HaplotypeCN: copy number haplotype inference with Hidden Markov Model and localized haplotype clustering.
Copy number variation (CNV) has been reported to be associated with disease and various cancers. Hence, identifying the accurate position and the type of CNV is currently a critical issue. There are many tools targeting on detecting CNV regions, constructing haplotype phases on CNV regions, or estimating the numerical copy numbers. However, none of them can do all of the three tasks at the same time. This paper presents a method based on Hidden Markov Model to detect parent specific copy number change on both chromosomes with signals from SNP arrays. A haplotype tree is constructed with dynamic branch merging to model the transition of the copy number status of the two alleles assessed at each SNP locus. The emission models are constructed for the genotypes formed with the two haplotypes. The proposed method can provide the segmentation points of the CNV regions as well as the haplotype phasing for the allelic status on each chromosome. The estimated copy numbers are provided as fractional numbers, which can accommodate the somatic mutation in cancer specimens that usually consist of heterogeneous cell populations. The algorithm is evaluated on simulated data and the previously published regions of CNV of the 270 HapMap individuals. The results were compared with five popular methods: PennCNV, genoCN, COKGEN, QuantiSNP and cnvHap. The application on oral cancer samples demonstrates how the proposed method can facilitate clinical association studies. The proposed algorithm exhibits comparable sensitivity of the CNV regions to the best algorithm in our genome-wide study and demonstrates the highest detection rate in SNP dense regions. In addition, we provide better haplotype phasing accuracy than similar approaches. The clinical association carried out with our fractional estimate of copy numbers in the cancer samples provides better detection power than that with integer copy number states.
Department of Computer Science, National Tsing Hua University, Hsinchu, Taiwan.
Yen-Jen
YJ
Lin
Department of Computer Science, National Tsing Hua University, Hsinchu, Taiwan.
Yu-Tin
YT
Chen
Institute of Statistics, National Tsing Hua University, Hsinchu, Taiwan.
Shu-Ni
SN
Hsu
Department of Resource Center for Clinical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Chien-Hua
CH
Peng
Department of Computer Science, National Tsing Hua University, Hsinchu, Taiwan; Department of Computer Science and Information Engineering, Providence University, Taichung, Taiwan.
Chuan-Yi
CY
Tang
Head and Neck Oncology Group, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Tzu-Chen
TC
Yen
Institute of Statistics, National Tsing Hua University, Hsinchu, Taiwan.
Wen-Ping
WP
Hsieh
D000465:Algorithms; D000483:Alleles; D002877:Chromosomes, Human; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D018628:Gene Dosage; D015894:Genome, Human; D006239:Haplotypes; D006801:Humans; D008390:Markov Chains; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D012984:Software