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Genotype, allele and haplotype frequencies of four TCL1A gene polymorphisms associated with musculoskeletal toxicity in the South Indian descent.

ABSTRACT: INTRODUCTION:Decline in circulating estrogen levels causes lessening of bone mass accompanied with musculoskeletal pain, which is the primary cause of treatment discontinuation in patients taking aromatase inhibitors. Evidence from recent genome-wide association studies (GWAS) suggests that the genetic variability underlying TCL1A gene increases the risk of aromatase inhibitors (AIs) - induced musculoskeletal toxicity. Currently, no data is available on the frequency distribution of TCL1A gene polymorphisms in Indians. METHODS:In this pilot study, we used TaqMan fluorescent probes to assess the genotypes of four TCL1A gene polymorphisms associated with musculoskeletal toxicity in 247 healthy homogenous South Indian subjects on real time thermocycler. Haplotype estimation and pairwise linkage disequilibrium (LD) analysis were executed by Haploview. RESULTS:The incidence of polymorphic variant allele (G) frequencies of rs7158782, rs7159713, rs2369049 and rs11849538 were 22.1%, 23.5%, 18.2% and 22.9% in the study population, respectively. The polymorphisms were found to be in complete LD with each other. Four different haplotypes, each of which having a frequency of above 1% were inferred in South Indians using an expectation-maximization algorithm. Notably, three haplotypes were found to be population specific viz H4 A-A-A-G (1.2%) for South India, H5 G-G-A-C (1.3%) for JPT and H6 G-G-G-C (40.4%) for YRI. Further, H3 G-G-A-G (2.3-16.3%) haplotype occurs primarily in Asians and is virtually absent in Africans. Overall, the genetic variability and haplotype profile of South Indian population revealed significant inter-racial variability compared with HapMap data. CONCLUSION:This documentation contributes for further investigations on the pharmacogenetics of AIs in South Indians.

SUBMITTER: Umamaheswaran G

PROVIDER: S-EPMC4097978 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Genotype, allele and haplotype frequencies of four TCL1A gene polymorphisms associated with musculoskeletal toxicity in the South Indian descent.

Umamaheswaran Gurusamy G Dkhar Steven Aibor SA Kumar Annan Sudarsan Arun AS Srinivasa Rao Katiboina RK Kadambari Dharanipragada D Adithan Chandrasekaran C

BioImpacts : BI 20140619 2

<h4>Introduction</h4>Decline in circulating estrogen levels causes lessening of bone mass accompanied with musculoskeletal pain, which is the primary cause of treatment discontinuation in patients taking aromatase inhibitors. Evidence from recent genome-wide association studies (GWAS) suggests that the genetic variability underlying TCL1A gene increases the risk of aromatase inhibitors (AIs) - induced musculoskeletal toxicity. Currently, no data is available on the frequency distribution of TCL1 ...[more]

PMID: 25035853

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Project description:BackgroundIn addition to heterogeneity and artificial selection, natural selection is one of the forces used to combat climate change and improve agrobiodiversity in evolutionary plant breeding. Accurate identification of the specific genomic effects of natural selection will likely accelerate transfer between populations. Thus, insights into changes in allele frequency, adequate population size, gene flow and drift are essential. However, observing such effects often involves a trade-off between costs and resolution when a large sample of genotypes for many loci is analysed. Pool genotyping approaches achieve high resolution and precision in estimating allele frequency when sequence coverage is high. Nevertheless, high-coverage pool sequencing of large genomes is expensive.ResultsThree pool samples (n = 300, 300, 288) from a barley backcross population were generated to assess the population's allele frequency. The tested population (BC2F21) has undergone 18 generations of natural adaption to conventional farming practice. The accuracies of estimated pool-based allele frequencies and genome coverage yields were compared using three next-generation sequencing genotyping methods. To achieve accurate allele frequency estimates with low sequence coverage, we employed a haplotyping approach. Low coverage allele frequencies of closely located single polymorphisms were aggregated into a single haplotype allele frequency, yielding 2-to-271-times higher depth and increased precision. When we combined different haplotyping tactics, we found that gene and chip marker-based haplotype analyses performed equivalently or better compared with simple contig haplotype windows. Comparing multiple pool samples and referencing against an individual sequencing approach revealed that whole-genome pool re-sequencing (WGS) achieved the highest correlation with individual genotyping (≥ 0.97). In contrast, transcriptome-based genotyping (MACE) and genotyping by sequencing (GBS) pool replicates were significantly associated with higher error rates and lower correlations, but are still valuable to detect large allele frequency variations.ConclusionsThe proposed strategy identified the allele frequency of populations with high accuracy at low cost. This is particularly relevant to evolutionary plant breeding of crops with very large genomes, such as barley. Whole-genome low coverage re-sequencing at 0.03 × coverage per genotype accurately estimated the allele frequency when a loci-based haplotyping approach was applied. The implementation of annotated haplotypes capitalises on the biological background and statistical robustness.

Dataset Information

Genotype, allele and haplotype frequencies of four TCL1A gene polymorphisms associated with musculoskeletal toxicity in the South Indian descent.

Publications

Genotype, allele and haplotype frequencies of four TCL1A gene polymorphisms associated with musculoskeletal toxicity in the South Indian descent.

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