Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago, bioRxiv, 2019-07-16

AbstractIndonesia is the world’s fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10% of tested genes are differentially expressed between the islands of Mentawai (Sumatra) and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.7% of genes strongly correlating with nearby CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by very local environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.

biorxiv genomics 0-100-users 2019

A single cell framework for multi-omic analysis of disease identifies malignant regulatory signatures in mixed phenotype acute leukemia, bioRxiv, 2019-07-10

AbstractIn order to identify the molecular determinants of human diseases, such as cancer, that arise from a diverse range of tissue, it is necessary to accurately distinguish normal and pathogenic cellular programs.1–3Here we present a novel approach for single-cell multi-omic deconvolution of healthy and pathological molecular signatures within phenotypically heterogeneous malignant cells. By first creating immunophenotypic, transcriptomic and epigenetic single-cell maps of hematopoietic development from healthy peripheral blood and bone marrow mononuclear cells, we identify cancer-specific transcriptional and chromatin signatures from single cells in a cohort of mixed phenotype acute leukemia (MPAL) clinical samples. MPALs are a high-risk subtype of acute leukemia characterized by a heterogeneous malignant cell population expressing both myeloid and lymphoid lineage-specific markers.4, 5Our results reveal widespread heterogeneity in the pathogenetic gene regulatory and expression programs across patients, yet relatively consistent changes within patients even across malignant cells occupying diverse portions of the hematopoietic lineage. An integrative analysis of transcriptomic and epigenetic maps identifies 91,601 putative gene-regulatory interactions and classifies a number of transcription factors that regulate leukemia specific genes, includingRUNX1-linked regulatory elements proximal toCD69. This work provides a template for integrative, multi-omic analysis for the interpretation of pathogenic molecular signatures in the context of developmental origin.

biorxiv genomics 100-200-users 2019

Mutational signatures are jointly shaped by DNA damage and repair, bioRxiv, 2019-06-29

SummaryMutations arise when DNA lesions escape DNA repair. To delineate the contributions of DNA damage and DNA repair deficiency to mutagenesis we sequenced 2,721 genomes of 54 C. elegans strains, each deficient for a specific DNA repair gene and wild-type, upon exposure to 12 different genotoxins. Combining genotoxins and repair deficiency leads to differential mutation rates or new mutational signatures in more than one third of experiments. Translesion synthesis polymerase deficiencies show dramatic and diverging effects. Knockout of Polκ dramatically exacerbates the mutagenicity of alkylating agents; conversely, Polζ deficiency reduces alkylation- and UV-induced substitution rates. Examples of DNA damage-repair deficiency interactions are also found in cancer genomes, although cases of hypermutation are surprisingly rare despite signs of positive selection in a number of DNA repair genes. Nevertheless, cancer risk may be substantially elevated even by small increases in mutagenicity according to evolutionary multi-hit theory. Overall, our data underscore how mutagenesis is a joint product of DNA damage and DNA repair, implying that mutational signatures may be more variable than currently anticipated.Highlights<jatslist list-type=bullet><jatslist-item>Combining exposure to DNA damaging agents and DNA repair deficiency in C. elegans leads to altered mutation rates and new mutational signatures<jatslist-item><jatslist-item>Mutagenic effects of genotoxic exposures are generally exacerbated by DNA repair deficiency<jatslist-item><jatslist-item>Mutagenesis of UVB and alkylating agents is reduced in translesion synthesis polymerase deficiencies<jatslist-item><jatslist-item>Human cancer genomes contain examples of DNA damagerepair interactions, but mutations in DNA repair genes usually only associate with moderate mutator phenotypes, in line with evolutionary theory<jatslist-item>

biorxiv genomics 100-200-users 2019

 

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