Abstract
Tandemly repeated DNA is highly mutable and causes at least 31 diseases, but it is hard to detect pathogenic repeat expansions genome-wide. Here, we report robust detection of human repeat expansions from careful alignments of long but error-prone (PacBio and nanopore) reads to a reference genome. Our method is robust to systematic sequencing errors, inexact repeats with fuzzy boundaries, and low sequencing coverage. By comparing to healthy controls, we prioritize pathogenic expansions within the top 10 out of 700,000 tandem repeats in whole genome sequencing data. This may help to elucidate the many genetic diseases whose causes remain unknown.
Highlights
A tandem repeat is a region where multiple adjacent copies of sequence reside in the genomic DNA
Nanopore sequencing of tandem repeat containing plasmids To test our method, we analyzed artificial DNA plasmids containing four different kinds of tandem repeat (CAG, CAA, GGGGCC, and iCCTG) that are known to cause human diseases
The MinION reads were aligned to plasmid reference sequences with copy number 6 (CAG), 15 (CAA), 3 (GGGGCC), and 15 (CCTG). tandem-genotypes predicted the copy number change in each read (Fig. 1): these predictions roughly agree with the actual copy number changes (Fig. 2, Additional file 1: Figure S1)
Summary
A tandem repeat is a region where multiple adjacent copies of sequence reside in the genomic DNA. These regions are highly variable among individuals due to replication error during cell division. They are a source of phenotypic variability in disease and health. More than 30 human diseases are caused by copy number alterations in tandem repeats [1]. Well-known examples of triplet-repeat expansion diseases in protein-coding regions are polyglutamine diseases (e.g., spinal and bulbar muscular atrophy, Huntington’s disease) [2, 3]. Triplet repeat expansion of CAG or CAA codons, which encode
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