There is a well‐established allometric relationship between brain and body mass in mammals. Deviation of relatively increased brain size from this pattern appears to coincide with enhanced cognitive ...abilities. To examine whether there is a phylogenetic structure to such episodes of changes in encephalization across mammals, we used phylogenetic techniques to analyse brain mass, body mass and encephalization quotient (EQ) among 630 extant mammalian species. Among all mammals, anthropoid primates and odontocete cetaceans have significantly greater variance in EQ, suggesting that evolutionary constraints that result in a strict correlation between brain and body mass have independently become relaxed. Moreover, ancestral state reconstructions of absolute brain mass, body mass and EQ revealed patterns of increase and decrease in EQ within anthropoid primates and cetaceans. We propose both neutral drift and selective factors may have played a role in the evolution of brain–body allometry.
Epigenetic differences exist between trauma-exposed individuals with and without post-traumatic stress disorder (PTSD). It is unclear whether these epigenetic differences pre-exist, or arise ...following, trauma and PTSD onset.
In pre- and post-trauma samples from a subset of Detroit Neighborhood Health Study participants, DNA methylation (DNAm) was measured at DNA methyltransferase 1 (DNMT1), DNMT3A, DNMT3B and DNMT3L. Pre-trauma DNAm differences and changes in DNAm from pre- to post-trauma were assessed between and within PTSD cases (n = 30) and age-, gender- and trauma exposure-matched controls (n = 30). Pre-trauma DNAm was tested for association with post-trauma symptom severity (PTSS) change. Potential functional consequences of DNAm differences were explored via bioinformatic search for putative transcription factor binding sites (TFBS).
DNMT1 DNAm increased following trauma in PTSD cases (p = 0.001), but not controls (p = 0.067). DNMT3A and DNMT3B DNAm increased following trauma in both cases (DNMT3A: p = 0.009; DNMT3B: p < 0.001) and controls (DNMT3A: p = 0.002; DNMT3B: p < 0.001). In cases only, pre-trauma DNAm was lower at a DNMT3B CpG site that overlaps with a TFBS involved in epigenetic regulation (p = 0.001); lower pre-trauma DNMT3B DNAm at this site was predictive of worsening of PTSS post-trauma (p = 0.034). Some effects were attenuated following correction for multiple hypothesis testing.
DNAm among trauma-exposed individuals shows both longitudinal changes and pre-existing epigenetic states that differentiate individuals who are resilient versus susceptible to PTSD. These distinctive DNAm differences within DNMT loci may contribute to genome-wide epigenetic profiles of PTSD.
Recent work suggests that epigenetic differences may be associated with psychiatric disorders. Here we investigate, in a community-based sample, whether methylation profiles distinguish between ...individuals with and without lifetime depression. We also investigate the physiologic consequences that may be associated with these profiles.
Using whole blood-derived genomic DNA from a subset of participants in the Detroit Neighborhood Health Study (DNHS), we applied methylation microarrays to assess genome-wide methylation profiles for over 14 000 genes in 33 persons who reported a lifetime history of depression and 67 non-depressed adults. Bioinformatic functional analyses were performed on the genes uniquely methylated and unmethylated in each group, and inflammatory biomarkers interleukin (IL)-6 and C-reactive protein (CRP) were measured to investigate the possible functional significance of the methylation profiles observed.
Uniquely unmethylated gene sets distinguished between those with versus without lifetime depression. In particular, some processes (e.g. brain development, tryptophan metabolism) showed patterns suggestive of increased methylation among individuals with depression whereas others (e.g. lipoprotein) showed patterns suggestive of decreased methylation among individuals with depression. IL-6 and CRP levels were elevated among those with lifetime depression and, among those with depression only, IL-6 methylation showed an inverse correlation with circulating IL-6 and CRP.
Genome-wide methylation profiles distinguish individuals with versus without lifetime depression in a community-based setting, and show coordinated signals with pathophysiological mechanisms previously implicated in the etiology of this disorder. Examining epigenetic mechanisms in concert with other dynamic markers of physiologic functioning should improve our understanding of the neurobiology of depression.
Abstract The placenta is fundamentally important for the success of pregnancy. Disruptions outside the normal range for placental function can result in pregnancy failure and other complications. The ...anatomy of the placenta varies greatly across mammals, as do key parameters in pregnancy such as neonatal body mass, length of gestation and number of offspring per pregnancy. An accurate understanding of the evolution of the mammalian placenta will require at minimum the integration of anatomical, developmental, physiological, genetic, and epigenetic data. Currently available data suggest that the placenta is a dynamic organ that has evolved rapidly in a lineage specific manner. Examination of the placenta from the perspective of human evolution shows that many anatomical features of the human placenta are relatively conserved. Despite the anatomical conservation of the human placenta there are many recently evolved placenta-specific genes (e.g. CGB , LGALS13 , GH2 ) that are important in the development and function of the human placenta. Other mammalian genomes have also evolved specific suites of placenta-expressed genes. For example, rodents have undergone expansions of the cathepsin and prolactin families, and artiodactyls have expanded their suite of pregnancy-associated glycoproteins. In addition to lineage specific birth and death of gene family members, the pattern of imprinted loci varies greatly among species. Taken together, these studies suggest that a strategy reliant upon the sampling of placentally expressed and imprinted genes from a phylogenetically diverse range of species is appropriate for unraveling the conserved and derived aspects of placental biology.
