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Complexity and diversity of F8 genetic variations in the 1000 genomes.

ABSTRACT: Hemophilia A (HA) is an X-linked bleeding disorder caused by deleterious mutations in the coagulation factor VIII gene (F8). To date, F8 mutations have been documented predominantly in European subjects and in American subjects of European descent. Information on F8 variants in individuals of more diverse ethnic backgrounds is limited.To discover novel and rare F8 variants, and to characterize F8 variants in diverse population backgrounds.We analyzed 2535 subjects, including 26 different ethnicities, whose data were available from the 1000 Genomes Project (1000G) phase 3 dataset, for F8 variants and their potential functional impact.We identified 3030 single nucleotide variants, 31 short deletions and insertions (Indels) and a large, 497 kb, deletion. Among all variants, 86.4% were rare variants and 55.6% were novel. Eighteen variants previously associated with HA were found in our study. Most of these 'HA variants' were ethnic-specific with low allele frequency; however, one variant (p.M2257V) was present in 27% of African subjects. The p.E132D, p.T281A, p.A303V and p.D422H 'HA variants' were identified only in males. Twelve novel missense variants were predicted to be deleterious. The large deletion was discovered in eight female subjects without affecting F8 transcription and the transcription of genes on the X chromosome.Characterizing F8 in the 1000G project highlighted the complexity of F8 variants and the importance of interrogating genetic variants on multiple ethnic backgrounds for associations with bleeding and thrombosis. The haplotype analysis and the orientation of duplicons that flank the large deletion suggested that the deletion was recurrent and originated by homologous recombination.

SUBMITTER: Li JN

PROVIDER: S-EPMC4928474 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Complexity and diversity of F8 genetic variations in the 1000 genomes.

Li J N JN Carrero I G IG Dong J F JF Yu F L FL

Journal of thrombosis and haemostasis : JTH 20151020 11

<h4>Background</h4>Hemophilia A (HA) is an X-linked bleeding disorder caused by deleterious mutations in the coagulation factor VIII gene (F8). To date, F8 mutations have been documented predominantly in European subjects and in American subjects of European descent. Information on F8 variants in individuals of more diverse ethnic backgrounds is limited.<h4>Objectives</h4>To discover novel and rare F8 variants, and to characterize F8 variants in diverse population backgrounds.<h4>Patients/method ...[more]

PMID: 26383047

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Project description:BackgroundThe APOL1 gene variants has been shown to be associated with an increased risk of multiple kinds of diseases, particularly in African Americans, but not in Caucasians and Asians. In this study, we explored the single nucleotide polymorphism (SNP) and haplotype diversity of APOL1 gene in different races provided by 1000 Genomes project.MethodsVariants of APOL1 gene in 1000 Genome Project were obtained and SNPs located in the regulatory region or coding region were selected for genetic variation analysis. Total 2504 individuals from 26 populations were classified as four groups that included Africa, Europe, Asia and Admixed populations. Tag SNPs were selected to evaluate the haplotype diversities in the four populations by HaploStats software.ResultsAPOL1 gene was surrounded by some of the most polymorphic genes in the human genome, variation of APOL1 gene was common, with up to 613 SNP (1000 Genome Project reported) and 99 of them (16.2%) with MAF ≥ 1%. There were 79 SNPs in the URR and 92 SNPs in 3'UTR. Total 12 SNPs in URR and 24 SNPs in 3'UTR were considered as common variants with MAF ≥ 1%. It is worth noting that URR-1 was presents lower frequencies in European populations, while other three haplotypes taken an opposite pattern; 3'UTR presents several high-frequency variation sites in a short segment, and the differences of its haplotypes among different population were significant (P < 0.01), UTR-1 and UTR-5 presented much higher frequency in African population, while UTR-2, UTR-3 and UTR-4 were much lower. APOL1 coding region showed that two SNP of G1 with higher frequency are actually pull down the haplotype H-1 frequency when considering all populations pooled together, and the diversity among the four populations be widen by the G1 two mutation (P 1 = 3.33E-4 vs P 2 = 3.61E-30).ConclusionsThe distributions of APOL1 gene variants and haplotypes were significantly different among the different populations, in either regulatory or coding regions. It could provide clues for the future genetic study of APOL1 related diseases.

Dataset Information

Complexity and diversity of F8 genetic variations in the 1000 genomes.

Publications

Complexity and diversity of F8 genetic variations in the 1000 genomes.

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