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Population stratification of a common APOBEC gene deletion polymorphism.

ABSTRACT: The APOBEC3 gene family plays a role in innate cellular immunity inhibiting retroviral infection, hepatitis B virus propagation, and the retrotransposition of endogenous elements. We present a detailed sequence and population genetic analysis of a 29.5-kb common human deletion polymorphism that removes the APOBEC3B gene. We developed a PCR-based genotyping assay, characterized 1,277 human diversity samples, and found that the frequency of the deletion allele varies significantly among major continental groups (global FST = 0.2843). The deletion is rare in Africans and Europeans (frequency of 0.9% and 6%), more common in East Asians and Amerindians (36.9% and 57.7%), and almost fixed in Oceanic populations (92.9%). Despite a worldwide frequency of 22.5%, analysis of data from the International HapMap Project reveals that no single existing tag single nucleotide polymorphism may serve as a surrogate for the deletion variant, emphasizing that without careful analysis its phenotypic impact may be overlooked in association studies. Application of haplotype-based tests for selection revealed potential pitfalls in the direct application of existing methods to the analysis of genomic structural variation. These data emphasize the importance of directly genotyping structural variation in association studies and of accurately resolving variant breakpoints before proceeding with more detailed population-genetic analysis.

SUBMITTER: Kidd JM

PROVIDER: S-EPMC1853121 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:<a href="https://www.nature.com/articles/s41467-017-00493-9" target="_blank">Chen T-W, Lee C-C, Liu H, Wu C-S, Pickering CR, Huang P-J, et al., Nature Communications 8, Article number: 465 (2017) doi:10.1038/s41467-017-00493-9</a>Oral squamous cell carcinoma is a prominent cancer worldwide, particularly in Taiwan. By integrating omics analyses in 50 matched samples, we uncover in Taiwanese patients a predominant mutation signature associated with cytidine deaminase APOBEC, which correlates with the upregulation of APOBEC3A expression in the APOBEC3 gene cluster at 22q13. APOBEC3A expression is significantly higher in tumors carrying APOBEC3B-deletion allele(s). High-level APOBEC3A expression is associated with better overall survival, especially among patients carrying APOBEC3B-deletion alleles, as examined in a second cohort (n=188; p=0.004). The frequency of APOBEC3B-deletion alleles is ~50% in 143 genotyped oral squamous cell carcinoma -Taiwan samples (27A3B-/-:89A3B+/-:27A3B+/+), compared to the 5.8% found in 314 OSCC-TCGA samples. We thus report a frequent APOBEC mutational profile, which relates to a APOBEC3B-deletion germline polymorphism in Taiwanese oral squamous cell carcinoma that impacts expression of APOBEC3A, and is shown to be of clinical prognostic relevance. Our finding might be recapitulated by genomic studies in other cancer types. Mass Spectrometry Data Sets, Provided BelowThe APOBEC-associated mutational signature enriched in the OSCC-Taiwan cohort was investigated to determine if this mutational signature might correlate with tumor-related alterations in APOBEC expression.RNA-Seq results from normal / tumor paired tissue samples were analyzed and data may be obtain from NCBI (<a href="https://www.ncbi.nlm.nih.gov/bioproject/PRJNA327548" target="_blank">BioProject:PRJNA327548</a> and <a href="https://trace.ncbi.nlm.nih.gov/Traces/sra/sra.cgi?study=SRP078156" target="_blank">SRA Study:SRP078156</a>). Corresponding enrichment of A3A-specific peptides in tumor proteomes was assessed by iTRAQ (isobaric Tags for Relative and Absolute Quantification) mass spectrometry protein quantification methods in 38 normal / tumor paired tissue samples. Peptides were digested, labeled by iTRAQ, and fractionated by on-line 2D-HPLC to 44 fractions. Each dataset (labeled as OSCC-Pxx, example OSCC-P01) contains 44 raw mass spectrometry data files (LTQ-Orbitrap ELITE). The iTRAQ 114 reagent was used to label the digestion products of 30-pairs of OSCC tissues, and iTRAQ 115 and 116 reagents were used to label peptides of non-tumor tissue and tumor tissue, respectively. The APOBEC3A (A3A) coding region is part of a APOBEC3 gene cluster at 22q13.<ul><li>Dataset imported into MassIVE from <a href="https://cptac-data-portal.georgetown.edu/cptac/s/S034">https://cptac-data-portal.georgetown.edu/cptac/s/S034</a> on 08/28/19</li></ul>

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Population stratification of a common APOBEC gene deletion polymorphism.

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