Natural genetic variation caused by small insertions and deletions in the human genome

Mills, Ryan E.; Pittard, W. Stephen; Mullaney, Julienne M.; Farooq, Umar; Creasy, Todd; Mahurkar, Anup; Kemeza, David M.; Strassler, Daniel S.; Ponting, Chris P.; Webber, Caleb; Devine, Scott E.

doi:10.1101/gr.115907.110

Cited by 223 publications

(219 citation statements)

References 68 publications

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“…So far the primary focus of evolutionary analysis has been singleamino-acid substitutions, and indel variation has been largely ignored in the assessment of functional divergence. Recent high throughput analyses on human tissues has cataloged the occurrence of coding indels in hundreds of conserved and essential genes as well as in protein isoforms via alternative splicing, thus highlighting indels as an abundant source of structural variation Mills et al 2011). Our characterization of an indel polymorphism in Lhr presents one functional argument supporting the prediction that coding indels play an important evolutionary role.…”

supporting

confidence: 60%

An Indel Polymorphism in the Hybrid Incompatibility Gene Lethal Hybrid Rescue of Drosophila Is Functionally Relevant

Maheshwari

Barbash

2012

Genetics

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Hybrid incompatibility (HI) genes are frequently observed to be rapidly evolving under selection. This observation has led to the attractive conjecture that selection-derived protein-sequence divergence is culpable for incompatibilities in hybrids. The Drosophila simulans HI gene Lethal hybrid rescue (Lhr) is an intriguing case, because despite having experienced rapid sequence evolution, its HI properties are a shared function inherited from the ancestral state. Using an unusual D. simulans Lhr hybrid rescue allele, Lhr 2 , we here identify a conserved stretch of 10 amino acids in the C terminus of LHR that is critical for causing hybrid incompatibility. Altering these 10 amino acids weakens or abolishes the ability of Lhr to suppress the hybrid rescue alleles Lhr 1 or Hmr 1 , respectively. Besides singleamino-acid substitutions, Lhr orthologs differ by a 16-aa indel polymorphism, with the ancestral deletion state fixed in D. melanogaster and the derived insertion state at very high frequency in D. simulans. Lhr 2 is a rare D. simulans allele that has the ancestral deletion state of the 16-aa polymorphism. Through a series of transgenic constructs we demonstrate that the ancestral deletion state contributes to the rescue activity of Lhr 2 . This indel is thus a polymorphism that can affect the HI function of Lhr. WHAT evolutionary forces drive speciation? A significant step toward answering this question has been the identification of hybrid incompatibility (HI) genes, that is, genes with "incompatible substitutions" that cause breakdown in interspecific hybrids. The next challenge is describing the evolutionary basis for the origin of such incompatible substitutions. The classic Dobzhansky-Muller (D-M) model elegantly explains how substitutions incompatible only in an interspecific context can evolve; however, it is agnostic on the nature of the intraspecific evolutionary forces that cause them (Presgraves 2010;Maheshwari and Barbash 2011). The model is equally consistent with incompatible substitutions evolving as functionally neutral mutations drifting to fixation or as functionally advantageous mutations being driven to fixation by natural selection.It is therefore particularly intriguing that so many HI genes show high rates of sequence divergence driven by positive selection. If this divergence corresponds to the incompatible substitutions then there is a direct link between the phenotype under selection and HI. This is very likely for the hybrid sterility gene OdsH, where the signature of selection is concentrated within the DNA-binding homeodomain, because functional analysis of OdsH orthologs has implicated divergent DNA-binding activity in hybrid incompatibility (Ting et al. 1998;Bayes and Malik 2009). However, such a direct link between sequence divergence and function remains to be established for other rapidly evolving HI genes.The HI gene Lethal hybrid rescue (Lhr) poses an interesting paradox. Lhr causes F 1 hybrid male lethality in crosses between Drosophila melanogaster and D. simulans...

