Abstract
BackgroundAllele frequency is one of the most important population indices and has been broadly applied to genetic/genomic studies. Estimation of allele frequency using genotypes is convenient but may lose data information and be sensitive to genotyping errors.ResultsThis study utilizes a unified intensity-measuring approach to estimating individual-level allele frequencies for 1,104 and 1,270 samples genotyped with the single-nucleotide-polymorphism arrays of the Affymetrix Human Mapping 100K and 500K Sets, respectively. Allele frequencies of all samples are estimated and adjusted by coefficients of preferential amplification/hybridization (CPA), and large ethnicity-specific and cross-ethnicity databases of CPA and allele frequency are established. The results show that using the CPA significantly improves the accuracy of allele frequency estimates; moreover, this paramount factor is insensitive to the time of data acquisition, effect of laboratory site, type of gene chip, and phenotypic status. Based on accurate allele frequency estimates, analytic methods based on individual-level allele frequencies are developed and successfully applied to discover genomic patterns of allele frequencies, detect chromosomal abnormalities, classify sample groups, identify outlier samples, and estimate the purity of tumor samples. The methods are packaged into a new analysis tool, ALOHA (Allele-frequency/Loss-of-heterozygosity/Allele-imbalance).ConclusionsThis is the first time that these important genetic/genomic applications have been simultaneously conducted by the analyses of individual-level allele frequencies estimated by a unified intensity-measuring approach. We expect that additional practical applications for allele frequency analysis will be found. The developed databases and tools provide useful resources for human genome analysis via high-throughput single-nucleotide-polymorphism arrays. The ALOHA software was written in R and R GUI and can be downloaded at http://www.stat.sinica.edu.tw/hsinchou/genetics/aloha/ALOHA.htm.
Highlights
Allele frequency is one of the most important population indices and has been broadly applied to genetic/genomic studies
This paper focuses on the intensity-measuring allele frequency because this allele frequency estimate is insensitivity to genotyping errors and preserves data information that might be lost in conventional genotype-based analyses
This paper mainly focuses on individual-level allele frequency and investigates its applications in genetic/genomic studies, including the discovery of allele frequency patterns, identification of chromosomal aberrations (including aneuploidy, loss of heterozygosity (LOH), and allelic imbalance (AI)), outlier detection, and sample classification
Summary
Allele frequency is one of the most important population indices and has been broadly applied to genetic/genomic studies. Allele frequency denotes the relative frequency of an allele compared with the total frequency of all alleles at a marker locus It is one of the most important population indices and has been broadly applied to genetic/ genomic research [1,2,3,4,5]. The generalized concept of allele frequency has two aspects: individual-level allele frequency and population-level allele frequency. Using the most abundant genetic marker in the human genome, namely the single-nucleotide polymorphism (SNP), both individual-level and populationlevel allele frequencies can be estimated using a (genotype-based) allele-counting approach and an (intensitybased) intensity-measuring approach (Appendix A). This paper focuses on the intensity-measuring allele frequency because this allele frequency estimate is insensitivity to genotyping errors and preserves data information that might be lost in conventional genotype-based analyses. The finding motivated us to analyze intensity-based allele frequencies for extraction of information lost in conventional genotype-based analyses
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