CpG island density and its correlations with genomic features in mammalian genomes

Background  

CpG islands, which are clusters of CpG dinucleotides in GC-rich regions, are considered gene markers and represent an important feature of mammalian genomes. Previous studies of CpG islands have largely been on specific loci or within one genome. To date, there seems to be no comparative analysis of CpG islands and their density at the DNA sequence level among mammalian genomes and of their correlations with other genome features.     

Insertional mutations in mammals and mammalian cells.

The retroposon sequences, their mechanisms of transposition and the occurrence of insertional mutation in the mammalian genome are reviewed. Insertional mutations fall into two broad categories: those due to the disruption of a gene following the physical integration of a foreign DNA sequence result in loss of gene product and would be expected to be associated with a recessive mutation. A second class of insertional mutation is well documented in which upon integration the promoter/enhancer activities inherent in the retroposon genome exert their influence on neighboring genes. This promoter/enhancer activity of integrated retroposons may have effects over relatively long distances and thus limit the possibilities of establishing an association between retroposon integration and mutation. It is emphasized that a systematic search for insertional mutations in the mammalian genome involves an extensive two-dimensional array of possible retroposon sequences and mutant alleles. Present results represent only a small portion of the total array. Future studies promise to be fruitful in efforts to isolate genes through insertional tagging, to characterize the mechanisms of retroposon transposition, as well as to study the stability of the mammalian genome.     

Divergence of Mammalian Higher Order Chromatin Structure Is Associated with Developmental Loci

Several recent studies have examined different aspects of mammalian higher order chromatin structure – replication timing, lamina association and Hi-C inter-locus interactions — and have suggested that most of these features of genome organisation are conserved over evolution. However, the extent of evolutionary divergence in higher order structure has not been rigorously measured across the mammalian genome, and until now little has been known about the characteristics of any divergent loci present. Here, we generate a dataset combining multiple measurements of chromatin structure and organisation over many embryonic cell types for both human and mouse that, for the first time, allows a comprehensive assessment of the extent of structural divergence between mammalian genomes. Comparison of orthologous regions confirms that all measurable facets of higher order structure are conserved between human and mouse, across the vast majority of the detectably orthologous genome. This broad similarity is observed in spite of many loci possessing cell type specific structures. However, we also identify hundreds of regions (from 100 Kb to 2.7 Mb in size) showing consistent evidence of divergence between these species, constituting at least 10% of the orthologous mammalian genome and encompassing many hundreds of human and mouse genes. These regions show unusual shifts in human GC content, are unevenly distributed across both genomes, and are enriched in human subtelomeric regions. Divergent regions are also relatively enriched for genes showing divergent expression patterns between human and mouse ES cells, implying these regions cause divergent regulation. Particular divergent loci are strikingly enriched in genes implicated in vertebrate development, suggesting important roles for structural divergence in the evolution of mammalian developmental programmes. These data suggest that, though relatively rare in the mammalian genome, divergence in higher order chromatin structure has played important roles during evolution.     

Gene amplification: yeast takes a turn

The origins of gene amplifications in mammalian cells have been difficult to analyze because of secondary genome rearrangements. Recent studies in budding yeast, including in this issue of Cell, have provided new insights into the role of palindromic sequences in gene amplification.     

A platypus' eye view of the mammalian genome

The genome of monotremes, like the animals themselves, is unique and strange. The importance of monotremes to genomics depends on their position as the earliest offshoot of the mammalian lineage. Although there has been controversy in the literature over the phylogenetic position of monotremes, this traditional interpretation is now confirmed by recent sequence comparisons. Characterizing the monotreme genome will therefore be important for studying the evolution and organization of the mammalian genome, and the proposal to sequence the platypus genome has been received enthusiastically by the genomics community. Recent investigations of X-chromosome inactivation, genomic imprinting and sex chromosome evolution provide good examples of the power of the monotreme genome to inform us about mammalian genome organization and evolution.     

Gene duplication and the uniqueness of vertebrate genomes circa 1970-1999

In this article I review research undertaken over the past 30 years into the role that gene duplication played in shaping vertebrate genomes. I discuss early karyotype studies that pointed to a relative stability of mammalian and avian genomes, the discovery and possible evolutionary significance of enormous genomes in urodele amphibians and lungfish, genome compaction in certain specialised bony fish, evidence for two rounds of total genome doubling in early vertebrate evolution and the fate of duplicated genes in polyploid fish.     

