An integrated analysis tool for analyzing hybridization intensities and genotypes using new-generation population-optimized human arrays

Mei-Chu Huang; Tzu-Po Chuang; Chien-Hsiun Chen; Jer-Yuarn Wu; Yuan-Tsong Chen; Ling-Hui Li; Hsin-Chou Yang

doi:10.1186/s12864-016-2478-8

An integrated analysis tool for analyzing hybridization intensities and genotypes using new-generation population-optimized human arrays

BMC Genomics. 2016 Mar 31:17:266. doi: 10.1186/s12864-016-2478-8.

Authors

Mei-Chu Huang^{1

2

3}, Tzu-Po Chuang^{4

5}, Chien-Hsiun Chen⁶, Jer-Yuarn Wu⁶, Yuan-Tsong Chen⁶, Ling-Hui Li⁷, Hsin-Chou Yang^{8

9

10

11

12

13}

Affiliations

¹ Bioinformatics Program, Taiwan International Graduate Program, Institute of Information Science, Academia Sinica, Taipei, 115, Taiwan.
² Institute of Statistical Science, Academia Sinica, No 128, Academia Rd, Sec 2, Nankang, Taipei, 115, Taiwan.
³ Institute of Biomedical Informatics, National Yang-Ming University, Taipei, 112, Taiwan.
⁴ Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, 115, Taiwan.
⁵ Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, 112, Taiwan.
⁶ Institute of Biomedical Sciences, Academia Sinica, Academia Rd, Sec 2, Nankang, Taipei, 115, Taiwan.
⁷ Institute of Biomedical Sciences, Academia Sinica, Academia Rd, Sec 2, Nankang, Taipei, 115, Taiwan. lli@ibms.sinica.edu.tw.
⁸ Bioinformatics Program, Taiwan International Graduate Program, Institute of Information Science, Academia Sinica, Taipei, 115, Taiwan. hsinchou@stat.sinica.edu.tw.
⁹ Institute of Statistical Science, Academia Sinica, No 128, Academia Rd, Sec 2, Nankang, Taipei, 115, Taiwan. hsinchou@stat.sinica.edu.tw.
¹⁰ Institute of Public Health, National Yang Ming University, Taipei, 112, Taiwan. hsinchou@stat.sinica.edu.tw.
¹¹ Department of Statistics, National Cheng Kung University, Tainan, 701, Taiwan. hsinchou@stat.sinica.edu.tw.
¹² Institute of Statistics, National Tsing Hua University, Hsinchu, 300, Taiwan. hsinchou@stat.sinica.edu.tw.
¹³ School of Public Health, National Defense Medical Center, Taipei, 114, Taiwan. hsinchou@stat.sinica.edu.tw.

Abstract

Background: Affymetrix Axiom single nucleotide polymorphism (SNP) arrays provide a cost-effective, high-density, and high-throughput genotyping solution for population-optimized analyses. However, no public software is available for the integrated genomic analysis of hybridization intensities and genotypes for this new-generation population-optimized genotyping platform.

Results: A set of statistical methods was developed for an integrated analysis of allele frequency (AF), allelic imbalance (AI), loss of heterozygosity (LOH), long contiguous stretch of homozygosity (LCSH), and copy number variation or alteration (CNV/CNA) on the basis of SNP probe hybridization intensities and genotypes. This study analyzed 3,236 samples that were genotyped using different SNP platforms. The proposed AF adjustment method considerably increased the accuracy of AF estimation. The proposed quick circular binary segmentation algorithm for segmenting copy number reduced the computation time of the original segmentation method by 30-67 %. The proposed CNV/CNA detection, which integrates AI and LOH/LCSH detection, had a promising true positive rate and well-controlled false positive rate in simulation studies. Moreover, our real-time quantitative polymerase chain reaction experiments successfully validated the CNVs/CNAs that were identified in the Axiom data analyses using the proposed methods; some of the validated CNVs/CNAs were not detected in the Affymetrix Array 6.0 data analysis using the Affymetrix Genotyping Console. All the analysis functions are packaged into the ALICE (AF/LOH/LCSH/AI/CNV/CNA Enterprise) software.

Conclusions: ALICE and the used genomic reference databases, which can be downloaded from http://hcyang.stat.sinica.edu.tw/software/ALICE.html , are useful resources for analyzing genomic data from the Axiom and other SNP arrays.

Keywords: AF/LOH/LCSH/AI/CNV/CNA Enterprise (ALICE); Allele frequency (AF); Allelic imbalance (AI); Circular binary segmentation (CBS); Copy number variation or alteration (CNV/CNA); Fluorescence intensity; Long contiguous stretch of homozygosity (LCSH); Loss of heterozygosity (LOH); Microarray; Single-nucleotide polymorphism (SNP).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allelic Imbalance
DNA Copy Number Variations
Gene Frequency
Genetics, Population / methods*
Genotype*
Homozygote
Humans
Hybridization, Genetic*
Loss of Heterozygosity
Models, Statistical
Oligonucleotide Array Sequence Analysis / methods*
Polymorphism, Single Nucleotide
Software*