2-AIN-505, 2-AIN-251: Seminar in Bioinformatics (1), (3)
Winter 2023

Andrea Guarracino, Silvia Buonaiuto, Leonardo Gomes {de Lima}, Tamara Potapova, Arang Rhie, Sergey Koren, Boris Rubinstein, Christian Fischer, Jennifer L. Gerton, Adam M. Phillippy, Vincenza Colonna, Erik Garrison. Recombination between heterologous human acrocentric chromosomes. Nature, 617(7960):335-343. 2023.

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The short arms of the human acrocentric chromosomes 13, 14, 15, 21 and 22 (SAACs) 
share large homologous regions, including ribosomal DNA repeats and extended 
segmental duplications(1,2). Although the resolution of these regions in the 
first complete assembly of a human genome-the Telomere-to-Telomere Consortium's 
CHM13 assembly (T2T-CHM13)-provided a model of their homology(3), it remained 
unclear whether 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-homologous sequences. Utilizing an all-to-all comparison of the human 
pangenome from the Human Pangenome Reference Consortium(4) (HPRC), we find that 
contigs from all of the SAACs form a community. A variation graph(5) constructed 
from centromere-spanning acrocentric contigs indicates the presence of regions in 
which most contigs appear nearly identical between heterologous acrocentric 
chromosomes in T2T-CHM13. Except on chromosome 15, we observe faster decay of 
linkage disequilibrium in the pseudo-homologous regions than in the corresponding 
short and long arms, indicating higher rates of recombination(6,7). The 
pseudo-homologous regions include sequences that have previously been shown to 
lie at the breakpoint of Robertsonian translocations(8), and their arrangement is 
compatible with crossover in inverted duplications on chromosomes 13, 14 and 21. 
The ubiquity of signals of recombination between heterologous acrocentric 
chromosomes seen in the HPRC draft pangenome suggests that these shared sequences 
form the basis for recurrent Robertsonian translocations, providing sequence and 
population-based confirmation of hypotheses first developed from cytogenetic 
studies 50 years ago(9).