Recombination between heterologous human acrocentric chromosomes

• Published in: bioRxiv
• Main Authors: Guarracino, Andrea, Buonaiuto, Silvia, Gomes De Lima, Leonardo, Potapova, Tamara, Rhie, Arang, Koren, Sergey, Rubinstein, Boris, Fischer, Christian, Human Pangenome Reference Consortium, Gerton, Jennifer L, Phillippy, Adam M, Colonna, Vincenza, Garrison, Erik
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 18.01.2023; Cold Spring Harbor Laboratory
• Edition: 1.2
• Subjects: Chromosome 15; Chromosome translocations; Chromosomes; Consortia; Genomes; Genomics; Homology; Linkage analysis; Linkage disequilibrium; Phylogeny; Recombination; Ribosomal DNA; Sex chromosomes; Telomeres
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2022.08.15.504037

The short arms of the human acrocentric chromosomes 13, 14, 15, 21, and 22 share large homologous regions, including the ribosomal DNA repeats and extended segmental duplications (Floutsakou et al. 2013; van Sluis et al. 2019). While the complete assembly of these regions in the Telomere-to-Telomere consortium's CHM13 provided a model of their homology (Nurk et al. 2022), it remained unclear if these patterns were ancestral or maintained by ongoing recombination exchange. Here, we show that acrocentric chromosomes contain pseudo-homologous regions (PHRs) indicative of recombination between non-homologs. Considering an all-to-all comparison of the high-quality human pangenome from the Human Pangenome Reference Consortium (HPRC) (Liao et al. 2022), we find that contigs from all of the acrocentric short arms form a community similar to those formed by single chromosomes or the sex chromosome pair. A variation graph (Garrison et al. 2018) constructed from centromere-spanning acrocentric contigs indicates the presence of regions where most contigs appear nearly identical between heterologous CHM13 acrocentrics. Except on chromosome 15, we observe faster decay of linkage disequilibrium in the PHRs than in the corresponding short and long arms, indicating higher rates of recombination (N. Li and Stephens 2003; Huttley et al. 1999). The PHRs include sequences previously shown to lie at the breakpoint of Robertsonian translocations (Jarmuz-Szymczak et al. 2014), and we show that their arrangement is compatible with crossover in inverted duplications on chromosomes 13, 14, and 21. The ubiquity of signals of recombination between heterologous chromosomes seen in the HPRC draft pangenome's acrocentric assemblies suggests that these shared sequences form the basis for recurrent Robertsonian translocations, providing sequence and population-based confirmation of hypotheses first developed cytogenetically fifty years ago (Hamerton et al. 1975).Competing Interest StatementThe authors have declared no competing interest.Footnotes* We have extended the work to relate our observation of recombination between heterologous acrocentric chromosomes to the sites of recurrent Robertsonian translocations. We extend our study of this locus with a whole genome phylogenetic survey of the SST1 array that lies at its center. Our specific definition of the pseudo-homologous regions has improved due to use of the sex chromosomes as a positive control, leading to an increase in the power of our linkage disequilibrium analysis. We have extensively rewritten the manuscript to improve its readability by a general scientific audience. We added a new figure that summarizes our results and have generally improved our figure presentation. We include extended information on zenodo and supplementary figures and the PHR BEDs alongside the manuscript here.* https://doi.org/10.5281/zenodo.6993789* https://github.com/pangenome/chromosome_communities