DNA Methylation and Genome Evolution

Presented on October 21, 2008 from 8:30-9:30 am in IBB Building room 1128 on the Georgia Tech campus.Runtime: 49:45 minutesDNA methylation is a primary epigenetic mechanism involved in several regulatory and developmental processes. In this talk, I will focus on the molecular evolutionary role of DNA methylation. An important property of DNA methylation is its propensity to increase specific types of point mutations. Using this property, we have developed analytical tools to investigate influence of DNA methylation on genome evolution. We show that (i) DNA methylation causes different genomic regions to follow qualitatively different molecular clocks, (ii) influence regional variability of nucleotide composition, (iii) affected evolution of vertebrate promoters. Finally, (iv) our survey shows that the influence of DNA methylation on genome evolution is widespread in animal taxa. While the model invertebrate species Drosophila melanogaster and Caenorhabditis elegans lack DNA methylation, the genome of a social bee Apis mellifera exhibits an unmistakable signature of DNA methylation at sequence and functional level

Heterogeneous Genomic Molecular Clocks in Primates

Copyright: © 2006 Kim et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.DOI: 10.1371/journal.pgen.0020163Using data from primates, we show that molecular clocks in sites that have been part of a CpG dinucleotide in recent past (CpG sites) and non-CpG sites are of markedly different nature, reflecting differences in their molecular origins. Notably, single nucleotide substitutions at non-CpG sites show clear generation-time dependency, indicating that most of these substitutions occur by errors during DNA replication. On the other hand, substitutions at CpG sites occur relatively constantly over time, as expected from their primary origin due to methylation. Therefore, molecular clocks are heterogeneous even within a genome. Furthermore, we propose that varying frequencies of CpG dinucleotides in different genomic regions may have contributed significantly to conflicting earlier results on rate constancy of mammalian molecular clock. Our conclusion that different regions of genomes follow different molecular clocks should be considered when inferring divergence times using molecular data and in phylogenetic analysis

The draft genome of a socially polymorphic halictid bee, Lasioglossum albipes

Background: Taxa that harbor natural phenotypic variation are ideal for ecological genomic approaches aimed at understanding how the interplay between genetic and environmental factors can lead to the evolution of complex traits. Lasioglossum albipes is a polymorphic halictid bee that expresses variation in social behavior among populations, and common-garden experiments have suggested that this variation is likely to have a genetic component. Results: We present the L. albipes genome assembly to characterize the genetic and ecological factors associated with the evolution of social behavior. The de novo assembly is comparable to other published social insect genomes, with an N50 scaffold length of 602 kb. Gene families unique to L. albipes are associated with integrin-mediated signaling and DNA-binding domains, and several appear to be expanded in this species, including the glutathione-s-transferases and the inositol monophosphatases. L. albipes has an intact DNA methylation system, and in silico analyses suggest that methylation occurs primarily in exons. Comparisons to other insect genomes indicate that genes associated with metabolism and nucleotide binding undergo accelerated evolution in the halictid lineage. Whole-genome resequencing data from one solitary and one social L. albipes female identify six genes that appear to be rapidly diverging between social forms, including a putative odorant receptor and a cuticular protein. Conclusions: L. albipes represents a novel genetic model system for understanding the evolution of social behavior. It represents the first published genome sequence of a primitively social insect, thereby facilitating comparative genomic studies across the Hymenoptera as a whole

DNA Methylation and Genome Evolution in Honeybee: Gene Length, Expression, Functional Enrichment Covary with the Evolutionary Signature of DNA Methylation

A growing body of evidence suggests that DNA methylation is functionally divergent among different taxa. The recently discovered functional methylation system in the honeybee Apis mellifera presents an attractive invertebrate model system to study evolution and function of DNA methylation. In the honeybee, DNA methylation is mostly targeted toward transcription units (gene bodies) of a subset of genes. Here, we report an intriguing covariation of length and epigenetic status of honeybee genes. Hypermethylated and hypomethylated genes in honeybee are dramatically different in their lengths for both exons and introns. By analyzing orthologs in Drosophila melanogaster, Acyrthosiphon pisum, and Ciona intestinalis, we show genes that were short and long in the past are now preferentially situated in hyper- and hypomethylated classes respectively, in the honeybee. Moreover, we demonstrate that a subset of high-CpG genes are conspicuously longer than expected under the evolutionary relationship alone and that they are enriched in specific functional categories. We suggest that gene length evolution in the honeybee is partially driven by evolutionary forces related to regulation of gene expression, which in turn is associated with DNA methylation. However, lineage-specific patterns of gene length evolution suggest that there may exist additional forces underlying the observed interaction between DNA methylation and gene lengths in the honeybee

