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Askar Gafurov, Tomas Vinar, Paul Medvedev, Brona Brejova. Fast Context-Aware Analysis of Genome Annotation Colocalization. Journal of computational biology : a journal of computational molecular cell biology, 31(10):946-964. 2024.

Download preprint: not available

Download from publisher: https://doi.org/10.1089/cmb.2024.0667

Related web page: not available

Bibliography entry: BibTeX

Abstract: 

An annotation is a set of genomic intervals sharing a particular function or 
property. Examples include genes or their exons, sequence repeats, regions with a 
particular epigenetic state, and copy number variants. A common task is to 
compare two annotations to determine if one is enriched or depleted in the 
regions covered by the other. We study the problem of assigning statistical 
significance to such a comparison based on a null model representing random 
unrelated annotations. To incorporate more background information into such 
analyses, we propose a new null model based on a Markov chain that differentiates 
among several genomic contexts. These contexts can capture various confounding 
factors, such as GC content or assembly gaps. We then develop a new algorithm for 
estimating p-values by computing the exact expectation and variance of the test 
statistic and then estimating the p-value using a normal approximation. Compared 
to the previous algorithm by Gafurov et al., the new algorithm provides three 
advances: (1) the running time is improved from quadratic to linear or 
quasi-linear, (2) the algorithm can handle two different test statistics, and (3) 
the algorithm can handle both simple and context-dependent Markov chain null 
models. We demonstrate the efficiency and accuracy of our algorithm on synthetic 
and real data sets, including the recent human telomere-to-telomere assembly. In 
particular, our algorithm computed p-values for 450 pairs of human genome 
annotations using 24 threads in under three hours. Moreover, the use of genomic 
contexts to correct for GC bias resulted in the reversal of some previously 
published findings.