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Recovery of non-reference sequences missing from the human reference genome.

ABSTRACT: BACKGROUND:The non-reference sequences (NRS) represent structure variations in human genome with potential functional significance. However, besides the known insertions, it is currently unknown whether other types of structure variations with NRS exist. RESULTS:Here, we compared 31 human de novo assemblies with the current reference genome to identify the NRS and their location. We resolved the precise location of 6113 NRS adding up to 12.8 Mb. Besides 1571 insertions, we detected 3041 alternate alleles, which were defined as having less than 90% (or none) identity with the reference alleles. These alternate alleles overlapped with 1143 protein-coding genes including a putative novel MHC haplotype. Further, we demonstrated that the alternate alleles and their flanking regions had high content of tandem repeats, indicating that their origin was associated with tandem repeats. CONCLUSIONS:Our study detected a large number of NRS including many alternate alleles which are previously uncharacterized. We suggested that the origin of alternate alleles was associated with tandem repeats. Our results enriched the spectrum of genetic variations in human genome.

SUBMITTER: Li R

PROVIDER: S-EPMC6796347 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Recovery of non-reference sequences missing from the human reference genome.

Li Ran R Tian Xiaomeng X Yang Peng P Fan Yingzhi Y Li Ming M Zheng Hongxiang H Wang Xihong X Jiang Yu Y

BMC genomics 20191016 1

<h4>Background</h4>The non-reference sequences (NRS) represent structure variations in human genome with potential functional significance. However, besides the known insertions, it is currently unknown whether other types of structure variations with NRS exist.<h4>Results</h4>Here, we compared 31 human de novo assemblies with the current reference genome to identify the NRS and their location. We resolved the precise location of 6113 NRS adding up to 12.8 Mb. Besides 1571 insertions, we detecte ...[more]

PMID: 31619167

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Project description:BackgroundStructural variants comprise diverse genomic arrangements including deletions, insertions, inversions, and translocations, which can generally be detected in humans through sequence comparison to the reference genome. Among structural variants, insertions are the least frequently identified variants, mainly due to ascertainment bias in the reference genome, lack of previous sequence knowledge, and low complexity of typical insertion sequences. Though recent developments in long-read sequencing deliver promise in annotating individual non-reference insertions, population-level catalogues on non-reference insertion variants have not been identified and the possible functional roles of these hidden variants remain elusive.ResultsTo detect non-reference insertion variants, we developed a pipeline, InserTag, which generates non-reference contigs by local de novo assembly and then infers the full-sequence of insertion variants by tracing contigs from non-human primates and other human genome assemblies. Application of the pipeline to data from 2535 individuals of the 1000 Genomes Project helped identify 1696 non-reference insertion variants and re-classify the variants as retention of ancestral sequences or novel sequence insertions based on the ancestral state. Genotyping of the variants showed that individuals had, on average, 0.92-Mbp sequences missing from the reference genome, 92% of the variants were common (allele frequency > 5%) among human populations, and more than half of the variants were major alleles. Among human populations, African populations were the most divergent and had the most non-reference sequences, which was attributed to the greater prevalence of high-frequency insertion variants. The subsets of insertion variants were in high linkage disequilibrium with phenotype-associated SNPs and showed signals of recent continent-specific selection.ConclusionsNon-reference insertion variants represent an important type of genetic variation in the human population, and our developed pipeline, InserTag, provides the frameworks for the detection and genotyping of non-reference sequences missing from human populations.

Dataset Information

Recovery of non-reference sequences missing from the human reference genome.

Publications

Recovery of non-reference sequences missing from the human reference genome.

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