Life (within Advancing the Frontiers of Bioscience Discovery)