The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD ...heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h
) for European-American females of 29% that is similar to h
for schizophrenia and is substantially higher than h
in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD-for both European- and African-American individuals-and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.
As the major glucose‐consuming organ in the human body, the dynamics of glucose metabolism in the brain deserve special attention. It has been shown that the brain's energy allocation as a percentage ...of the total energy budget of the individual peaks during childhood and declines through adolescence until reaching the stable allocation level seen in the adult. This pattern of glucose consumption has not been observed in other species, including our close primate relatives, and is therefore potentially either a driver or a consequence of human cognition. Furthermore, the allocation of glucose usage in the brain changes as the individual ages, with a surprising amount dedicated to glycolysis rather than oxidative phosphorylation pathway. This suggests that, at certain developmental stages, glucose‐fuelled anabolic pathways, in addition to ATP generation, are the driving forces behind the brain's high energy requirement. In this study, we explore the most recent work pertaining to the dynamic glucose uptake and allocation of the developing human brain and investigate several genes that may play a role in regulating these processes.
Rodent models implicate metabotropic glutamate receptors (mGluRs) and downstream signaling pathways in addictive behaviors through metaplasticity. One way mGluRs can influence synaptic plasticity is ...by regulating the local translation of AMPA receptor trafficking proteins via eukaryotic elongation factor 2 (eEF2). However, genetic variation in this pathway has not been examined with human alcohol use phenotypes. Among a sample of adults living in Detroit, Michigan (Detroit Neighborhood Health Study; n = 788; 83% African American), 206 genetic variants across the mGluR-eEF2-AMPAR pathway (including GRM1, GRM5, HOMER1, HOMER2, EEF2K, MTOR, EIF4E, EEF2, CAMK2A, ARC, GRIA1 and GRIA4) were found to predict number of drinking days per month (corrected P-value < 0.01) when considered as a set (set-based linear regression conducted in PLINK). In addition, a CpG site located in the 3'-untranslated region on the north shore of EEF2 (cg12255298) was hypermethylated in those who drank more frequently (P < 0.05). Importantly, the association between several genetic variants within the mGluR-eEF2-AMPAR pathway and alcohol use behavior (i.e., consumption and alcohol-related problems) replicated in the Grady Trauma Project (GTP), an independent sample of adults living in Atlanta, Georgia (n = 1034; 95% African American), including individual variants in GRM1, GRM5, EEF2, MTOR, GRIA1, GRIA4 and HOMER2 (P < 0.05). Gene-based analyses conducted in the GTP indicated that GRM1 (empirical P < 0.05) and EEF2 (empirical P < 0.01) withstood multiple test corrections and predicted increased alcohol consumption and related problems. In conclusion, insights from rodent studies enabled the identification of novel human alcohol candidate genes within the mGluR-eEF2-AMPAR pathway.
The placenta is essential for the success of therian mammalian reproduction. Intense selective pressure has shaped changes in placental anatomy and function during mammalian cladogenesis. Here we ...challenge the view that the hemochorial placenta is a derived feature in haplorhine primates. Using phylogenetic and statistical analyses of molecular and morphological data, we demonstrate that the ancestral eutherian mammalian placenta had the distinctive features of (i) hemochorial placental interface, (ii) a discoid shape, and (iii) a labyrinthine maternofetal interdigitation. These results reveal that the first eutherians had a deeply invasive placenta and imply that the major role of the placenta in sustaining pregnancy and promoting gestational development existed throughout the eutherian lineage that descended to humans from the last common ancestor of placental mammals. The ancestral state reconstructions demonstrate both clade-specific patterns of placentation and specific cases of convergent evolution within individual eutherian clades. Determining the mammalian pattern of change in placental morphology is important for understanding the evolutionary pressures faced by these lineages. The effects of selection pressures on the efficiency of placentation may stem from changes in nutritional demand, gestational length, number of embryos per pregnancy, uterine shape, and maternal body constitution. The influence of these factors on placental development needs further investigation.
Galectins are multifunctional regulators of fundamental cellular processes. They are also involved in innate and adaptive immune responses, and play a functional role in immune–endocrine crosstalk. ...Some galectins have attracted attention in the reproductive sciences because they are highly expressed at the maternal–fetal interface, their functional significance in eutherian pregnancies has been documented, and their dysregulated expression is observed in the ‘great obstetrical syndromes’. The evolution of these galectins has been linked to the emergence of eutherian mammals. Based on published evidence, galectins expressed at the maternal–fetal interface may serve as important proteins involved in maternal–fetal interactions, and the study of these galectins may facilitate the prediction, prevention, diagnosis, and treatment of pregnancy complications.
Abstract The genomes of over a dozen placental mammal species are now publicly available. These genome sequences have the potential to provide insight into the development and evolution of the ...placenta. In particular, the variable anatomy of the placenta has likely been affected by natural selection on the genomes of living and extinct mammals. In this note the current availability of mammal genome sequences is reviewed, and strengths and limitations of these data are discussed. Additionally, museums, zoos, and commercial entities are available to provide genomic resources to the placental research community. Recommendations for tissue storage conditions of placentas in genomic research are given.
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