比较基因组学在哺乳动物进化研究中的应用

哺乳动物经过长期进化,使其基因组在结构和功能上存在着明显的差异,构成了表型进化的基础。随着人类、部分哺乳动物基因组测序的完成,以比较基因组学为主要研究手段的哺乳动物进化研究应运而生,从而为在基因组水平上深入认识哺乳动物进化关系、揭示生命的起源和进化提供依据。对比较基因组学的主要研究方法进行了综述,进而探讨其在哺乳动物进化研究中的应用,并对哺乳动物比较基因组学的发展进行了展望。     

A genomic approach to examine the complex evolution of laurasiatherian mammals

Recent phylogenomic studies have failed to conclusively resolve certain branches of the placental mammalian tree, despite the evolutionary analysis of genomic data from 32 species. Previous analyses of single genes and retroposon insertion data yielded support for different phylogenetic scenarios for the most basal divergences. The results indicated that some mammalian divergences were best interpreted not as a single bifurcating tree, but as an evolutionary network. In these studies the relationships among some orders of the super-clade Laurasiatheria were poorly supported, albeit not studied in detail. Therefore, 4775 protein-coding genes (6,196,263 nucleotides) were collected and aligned in order to analyze the evolution of this clade. Additionally, over 200,000 introns were screened in silico, resulting in 32 phylogenetically informative long interspersed nuclear elements (LINE) insertion events. The present study shows that the genome evolution of Laurasiatheria may best be understood as an evolutionary network. Thus, contrary to the common expectation to resolve major evolutionary events as a bifurcating tree, genome analyses unveil complex speciation processes even in deep mammalian divergences. We exemplify this on a subset of 1159 suitable genes that have individual histories, most likely due to incomplete lineage sorting or introgression, processes that can make the genealogy of mammalian genomes complex. These unexpected results have major implications for the understanding of evolution in general, because the evolution of even some higher level taxa such as mammalian orders may sometimes not be interpreted as a simple bifurcating pattern.     

Cross-species enhancer prediction using machine learning

Cis-regulatory elements (CREs) are non-coding parts of the genome that play a critical role in gene expression regulation. Enhancers, as an important example of CREs, interact with genes to influence complex traits like disease, heat tolerance and growth rate. Much of what is known about enhancers come from studies of humans and a few model organisms like mouse, with little known about other mammalian species. Previous studies have attempted to identify enhancers in less studied mammals using comparative genomics but with limited success. Recently, Machine Learning (ML) techniques have shown promising results to predict enhancer regions. Here, we investigated the ability of ML methods to identify enhancers in three non-model mammalian species (cattle, pig and dog) using human and mouse enhancer data from VISTA and publicly available ChIP-seq. We tested nine models, using four different representations of the DNA sequences in cross-species prediction using both the VISTA dataset and species-specific ChIP-seq data. We identified between 809,399 and 877,278 enhancer-like regions (ELRs) in the study species (11.6–13.7% of each genome). These predictions were close to the ~8% proportion of ELRs that covered the human genome. We propose that our ML methods have predictive ability for identifying enhancers in non-model mammalian species. We have provided a list of high confidence enhancers at https://github.com/DaviesCentreInformatics/Cross-species-enhancer-prediction and believe these enhancers will be of great use to the community.     

High‐resolution analysis of DNA synthesis start sites and nucleosome architecture at efficient mammalian replication origins

DNA replication origins are poorly characterized genomic regions that are essential to recruit and position the initiation complex to start DNA synthesis. Despite the lack of specific replicator sequences, initiation of replication does not occur at random sites in the mammalian genome. This has lead to the view that DNA accessibility could be a major determinant of mammalian origins. Here, we performed a high‐resolution analysis of nucleosome architecture and initiation sites along several origins of different genomic location and firing efficiencies. We found that mammalian origins are highly variable in nucleosome conformation and initiation patterns. Strikingly, initiation sites at efficient CpG island‐associated origins always occur at positions of high‐nucleosome occupancy. Origin recognition complex (ORC) binding sites, however, occur at adjacent but distinct positions marked by labile nucleosomes. We also found that initiation profiles mirror nucleosome architecture, both at endogenous origins and at a transgene in a heterologous system. Our studies provide a unique insight into the relationship between chromatin structure and initiation sites in the mammalian genome that has direct implications for how the replication programme can be accommodated to diverse epigenetic scenarios.     

Recent advances in developing molecular tools for targeted genome engineering of mammalian cells

Various biological molecules naturally existing in diversified species including fungi, bacteria, and bacteriophage have functionalities for DNA binding and processing. The biological molecules have been recently actively engineered for use in customized genome editing of mammalian cells as the molecule-encoding DNA sequence information and the underlying mechanisms how the molecules work are unveiled. Excitingly, multiple novel methods based on the newly constructed artificial molecular tools have enabled modifications of specific endogenous genetic elements in the genome context at efficiencies that are much higher than that of the conventional homologous recombination based methods. This minireview introduces the most recently spotlighted molecular genome engineering tools with their key features and ongoing modifications for better performance. Such ongoing efforts have mainly focused on the removal of the inherent DNA sequence recognition rigidity from the original molecular platforms, the addition of newly tailored targeting functions into the engineered molecules, and the enhancement of their targeting specificity. Effective targeted genome engineering of mammalian cells will enable not only sophisticated genetic studies in the context of the genome, but also widely-applicable universal therapeutics based on the pinpointing and correction of the disease-causing genetic elements within the genome in the near future. [BMB Reports 2015; 48(1): 6-12]     