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supporting

confidence: 60%

An Indel Polymorphism in the Hybrid Incompatibility Gene Lethal Hybrid Rescue of Drosophila Is Functionally Relevant

Maheshwari

Barbash

2012

Genetics

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“…Cells were cultured in Dulbecco's Modified Eagle's Medium supplemented with 10% FBS and 1% penicillin-streptomycin at 37 C in a humidified 5% CO 2 incubator. The cell lines were characterized by DNA fingerprinting analysis using short tandem repeat markers.…”

Section: Cell Culture and Luciferase Reporter Assaymentioning

confidence: 99%

An Insertion/Deletion Polymorphism within RERT-lncRNA Modulates Hepatocellular Carcinoma Risk

Zhu

Gao

et al. 2012

Cancer Research

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The Prolyl hydroxylase 1 (EGLN2) is known to affect tumorigenesis by regulating the degradation of hypoxiainducible factor. Polymorphisms in EGLN2 may facilitate cancer cell survival under hypoxic conditions and directly associate with cancer susceptibility. Here, we examined the contribution of a 4-bp insertion/deletion polymorphism (rs10680577) within the distal promoter of EGLN2 to the risk of hepatocelluar carcinoma (HCC) in Chinese populations. The contribution of rs10680577 to HCC risk was investigated in 623 HCC cases and 1,242 controls and replicated in an independent case-control study consisting of 444 HCC cases and 450 controls. Logistic regression analysis showed that the deletion allele of rs10680577 was significantly associated with increased risk for HCC occurrence in both case-control studies [OR ¼ 1.40; 95% confidence interval (CI) ¼ 1.18-1.66, P < 0.0001; OR ¼ 1.49; 95% CI ¼ 1.18-1.88, P ¼ 0.0007]. Such positive association was more pronounced in current smokers (OR ¼ 3.49, 95% CI ¼ 2.24-5.45) than nonsmokers (OR ¼ 1.24, 95% CI ¼ 1.03-1.50; heterogeneity P ¼ 0.0002). Genotype-phenotype correlation studies showed that the deletion allele was significantly correlated with higher expression of both EGLN2 and RERT-lncRNA [a long noncoding RNA whose sequence overlaps with Ras-related GTP-binding protein 4b (RAB4B) and EGLN2)] in vivo and in vitro. Furthermore, RERT-lncRNA expression was also significantly correlated with EGLN2 expression in vivo, consistent with in vitro gain-offunction study that showed overexpressing RERT-lncRNA upregulated EGLN2. Finally, in silico prediction suggested that the insertion allele could disrupt the structure of RERT-lncRNA. Taken together, our findings provided strong evidence for the hypothesis that rs10680577 contributes to hepatocarcinogenesis, possibly by affecting RERT-lncRNA structure and subsequently EGLN2 expression, making it a promising biomarker for early diagnosis of HCC. Cancer Res; 72(23); 6163-72. Ó2012 AACR.

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“…The clinical significance of DIPs is increasingly recognized because they play important roles in inherited traits, diseases, and diversity (2 ). Recent studies have associated this type of polymorphism with variation in drug responses (4,5 ) and risk of carcinogenesis (6,7 ).…”

confidence: 99%

Comparison of 3 Methodologies for Genotyping of Small Deletion and Insertion Polymorphisms

et al. 2016

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BACKGROUND:The quantification of genomic chimerism is increasingly recognized for its clinical significance after transplantation. Before the measurement of chimerism, accurate genotyping of genetic polymorphisms for informative alleles that can distinguish donor DNA from recipient DNA is essential. The ease of allelic discrimination of small deletion and insertion polymorphisms (DIPs) makes DIPs attractive markers to track chimerism. Current methodologies for the genotyping of DIPs are largely based on "open-tube" approaches. "Closedtube" approaches involving no or minimal post-PCR handling are preferred. We compared 3 distinct methodologies to determine an optimal platform for DIP genotyping.

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Natural genetic variation caused by small insertions and deletions in the human genome

Cited by 223 publications

References 68 publications

An Indel Polymorphism in the Hybrid Incompatibility Gene Lethal Hybrid Rescue of Drosophila Is Functionally Relevant

An Indel Polymorphism in the Hybrid Incompatibility Gene Lethal Hybrid Rescue of Drosophila Is Functionally Relevant

An Insertion/Deletion Polymorphism within RERT-lncRNA Modulates Hepatocellular Carcinoma Risk

Comparison of 3 Methodologies for Genotyping of Small Deletion and Insertion Polymorphisms

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