Parental ages and levels of DNA methylation in the newborn are correlated.

BACKGROUND: Changes in DNA methylation patterns with age frequently have been observed and implicated in the normal aging process and its associated increasing risk of disease, particularly cancer. Additionally, the offspring of older parents are at significantly increased risk of cancer, diabetes, and neurodevelopmental disorders. Only a proportion of these increased risks among the children of older parents can be attributed to nondisjunction and chromosomal rearrangements. RESULTS: Using a genome-wide survey of 27,578 CpG dinucleotides in a cohort of 168 newborns, we examined the relationship between DNA methylation in newborns and a variety of parental and newborn traits. We found that methylation levels of 144 CpGs belonging to 142 genes were significantly correlated with maternal age. A weaker correlation was observed with paternal age. Among these genes, processes related to cancer were over-represented, as were functions related to neurological regulation, glucose/carbohydrate metabolism, nucleocytoplasmic transport, and transcriptional regulation. CpGs exhibiting gender differences in methylation were overwhelmingly located on the X chromosome, although a small subset of autosomal CpGs were found in genes previously shown to exhibit gender-specific differences in methylation levels. CONCLUSIONS: These results indicate that there are differences in CpG methylation levels at birth that are related to parental age and that could influence disease risk in childhood and throughout life.

Racial differences in gene-specific DNA methylation levels are present at birth.

BACKGROUND: DNA methylation patterns differ among children and adults and play an unambiguous role in several disease processes, particularly cancers. The origin of these differences is inadequately understood, and this is a question of specific relevance to childhood and adult cancer. METHODS: DNA methylation levels at 26,485 autosomal CpGs were assayed in 201 newborns (107 African American and 94 Caucasian). Nonparametric analyses were performed to examine the relation between these methylation levels and maternal parity, maternal age, newborn gestational age, newborn gender, and newborn race. To identify the possible influences of confounding, stratification was performed by a second and third variable. For genes containing CpGs with significant differences in DNA methylation levels between races, analyses were performed to identify highly represented gene ontological terms and functional pathways. RESULTS: 13.7% (3623) of the autosomal CpGs exhibited significantly different levels of DNA methylation between African Americans and Caucasians; 2% of autosomal CpGs had significantly different DNA methylation levels between male and female newborns. Cancer pathways, including four (pancreatic, prostate, bladder, and melanoma) with substantial differences in incidence between the races, were highly represented among the genes containing significant race-divergent CpGs. CONCLUSIONS: At birth, there are significantly different DNA methylation levels between African Americans and Caucasians at a subset of CpG dinucleotides. It is possible that some of the epigenetic precursors to cancer exist at birth and that these differences partially explain the different incidence rates of specific cancers between the races.

Genome-wide expression profiling in Geobacter sulfurreducens: identification of Fur and RpoS transcription regulatory sites in a relGsu mutant.

Rel(Gsu) is the single Geobacter sulfurreducens homolog of RelA and SpoT proteins found in many organisms. These proteins are involved in the regulation of levels of guanosine 3', 5' bispyrophosphate, ppGpp, a molecule that signals slow growth and stress response under nutrient limitation in bacteria. We used information obtained from genome-wide expression profiling of the rel(Gsu) deletion mutant to identify putative regulatory sites involved in transcription networks modulated by Rel(Gsu) or ppGpp. Differential gene expression in the rel(Gsu) deletion mutant, as compared to the wild type, was available from two growth conditions, steady state chemostat cultures and stationary phase batch cultures. Hierarchical clustering analysis of these two datasets identified several groups of operons that are likely co-regulated. Using a search for conserved motifs in the upstream regions of these co-regulated operons, we identified sequences similar to Fur- and RpoS-regulated sites. These findings suggest that Fur- and RpoS-dependent gene expression in G. sulfurreducens is affected by Rel(Gsu)-mediated signaling.

Higher-level systematics of rodents and divergence time estimates based on two congruent nuclear genes.

Phylogenetic analysis of over 4600 aligned nucleotide sequences from two nuclear genes, growth hormone receptor and BRCA1, provided congruent phylogenies depicting relationships among the major lineages of rodents. Separate and combined analyses resulted in five major conclusions: (1) strong support for a monophyletic Myodonta (containing the superfamilies Muroidea + Dipodoidea), with subfamily Gerbillinae being more closely related to Murinae than is Sigmodontinae; (2) a sister-group relationship between the family Castoridae and the superfamily Geomyoidea; (3) monophyly of Ctenohystrica (containing the suborders Sciuravida and Hystricognatha); (4) a near polytomy among Myodonta (suborder Myomorpha), Pedetes (family Pedetidae, suborder Anomaluromorpha), Castoridae (suborder Sciuromorpha) + Geomyoidea (suborder Myomorpha), and Ctenohystrica; and (5) basal position of a monophyletic group containing Graphiurus (family Gliridae, suborder Myomorpha) + two members of the Sciuromorpha (Sciuridae + Aplodontidae). Divergence dates among rodents and primates were also estimated using the combined data. Applying a global molecular clock and a primate calibration point, divergence dates among rodents exceeded fossil-based dates but were generally compatible with other molecule-based dates estimated under similar conditions. However, when a relaxed molecular clock was applied, estimated divergence dates were highly compatible with the fossil record.

Molecular support for Afrotheria and the polyphyly of Lipotyphla based on analyses of the growth hormone receptor gene.

The order Lipotyphla has generally been viewed as a difficult group to classify. For example, recent morphologically based analyses only weakly support the lipotyphla while molecular evidence renders it polyphyletic, placing the golden moles and tenrecs in the superorder known as Afrotheria. Afrotheria is an hypothesized order that contains elephants, sirenians, hyraxes, aardvarks, elephant shrews, tenrecs, and golden moles. Within this group, it has been suggested that the African lipotyphlans (tenrecs and golden moles) form a monophyletic order sometimes referred to as "Afroscoricida," but more appropriately termed Tenrecoidea. The paper presents a molecular analysis of 36 taxa including representatives of five of the six families in Lipotyphla (Solenodontidae is absent) and all orders within Afrotheria. Parsimony analyses were completed using data from the nucleotide sequence of the tenth exon of the growth hormone receptor gene (GHR). These analyses support both the polyphyly of Lipotyphla and the monophyly of Afrotheria with high bootstrap and jackknife support. In addition, the remaining lipotyphlans (known as Eulipotyphla) appear polyphyletic, as does Tenrecoidea.