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Landscape of insertion polymorphisms in the human genome.

ABSTRACT: Nucleotide substitutions, small (<50 bp) insertions or deletions (indels), and large (>50 bp) deletions are well-known causes of genetic variation within the human genome. We recently reported a previously unrecognized form of polymorphic insertions, termed templated sequence insertion polymorphism (TSIP), in which the inserted sequence was templated from a distant genomic region, and was inserted in the genome through reverse transcription of an RNA intermediate. TSIPs can be grouped into two classes based on nucleotide sequence features at the insertion junctions; class 1 TSIPs show target site duplication, polyadenylation, and preference for insertion at a 5'-TTTT/A-3' sequence, suggesting a LINE-1 based insertion mechanism, whereas class 2 TSIPs show features consistent with repair of a DNA double strand break by nonhomologous end joining. To gain a more complete picture of TSIPs throughout the human population, we evaluated whole-genome sequence from 52 individuals, and identified 171 TSIPs. Most individuals had 25-30 TSIPs, and common (present in >20% of individuals) TSIPs were found in individuals throughout the world, whereas rare TSIPs tended to cluster in specific geographic regions. The number of rare TSIPs was greater than the number of common TSIPs, suggesting that TSIP generation is an ongoing process. Intriguingly, mitochondrial sequences were a frequent template for class 2 insertions, used more commonly than any nuclear chromosome. Similar to single nucleotide polymorphisms and indels, we suspect that these TSIPs may be important for the generation of human diversity and genetic diseases, and can be useful in tracking historical migration of populations.

SUBMITTER: Onozawa M

PROVIDER: S-EPMC4419790 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Landscape of insertion polymorphisms in the human genome.

Onozawa Masahiro M Goldberg Liat L Aplan Peter D PD

Genome biology and evolution 20150304 4

Nucleotide substitutions, small (<50 bp) insertions or deletions (indels), and large (>50 bp) deletions are well-known causes of genetic variation within the human genome. We recently reported a previously unrecognized form of polymorphic insertions, termed templated sequence insertion polymorphism (TSIP), in which the inserted sequence was templated from a distant genomic region, and was inserted in the genome through reverse transcription of an RNA intermediate. TSIPs can be grouped into two c ...[more]

PMID: 25745018

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Project description:BackgroundPolymorphic Alu elements account for 17% of structural variants in the human genome. The majority of these belong to the youngest AluY subfamilies, and most structural variant discovery efforts have focused on identifying Alu polymorphisms from these currently retrotranspositionally active subfamilies. In this report we analyze polymorphisms from the evolutionarily older AluS subfamily, whose peak activity was tens of millions of years ago. We annotate the AluS polymorphisms, assess their likely mechanism of origin, and evaluate their contribution to structural variation in the human genome.ResultsOf 52 previously reported polymorphic AluS elements ascertained for this study, 48 were confirmed to belong to the AluS subfamily using high stringency subfamily classification criteria. Of these, the majority (77%, 37/48) appear to be deletion polymorphisms. Two polymorphic AluS elements (4%) have features of non-classical Alu insertions and one polymorphic AluS element (2%) likely inserted by a mechanism involving internal priming. Seven AluS polymorphisms (15%) appear to have arisen by the classical target-primed reverse transcription (TPRT) retrotransposition mechanism. These seven TPRT products are 3' intact with 3' poly-A tails, and are flanked by target site duplications; L1 ORF2p endonuclease cleavage sites were also observed, providing additional evidence that these are L1 ORF2p endonuclease-mediated TPRT insertions. Further sequence analysis showed strong conservation of both the RNA polymerase III promoter and SRP9/14 binding sites, important for mediating transcription and interaction with retrotransposition machinery, respectively. This conservation of functional features implies that some of these are fairly recent insertions since they have not diverged significantly from their respective retrotranspositionally competent source elements.ConclusionsOf the polymorphic AluS elements evaluated in this report, 15% (7/48) have features consistent with TPRT-mediated insertion, thus suggesting that some AluS elements have been more active recently than previously thought, or that fixation of AluS insertion alleles remains incomplete. These data expand the potential significance of polymorphic AluS elements in contributing to structural variation in the human genome. Future discovery efforts focusing on polymorphic AluS elements are likely to identify more such polymorphisms, and approaches tailored to identify deletion alleles may be warranted.

Project description:BACKGROUND:Structural 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. RESULTS:To 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. CONCLUSIONS:Non-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.

Project description:The human genome hosts several active families of transposable elements (TEs), including the Alu, LINE-1, and SVA retrotransposons that are mobilized via reverse transcription of RNA intermediates. We evaluated how insertion polymorphisms generated by human retrotransposon activity may be related to common health and disease phenotypes that have been previously interrogated through genome-wide association studies (GWAS). To address this question, we performed a genome-wide screen for retrotransposon polymorphism disease associations that are linked to TE induced gene regulatory changes. Our screen first identified polymorphic retrotransposon insertions found in linkage disequilibrium (LD) with single nucleotide polymorphisms that were previously associated with common complex diseases by GWAS. We further narrowed this set of candidate disease associated retrotransposon polymorphisms by identifying insertions that are located within tissue-specific enhancer elements. We then performed expression quantitative trait loci analysis on the remaining set of candidates in order to identify polymorphic retrotransposon insertions that are associated with gene expression changes in B-cells of the human immune system. This progressive and stringent screen yielded a list of six retrotransposon insertions as the strongest candidates for TE polymorphisms that lead to disease via enhancer-mediated changes in gene regulation. For example, we found an SVA insertion within a cell-type specific enhancer located in the second intron of the B4GALT1 gene. B4GALT1 encodes a glycosyltransferase that functions in the glycosylation of the Immunoglobulin G (IgG) antibody in such a way as to convert its activity from pro- to anti-inflammatory. The disruption of the B4GALT1 enhancer by the SVA insertion is associated with down-regulation of the gene in B-cells, which would serve to keep the IgG molecule in a pro-inflammatory state. Consistent with this idea, the B4GALT1 enhancer SVA insertion is linked to a genomic region implicated by GWAS in both inflammatory conditions and autoimmune diseases, such as systemic lupus erythematosus and Crohn's disease. We explore this example and the other cases uncovered by our genome-wide screen in an effort to illuminate how retrotransposon insertion polymorphisms can impact human health and disease by causing changes in gene expression.

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Landscape of insertion polymorphisms in the human genome.

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Landscape of insertion polymorphisms in the human genome.

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