TY - JOUR

T1 - DamMet

T2 - ancient methylome mapping accounting for errors, true variants, and post-mortem DNA damage

AU - Hanghøj, Kristian

AU - Renaud, Gabriel

AU - Albrechtsen, Anders

AU - Orlando, Ludovic

N1 - © The Author(s) 2019. Published by Oxford University Press.

PY - 2019

Y1 - 2019

N2 - BACKGROUND: Recent computational advances in ancient DNA research have opened access to the detection of ancient DNA methylation footprints at the genome-wide scale. The most commonly used approach infers the methylation state of a given genomic region on the basis of the amount of nucleotide mis-incorporations observed at CpG dinucleotide sites. However, this approach overlooks a number of confounding factors, including the presence of sequencing errors and true variants. The scale and distribution of the inferred methylation measurements are also variable across samples, precluding direct comparisons.FINDINGS: Here, we present DamMet, an open-source software program retrieving maximum likelihood estimates of regional CpG methylation levels from ancient DNA sequencing data. It builds on a novel statistical model of post-mortem DNA damage for dinucleotides, accounting for sequencing errors, genotypes, and differential post-mortem cytosine deamination rates at both methylated and unmethylated sites. To validate DamMet, we extended gargammel, a sequence simulator for ancient DNA data, by introducing methylation-dependent features of post-mortem DNA decay. This new simulator provides direct validation of DamMet predictions. Additionally, the methylation levels inferred by DamMet were found to be correlated to those inferred by epiPALEOMIX and both on par and directly comparable to those measured from whole-genome bisulphite sequencing experiments of fresh tissues.CONCLUSIONS: DamMet provides genuine estimates for local DNA methylation levels in ancient individual genomes. The returned estimates are directly cross-sample comparable, and the software is available as an open-source C++ program hosted at https://gitlab.com/KHanghoj/DamMet along with a manual and tutorial.

AB - BACKGROUND: Recent computational advances in ancient DNA research have opened access to the detection of ancient DNA methylation footprints at the genome-wide scale. The most commonly used approach infers the methylation state of a given genomic region on the basis of the amount of nucleotide mis-incorporations observed at CpG dinucleotide sites. However, this approach overlooks a number of confounding factors, including the presence of sequencing errors and true variants. The scale and distribution of the inferred methylation measurements are also variable across samples, precluding direct comparisons.FINDINGS: Here, we present DamMet, an open-source software program retrieving maximum likelihood estimates of regional CpG methylation levels from ancient DNA sequencing data. It builds on a novel statistical model of post-mortem DNA damage for dinucleotides, accounting for sequencing errors, genotypes, and differential post-mortem cytosine deamination rates at both methylated and unmethylated sites. To validate DamMet, we extended gargammel, a sequence simulator for ancient DNA data, by introducing methylation-dependent features of post-mortem DNA decay. This new simulator provides direct validation of DamMet predictions. Additionally, the methylation levels inferred by DamMet were found to be correlated to those inferred by epiPALEOMIX and both on par and directly comparable to those measured from whole-genome bisulphite sequencing experiments of fresh tissues.CONCLUSIONS: DamMet provides genuine estimates for local DNA methylation levels in ancient individual genomes. The returned estimates are directly cross-sample comparable, and the software is available as an open-source C++ program hosted at https://gitlab.com/KHanghoj/DamMet along with a manual and tutorial.

U2 - 10.1093/gigascience/giz025

DO - 10.1093/gigascience/giz025

M3 - Journal article

C2 - 31004132

VL - 8

JO - GigaScience

JF - GigaScience

SN - 2047-217X

IS - 4

M1 - giz025

ER -