Methods for estimating genome-wide copy number variations

Abstract

Methods for determining the copy number of a genomic region at a detection position of a target sequence in a sample are disclosed. Genomic regions of a target sequence in a sample are sequenced and measurement data for sequence coverage is obtained. Sequence coverage bias is corrected and may be normalized against a baseline sample. Hidden Markov Model (HMM) segmentation, scoring, and output are performed, and in some embodiments population-based no-calling and identification of low-confidence regions may also be performed. A total copy number value and region-specific copy number value for a plurality of regions are then estimated.

What is claimed is: 
     
         1 . A non-transitory computer-readable medium comprising instructions tangibly embodied thereon, the instructions when executed by a computer processor causing the processor to perform the operations of:
 obtaining, using the computer processor, coverage values for each given position in a baseline or reference sample for the sequence coverage of said target polynucleotide using data generated from mate-pair mappings;   correcting, using the computer processor, the coverage values for each given position for sequence coverage bias, wherein correcting the coverage values for each given position in a baseline or reference sample comprises performing ploidy-aware baseline correction; and   estimating, using the computer processor, a total copy number value and region-specific copy number value for each of a plurality of genomic regions based at least on the corrected coverage values for each given position in a baseline or reference sample.   
     
     
         2 . A non-transitory computer-readable medium comprising instructions tangibly embodied thereon, the instructions when executed by a computer processor causing the processor to perform the operations of:
 obtaining, using the computer processor, coverage values for each given position in a baseline or reference sample for the sequence coverage of said target polynucleotide using data generated from mate-pair mappings;   correcting, using the computer processor, the coverage values for each given position for sequence coverage bias, wherein correcting the coverage values for each given position in a baseline or reference sample comprises performing ploidy-aware baseline correction; and   performing Hidden Markov Model (HMM) segmentation, scoring, and output based on the corrected coverage values for each given position in a baseline or reference sample;   based on the HMM scoring and output, performing population-based no-calling and identification of low-confidence regions; and   based on the HMM scoring and output, estimating a total copy number value and region-specific copy number value for a plurality of regions.   
     
     
         3 . A system of determining copy number variation of a genomic region at a detection position of a target polynucleotide sequence, comprising:
 a computer processor; and   a computer-readable storage medium coupled to said computer processor, the storage medium having instructions tangibly embodied thereon, the instructions when executed by said processor causing said processor to perform the operations of:   obtaining, using the computer processor, coverage values for each given position in a baseline or reference sample for the sequence coverage of said target polynucleotide using data generated from mate-pair mappings;   correcting, using the computer processor, the coverage values for each given position for sequence coverage bias, wherein correcting the coverage values for each given position in a baseline or reference sample comprises performing ploidy-aware baseline correction; and   estimating, using a computer, a total copy number value and region-specific copy number value for each of a plurality of genomic regions based at least on the corrected coverage values for each given position in a baseline or reference sample.