We report a high-quality draft of the genome sequence of the grey, short-tailed opossum (Monodelphis domestica). As the first metatherian ('marsupial') species to be sequenced, the opossum provides a unique perspective on the organization and evolution of mammalian genomes. Distinctive features of the opossum chromosomes provide support for recent theories about genome evolution and function, including a strong influence of biased gene conversion on nucleotide sequence composition, and a relationship between chromosomal characteristics and X chromosome inactivation. Comparison of opossum and eutherian genomes also reveals a sharp difference in evolutionary innovation between protein-coding and non-coding functional elements. True innovation in protein-coding genes seems to be relatively rare, with lineage-specific differences being largely due to diversification and rapid turnover in gene families involved in environmental interactions. In contrast, about 20% of eutherian conserved non-coding elements (CNEs) are recent inventions that postdate the divergence of Eutheria and Metatheria. A substantial proportion of these eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation.

ABSTRACT:Epigenetics is the study of the heritable changes in gene expression that occur without a change in the DNA sequence itself. These heritable epigenetic changes include chromatin folding and attachment to the nuclear matrix, packaging of DNA around nucleosomes, histone modifications, and DNA methylation. The epigenome is particularly susceptible to dysregulation during gestation, neonatal development, puberty, and old age. Nevertheless, it is most vulnerable to environmental factors during embryogenesis because the DNA synthetic rate is high, and the elaborate DNA methylation patterning and chromatin structure required for normal tissue development is established during early development. Metastable epialleles are alleles that are variably expressed in genetically identical individuals due to epigenetic modifications established during early development and are thought to be particularly vulnerable to environmental influences. The viable yellow agouti (A vy ) allele, whose expression is correlated to DNA methylation, is a murine metastable epiallele, which has been used as an epigenetic biosensor for environmental factors affecting the fetal epigenome. In this review, we introduce epigenetic gene regulation, describe important epigenetic phenomenon in mammals, summarize literature linking the early environment to developmental plasticity of the fetal epigenome, and promote the necessity to identify epigenetically labile genes in the mouse and human genomes. H istorically, DNA has been considered the sole unit of biologic inheritance. Therefore, research was designed to investigate how individuals with different genotypes respond to various environmental factors and how these responses change over time. Recently, however, the revelation that epigenetic marks are influenced by environmental factors (1,2), and may also be inherited transgenerationally (3,4) has promoted the investigation of how epigenetic variability affects phenotype. If the genome is thought of as being similar to the hardware in a computer, the epigenome is the software that directs the computer's operation. Thus, identifying epigenetic targets and defining how they are dysregulated in human disease by environmental exposures will allow for the development of innovative novel diagnostic, treatment, and prevention strategies that target the "epigenomic software" rather than the "genomic hardware."The term "epigenetics" was first defined in the 1940s by developmental biologist Conrad Waddington as "the interactions of genes with their environment, which bring the phenotype into being (5)." Subsequently, in 1975, Holliday and Pugh proposed covalent chemical DNA modifications, including methylation of cytosine-guanine (CpG) dinucleotides, as the molecular mechanism to explain Conrad's hypothesis (6). Several years later, the revelations that X-inactivation in mammals and genomic imprinting are regulated by epigenetic mechanisms highlighted the heritable nature of epigenetic gene regulation mechanisms (7,8). The genomics revolution inspired t...

Genomic imprinting results in parent-of-origin-dependent, monoallelic expression of genes. The functional haploid state of these genes has far-reaching consequences. Not only has imprinting been implicated in accelerating mammalian speciation, there is growing evidence that it is also involved in the pathogenesis of several human conditions, particularly cancer and neurological disorders. Epigenetic regulatory mechanisms govern the parental allele-specific silencing of imprinted genes, and many theories have attempted to explain the driving force for the evolution of this unique form of gene control. This review discusses the evolution of imprinting in Therian mammals, and the importance of imprinted genes in human health and disease.