Telogator: a method for reporting chromosome-specific telomere lengths from long reads

Abstract

Motivation: Telomeres are the repetitive sequences found at the ends of eukaryotic chromosomes and are often thought of as a 'biological clock,' with their average length shortening during division in most cells. In addition to their association with senescence, abnormal telomere lengths are well known to be associated with multiple cancers, short telomere syndromes and as risk factors for a broad range of diseases. While a majority of methods for measuring telomere length will report average lengths across all chromosomes, it is known that aberrations in specific chromosome arms are biomarkers for certain diseases. Due to their repetitive nature, characterizing telomeres at this resolution is prohibitive for short read sequencing approaches, and is challenging still even with longer reads.

Results: We present Telogator: a method for reporting chromosome-specific telomere length from long read sequencing data. We demonstrate Telogator's sensitivity in detecting chromosome-specific telomere length in simulated data across a range of read lengths and error rates. Telogator is then applied to 10 germline samples, yielding a high correlation with short read methods in reporting average telomere length. In addition, we investigate common subtelomere rearrangements and identify the minimum read length required to anchor telomere/subtelomere boundaries in samples with these haplotypes.

Availability and implementation: Telogator is written in Python3 and is available at github.com/zstephens/telogator.

Supplementary information: Supplementary data are available at Bioinformatics online.

Fig. 1.

Overview of Telogator. ‘Tel’ and ‘subtel’ are used as abbreviations for telomere and subtelomere, respectively. ‘T2T + alt’ indicates the telomere-to-telomere reference genome augmented with alternate subtelomere assemblies

Fig. 2.

An example read from HG002 showing the kmer density and telomere scoring functions for a telomere in chr2p. The red highlighted section indicates read coordinates identified as telomere sequence

Fig. 3.

An example violin plot produced by Telogator on simulated data (read length 20k, error rate 10%). Black lines indicate the ground truth telomere length

Fig. 4.

Telomere length estimation error for different sequencing error rates and read lengths

Fig. 5.

Percentage of telomeres identified by Telogator at different average coverage rates

Fig. 6.

Chromosome-specific telomere length for HG002 (NA24385). The lines indicate the mean TL at each chromosome arm

Fig. 7.

Comparison of average TLs reported by Telogator versus TelomereHunter

Fig. 8.

Correlation of TL as reported from PacBio reads versus Nanopore

Fig. 9.

Very long Nanopore reads were found to span a 100 kb section of subtelomere 20q between telomere sequence and subtelomere 6p in HG002