| 摘要 |
The contributions of different tissues to a DNA mixture are determined using methylation levels at particular genomic sites. Tissue-specific methylation levels of M tissue types can be used to deconvolve mixture methylation levels measured in the DNA mixture, to determine fraction contributions of each of the M tissue types. Various types of genomic sites can be chosen to have particular properties across tissue types and across individuals, so as to provide increased accuracy in determining contributions of the various tissue types. The fractional contributions can be used to detect abnormal contributions of a particular tissue, indicating a disease state for the tissue. A differential in fractional contributions for different sizes of DNA fragments can also be used to identify a diseased state of a particular tissue. A sequence imbalance for a particular chromosomal region can be detected in a particular tissue, e.g., identifying a location of a tumor. |
| 主权项 |
1. A method of analyzing a biological sample of an organism, the biological sample including a mixture of cell-free DNA molecules from a plurality of tissues types, including a first tissue type, the method comprising:
analyzing, by a computer system, a plurality of cell-free DNA molecules from the biological sample, the plurality of cell-free DNA molecules being at least 1,000 cell-free DNA molecules, wherein analyzing a cell-free DNA molecule includes:
identifying a location of the cell-free DNA molecule in a reference genome corresponding to the organism; identifying a first set of the plurality of cell-free DNA molecules that are each located at any one of N genomic sites of a first chromosomal region of the reference genome corresponding to the organism, N being an integer greater than or equal to 10; measuring N first mixture methylation levels at the N genomic sites using the first set of the plurality of cell-free DNA molecules; determining, by the computer system, a first fractional contribution of the first tissue type in the mixture using the N first methylation levels; identifying a second set of the plurality of cell-free DNA molecules that are each located at any one of K genomic sites of a second chromosomal region of the reference genome corresponding to the organism, K being an integer greater than or equal to 10, wherein the second chromosomal region is different from the first chromosomal region; measuring K second mixture methylation levels at the K genomic sites using the second set of the plurality of cell-free DNA molecules; determining, by the computer system, a second fractional contribution of the first tissue type in the mixture using the K second methylation levels; computing a first separation value between the first fractional contribution and the second fractional contribution; and comparing the first separation value to a threshold value to determine a classification of whether the first tissue type has a sequence imbalance for the first chromosomal region. |
