A likelihood approach to testing hypotheses on the co-evolution of epigenome and genome

Central questions to epigenome evolution include whether interspecies changes of histone modifications are independent of evolutionary changes of DNA, and if there is dependence whether they depend on any specific types of DNA sequence changes. Here, we present a likelihood approach for testing hypotheses on the co-evolution of genome and histone modifications. The gist of this approach is to convert evolutionary biology hypotheses into probabilistic forms, by explicitly expressing the joint probability of multispecies DNA sequences and histone modifications, which we refer to as a class of Joint Evolutionary Model for the Genome and the Epigenome (JEMGE). JEMGE can be summarized as a mixture model of four components representing four evolutionary hypotheses, namely dependence and independence of interspecies epigenomic variations to underlying sequence substitutions and to underlying sequence insertions and deletions (indels). We implemented a maximum likelihood method to fit the models to the data. Based on comparison of likelihoods, we inferred whether interspecies epigenomic variations depended on substitution or indels in local genomic sequences based on DNase hypersensitivity and spermatid H3K4me3 ChIP-seq data from human and rhesus macaque. Approximately 5.5% of homologous regions in the genomes exhibited H3K4me3 modification in either species, among which approximately 67% homologous regions exhibited local-sequence-dependent interspecies H3K4me3 variations. Substitutions accounted for less local-sequence-dependent H3K4me3 variations than indels. Among transposon-mediated indels, ERV1 insertions and L1 insertions were most strongly associated with H3K4me3 gains and losses, respectively. By initiating probabilistic formulation on the co-evolution of genomes and epigenomes, JEMGE helps to bring evolutionary biology principles to comparative epigenomic studies.Author summary: Epigenetic modifications play a significant role in gene regulations and thus heavily influence phenotypic outcomes. Whereas cross-species epigenomic comparisons have been fruitful in revealing the function of epigenetic modifications, it still remains unclear how the epigenome changes across species. A central question in epigenome evolution studies is whether interspecies epigenomic variations rely on genomic changes in cis and, if partially yes, whether different genomic changes have distinct impacts. To tackle this question, we initiated a likelihood-based approach, in which different hypotheses related to the co-evolution of the genome and the epigenome could be converted into probabilistic models. By fitting the models to actual data, each model yielded a likelihood, and the hypothesis corresponded to the largest likelihood was selected as most supported by observed data. In this work, we focused on the influence of two types of underlying sequence changes: substitutions, and insertions and deletions (indels). We quantitatively assessed the dependence of H3K4me3 variations on substitutions and indels between human and rhesus, and separated their relative impacts within each genomic region with H3K4me3. The methodology presented here provides a framework for modeling the epigenome together with the genome and a quantitative approach to test different evolutionary hypotheses.