Cell type-specific epigenetic links to schizophrenia risk in the brain

Background The importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generate cell type-specific whole-genome methylomes (N = 95) and transcriptomes (N = 89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls. Results The methylomes of the two cell types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation differences between cases and controls are subtle compared to cell type differences, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell type differentially methylated sites, highlighting the significance of cell type-specific epigenetic dysregulation in a complex neuropsychiatric disorder. Conclusions Our results provide novel and comprehensive methylome and transcriptome data from distinct cell populations within patient-derived brain tissues. This data clearly demonstrate that cell type epigenetic-differentiated sites are preferentially targeted by disease-associated epigenetic dysregulation. We further show reduced cell type epigenetic distinction in schizophrenia.GK is a Jon Heighten Scholar in Autism Research at UT Southwestern. This work was supported by the Uehara Memorial Foundation to NU; JSPS Grant-in-Aid for Early-Career Scientists (18 K14814) to NU; Scientific Research (C) (18K06977) to KT; Takeda Science Foundation to NU; the JSPS Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2603) to SB, NU, KT, and GK; the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Human Cognition – Scholar Award to GK; National Science Foundation (SBE-131719) to SVY; the National Chimpanzee Brain Resource, NIH R24NS092988, the NIH National Center for Research Resources P51RR165 (superseded by the Office of Research Infrastructure Programs/OD P51OD11132) to TMP; and the NIMH (MH103517) to TMP, GK, and SVY. Human tissue samples were obtained from the NIH NeuroBioBank (The Harvard Brain Tissue Resource Center, funded through HHSN-271-2013-00030C; the Human Brain and Spinal Fluid Mendizabal et al. Genome Biology (2019) 20:135 Page 18 of 21 Resource Center, VA West Los Angeles Healthcare Center; and the University of Miami Brain Endowment Bank) and the UT Psychiatry Psychosis Research Program (Dallas Brain Collection)

Functional Conservation of DNA Methylation in the Pea Aphid and the Honeybee

DNA methylation is a fundamental epigenetic mark known to have wide-ranging effects on gene regulation in a variety of animal taxa. Comparative genomic analyses can help elucidate the function of DNA methylation by identifying conserved features of methylated genes and other genomic regions. In this study, we used computational approaches to distinguish genes marked by heavy methylation from those marked by little or no methylation in the pea aphid, Acyrthosiphon pisum. We investigated if these two classes had distinct evolutionary histories and functional roles by conducting comparative analysis with the honeybee, Apis (Ap.) mellifera. We found that highly methylated orthologs in A. pisum and Ap. mellifera exhibited greater conservation of methylation status, suggesting that highly methylated genes in ancestral species may remain highly methylated over time. We also found that methylated genes tended to show different rates of evolution than unmethylated genes. In addition, genes targeted by methylation were enriched for particular biological processes that differed from those in relatively unmethylated genes. Finally, methylated genes were preferentially ubiquitously expressed among alternate phenotypes in both species, whereas genes lacking signatures of methylation were preferentially associated with condition-specific gene expression. Overall, our analyses support a conserved role for DNA methylation in insects with comparable methylation systems

What are the determinants of gene expression levels and breadths in the human genome?

In complex organisms, different tissues express different genes, which ultimately shape the function and phenotype of each tissue. An important goal of modern biology is to understand how some genes are turned on and off in specific tissues and how the numbers of different gene expression products are determined. These aspects are named ‘expression breadth’ (or ‘tissue specificity’) and ‘expression level’, respectively. Here, we show that we can predict substantial amount of variation in levels and breadths of gene expression using genomic information of each gene. Interestingly, many genomic traits are correlated with both aspects of gene expression in similar directions, suggesting shared molecular pathways. However, to elucidate distinctive molecular mechanisms governing gene expression levels and breadths, we need to identify the relative significance of each genomic trait on these two aspects of gene expression. To this end, we developed a novel multivariate multiple regression method. Using this new method, we show that gene compactness (in particular, the mean size of exons), codon usage bias and non-synonymous rates have a stronger influence on expression levels compared with their effects on expression breadths. In contrast, the propensity of promoter DNA methylation is a stronger indicator of expression breadths than of expression levels. Interestingly, intron DNA methylation exhibits an opposite pattern to the promoter DNA methylation in the human genome, suggesting that DNA methylation may play multiple roles depending upon its genomic targets. Furthermore, synonymous rates have stronger associations with expression breadths than with expression levels in the human genome. These findings provide clues toward distinctive molecular mechanisms regulating different aspects of gene expression

Mutations of Different Molecular Origins Exhibit Contrasting Patterns of Regional Substitution Rate Variation

Transitions at CpG dinucleotides, referred to as “CpG substitutions”, are a major mutational input into vertebrate genomes and a leading cause of human genetic disease. The prevalence of CpG substitutions is due to their mutational origin, which is dependent on DNA methylation. In comparison, other single nucleotide substitutions (for example those occurring at GpC dinucleotides) mainly arise from errors during DNA replication. Here we analyzed high quality BAC-based data from human, chimpanzee, and baboon to investigate regional variation of CpG substitution rates

Evolution of MicroRNAs and the Diversification of Species

MicroRNAs (miRNAs) are ancient, short noncoding RNA molecules that regulate the transcriptome through post-transcriptional mechanisms. miRNA riboregulation is involved in a diverse range of biological processes, and misregulation is implicated in disease. It is generally thought that miRNAs function to canalize cellular outputs, for instance as “fail-safe” repressors of gene misexpression. Genomic surveys in humans have revealed reduced genetic polymorphism and the signature of negative selection for both miRNAs themselves and the target sequences to which they are predicted to bind. We investigated the evolution of miRNAs and their binding sites across cichlid fishes from Lake Malawi (East Africa), where hundreds of diverse species have evolved in the last million years. Using low-coverage genome sequence data, we identified 100 cichlid miRNA genes with mature regions that are highly conserved in other animal species. We computationally predicted target sites on the 3′-untranslated regions (3′-UTRs) of cichlid genes to which miRNAs may bind and found that these sites possessed elevated single nucleotide polymorphism (SNP) densities. Furthermore, polymorphic sites in predicted miRNA targets showed higher minor allele frequencies on average and greater genetic differentiation between Malawi lineages when compared with a neutral expectation and nontarget 3′-UTR SNPs. Our data suggest that divergent selection on miRNA riboregulation may have contributed to the diversification of cichlid species and may similarly play a role in rapid phenotypic evolution of other natural systems