Roadblocks and detours during DNA replication: Mechanisms of mutagenesis in mammalian cells

Mutations in specific genes result in birth defects, cancer, inherited diseases or lethality. The frequency with which DNA damage is converted to mutations increases dramatically when the cellular genome is replicated. Although DNA damage poses special problems to the fidelity of DNA replication, efficient mechanisms exist in mammalian cells which function to replicate their genome despite the presence of many damaged sites. These mechanisms operate in either error-prone or error-free modes of DNA synthesis, and frequently involve DNA strand-pairing reactions. Genetic studies in yeast and other eukaryotes suggest that replication through DNA damage is highly regulated and catalysed by complex biochemical machineries composed of many specialised gene products. Knowledge of the molecular details by which such factors facilitate the replication of damaged DNA in mammalian cells should reveal basic rules about how DNA damage induces mutagenesis and carcinogenesis.     

The complete genome sequence of a dog: a perspective

A complete, high-quality reference sequence of a dog genome was recently produced by a team of researchers led by the Broad Institute, achieving another major milestone in deciphering the genomic landscape of mammalian organisms. The genome sequence provides an indispensable resource for comparative analysis and novel insights into dog and human evolution and history. Together with the survey sequence of a poodle previously published in 2003, the two dog genome sequences allowed identification of more than 2.5 million single nucleotide polymorphisms within and between dog breeds, which can be used in evolutionary analysis, behavioral studies and disease gene mapping.(1)     

Structure and expression of a newt cardio-skeletal myosin gene. Implications for the C value paradox

As part of our studies on the fate of the muscle lineage during amphibian limb regeneration, we have isolated genomic and cDNA sequences from a myosin heavy chain in the newt (Notophthalmus viridescens). Notwithstanding the technical problems inherent in analysing the large newt genome, genomic and cDNA sequences have been isolated and subjected to analysis by restriction mapping. Northern hybridization, Southern hybridization and DNA sequencing. We believe these to be the first single copy newt gene sequences to have been subjected to this type of analysis. The newt gene sequences showed a striking difference from mammalian myosins in both the estimated sizes of the gene and its intervening sequences; these being much larger than in the mammalian models, it is speculated that this could contribute to the exceptional size of the newt genome. By contrast, the coding sequences displayed very high levels of sequence homology to mammalian myosins. In particular, the amino acid sequence of the newt myosin was found to have greatest homology with rat and human myosin isotypes having a similar cardio-skeletal muscle expression pattern. Despite a long evolutionary separation, newt and mammalian cardio-skeletal myosins have remained more similar to each other than have the human or rat cardiac forms to skeletal myosins within their own respective species.     

Chromatin Architecture in the Fly: Living without CTCF/Cohesin Loop Extrusion?

The organization of the genome into topologically associated domains (TADs) appears to be a fundamental process occurring across a wide range of eukaryote organisms, and it likely plays an important role in providing an architectural foundation for gene regulation. Initial studies emphasized the remarkable parallels between TAD organization in organisms as diverse as Drosophila and mammals. However, whereas CCCTC‐binding factor (CTCF)/cohesin loop extrusion is emerging as a key mechanism for the formation of mammalian topological domains, the genome organization in Drosophila appears to depend primarily on the partitioning of chromatin state domains. Recent work suggesting a fundamental conserved role of chromatin state in building domain architecture is discussed and insights into genome organization from recent studies in Drosophila are considered.     

Mammalian sex chromosomes: Evolution of organization and function

Comparisons of chromosome size, morphology and gene arrangements between mammals of different species permit us to deduce the genome characteristics of the common ancestor, and to chart the changes that have occurred during the divergence of the two lineages. The more distantly related are the species compared, the more remote the common ancestor whose characteristics can be deduced. This means that, providing there are sufficient similarities to warrant comparison, the more divergent the species compared, the more significant the contribution to our understanding of the organization of an ancestral mammalian genome and the process of mammalian genome evolution. One of the genetic surprises of the last decade was the discovery that, although gross karyotypes of distantly related orders of eutherian mammals (e.g. cat, cow, rabbit, man) have diverged extensively, gene mapping studies reveal the presence of large chromosome segments conserved across at least 60 million years (O'Brien et al. 1988). This finding makes it worthwhile to extend genetic comparisons to the two groups of mammals most distantly related to eutherian mammals--marsupials and monotremes. Here we will review comparisons of the sex chromosomes in these three major groups of extant mammals, and show how they have led us to a new view of the evolution of mammalian sex chromosome organization and function in sex determination and X chromosome inactivation.