FinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA

Yaping Liu; Sarah C Reed; Christopher Lo; Atish D Choudhury; Heather A Parsons; Daniel G Stover; Gavin Ha; Gregory Gydush; Justin Rhoades; Denisse Rotem; Samuel Freeman; David W Katz; Ravi Bandaru; Haizi Zheng; Hailu Fu; Viktor A Adalsteinsson; Manolis Kellis

doi:10.1038/s41467-024-47196-6

FinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA

Nat Commun. 2024 Mar 30;15(1):2790. doi: 10.1038/s41467-024-47196-6.

Authors

Yaping Liu^{1

2

3

4

5

6

7

8

9}, Sarah C Reed^{10

11}, Christopher Lo¹⁰, Atish D Choudhury^{10

12}, Heather A Parsons¹², Daniel G Stover¹², Gavin Ha¹⁰, Gregory Gydush¹⁰, Justin Rhoades¹⁰, Denisse Rotem¹⁰, Samuel Freeman¹⁰, David W Katz^{13

14

15}, Ravi Bandaru^{13

14

15}, Haizi Zheng¹⁵, Hailu Fu^{13

14

15}, Viktor A Adalsteinsson¹⁶, Manolis Kellis^{17

18}

Affiliations

¹ Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. lyping1986@gmail.com.
² Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, 60611, USA. lyping1986@gmail.com.
³ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA. lyping1986@gmail.com.
⁴ Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA. lyping1986@gmail.com.
⁵ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA. lyping1986@gmail.com.
⁶ University of Cincinnati Center for Environmental Genetics, Cincinnati, OH, 45229, USA. lyping1986@gmail.com.
⁷ University of Cincinnati Cancer Center, Cincinnati, OH, 45229, USA. lyping1986@gmail.com.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. lyping1986@gmail.com.
⁹ Massachusetts Institute of Technology, Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, 02139, USA. lyping1986@gmail.com.
¹⁰ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
¹¹ Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN, USA.
¹² Dana-Farber Cancer Institute, Boston, MA, USA.
¹³ Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
¹⁴ Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, 60611, USA.
¹⁵ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
¹⁶ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. viktor@broadinstitute.org.
¹⁷ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. manoli@mit.edu.
¹⁸ Massachusetts Institute of Technology, Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, 02139, USA. manoli@mit.edu.

Abstract

Analysis of DNA methylation in cell-free DNA reveals clinically relevant biomarkers but requires specialized protocols such as whole-genome bisulfite sequencing. Meanwhile, millions of cell-free DNA samples are being profiled by whole-genome sequencing. Here, we develop FinaleMe, a non-homogeneous Hidden Markov Model, to predict DNA methylation of cell-free DNA and, therefore, tissues-of-origin, directly from plasma whole-genome sequencing. We validate the performance with 80 pairs of deep and shallow-coverage whole-genome sequencing and whole-genome bisulfite sequencing data.

MeSH terms

Cell-Free Nucleic Acids* / genetics
DNA Methylation* / genetics
High-Throughput Nucleotide Sequencing
Sequence Analysis, DNA / methods
Sulfites
Whole Genome Sequencing / methods

Substances

hydrogen sulfite
Sulfites
Cell-Free Nucleic Acids

Grants and funding

R56 HG012360/HG/NHGRI NIH HHS/United States