UPS-indel: a Universal Positioning System for Indels

Abstract

Storing biologically equivalent indels as distinct entries in databases causes data redundancy, and misleads downstream analysis. It is thus desirable to have a unified system for identifying and representing equivalent indels. Moreover, a unified system is also desirable to compare the indel calling results produced by different tools. This paper describes UPS-indel, a utility tool that creates a universal positioning system for indels so that equivalent indels can be uniquely determined by their coordinates in the new system, which also can be used to compare different indel calling results. UPS-indel identifies 15% redundant indels in dbSNP, 29% in COSMIC coding, and 13% in COSMIC noncoding datasets across all human chromosomes, higher than previously reported. Comparing the performance of UPS-indel with existing variant normalization tools vt normalize, BCFtools, and GATK LeftAlignAndTrimVariants shows that UPS-indel is able to identify 456,352 more redundant indels in dbSNP; 2,118 more in COSMIC coding, and 553 more in COSMIC noncoding indel dataset in addition to the ones reported jointly by these tools. Moreover, comparing UPS-indel to state-of-the-art approaches for indel call set comparison demonstrates its clear superiority in finding common indels among call sets. UPS-indel is theoretically proven to find all equivalent indels, and thus exhaustive.

Uncovering missed indels by leveraging unmapped reads

“…An indel already in the originally mapped reads can be called again in the newly mapped reads. These “re-identified” indels are discarded to avoid indel redundancy 31 and the remaining are considered as “novel indels”.…”

VarSCAT: A computational tool for sequence context annotations of genomic variants

“…For example, the Human Genome Variation Society (HGVS) recommends a 3’-aligned position for variant nomenclature with respect to the transcript sequence orientation [ 24 ]. The indels in the equivalent region may lead to redundant indels in databases [ 25 , 26 ]. Krawitz et al 2010 illustrated that indel breakpoint ambiguities can affect the sensitivity of indel calling and suggested the unambiguous annotation of an indel, which should have a single coordinate and an equivalent indel region, depending on its sequence context [ 22 ].…”

VarSCAT: A computational tool for sequence context annotations of genomic variants

“…Breakpoint ambiguities may cause potential problems for downstream annotations, such as the Human Genome Variation Society (HGVS) nomenclature of variants, which recommends a 3'aligned position but may lead to redundancies of biologically equivalent indels [24,25]. Study [22] illustrated that indel breakpoint ambiguities can affect the sensitivity of indel calling and suggested the unambiguous annotation of an indel, which should have a single coordinate and an equivalent indel region, depending on its sequence context.…”

“…Breakpoint ambiguity is caused by microhomological subsequences surrounding an indel site, which create an equivalent region for the indel, making it impossible to identify the exact breakpoint position of the indel but to locate the breakpoint at a 5’-aligned position [22,23]. Breakpoint ambiguities may cause potential problems for downstream annotations, such as the Human Genome Variation Society (HGVS) nomenclature of variants, which recommends a 3’-aligned position but may lead to redundancies of biologically equivalent indels [24,25]. Study [22] illustrated that indel breakpoint ambiguities can affect the sensitivity of indel calling and suggested the unambiguous annotation of an indel, which should have a single coordinate and an equivalent indel region, depending on its sequence context.…”

“…The 'TandemRepeat' function of the Genome Annotation Toolkit (GATK) variant annotation module can annotate copy numbers and repeat motifs from a input Variant Call Format (VCF) file if the variant is located in perfect STRs [34]. UPS-indel is a web service with an additional command-line interface that uses a universal positioning system to mark potential breakpoint ambiguities and determine the unique coordinates of indels from VCF input files [25]. SeqTailor is a web server for extracting DNA or protein sequences with reference and alternative alleles directly from VCF input files, which is useful for retrieving information about the sequence contexts of variant sites [35].…”