A method, implemented at a computer system that includes one or more processors and system memory, for evaluation of copy number of a nucleic acid sequence of interest in a test sample, the method comprising: (a) providing, at the computer system, sequence reads obtained by a nucleic acid sequencer from the test sample, which test sample comprises nucleic acid molecules from one or more genomes; (b) aligning, by the computer system, the sequence reads of the test sample to a reference genome comprising the nucleic acid sequence of interest, thereby providing test sequence tags; (c) determining, by the computer system, a coverage of the test sequence tags located in each bin, wherein the reference genome is divided into a plurality of bins, and wherein the coverage indicates an abundance of sequence tags in a bin; (d) providing, by the computer system, a global profile for the nucleic acid sequence of interest, wherein the global profile comprises an expected coverage in each bin, and wherein the expected coverage is obtained from a training set of unaffected training samples comprising nucleic acid molecules sequenced and aligned in the same manner as the test sample, the expected coverage exhibiting variation from bin to bin; (e) adjusting, by the computer system, the coverage of the test sequence tags in each bin of at least the nucleic acid sequence of interest using the expected coverage in each bin, thereby obtaining global-profile-corrected coverages for the nucleic acid sequence of interest; (f) adjusting, by the computer system, the global-profile-corrected coverages for the nucleic acid sequence of interest based on a relation between GC content levels of the test sample and the global-profile-corrected coverages of the test sample, thereby obtaining sample-GC-corrected coverages for the nucleic acid sequence of interest; and (g) evaluating, by the computer system, a copy number of the nucleic acid sequence of interest in the test sample based on the sample-GC-corrected coverages, wherein the sample-GC-corrected coverages improve a signal level and/or reduce a noise level for determining the copy number of the nucleic acid sequence of interest. (a) providing, at the computer system, sequence reads obtained by a nucleic acid sequencer from the test sample, which test sample comprises nucleic acid molecules from one or more genomes; (b) aligning, by the computer system, the sequence reads of the test sample to a reference genome comprising the nucleic acid sequence of interest, thereby providing test sequence tags; (c) determining, by the computer system, a coverage of the test sequence tags located in each bin, wherein the reference genome is divided into a plurality of bins, and wherein the coverage indicates an abundance of sequence tags in a bin; (d) providing, by the computer system, a global profile for the nucleic acid sequence of interest, wherein the global profile comprises an expected coverage in each bin, and wherein the expected coverage is obtained from a training set of unaffected training samples comprising nucleic acid molecules sequenced and aligned in the same manner as the test sample, the expected coverage exhibiting variation from bin to bin; (e) adjusting, by the computer system, the coverage of the test sequence tags in each bin of at least the nucleic acid sequence of interest using the expected coverage in each bin, thereby obtaining global-profile-corrected coverages for the nucleic acid sequence of interest; (f) adjusting, by the computer system, the global-profile-corrected coverages for the nucleic acid sequence of interest based on a relation between GC content levels of the test sample and the global-profile-corrected coverages of the test sample, thereby obtaining sample-GC-corrected coverages for the nucleic acid sequence of interest; and (g) evaluating, by the computer system, a copy number of the nucleic acid sequence of interest in the test sample based on the sample-GC-corrected coverages, wherein the sample-GC-corrected coverages improve a signal level and/or reduce a noise level for determining the copy number of the nucleic acid sequence of interest.