Molecular evolution of the intracellular targeting of alanine:glyoxylate aminotransferase

The subcellular distribution of the hepatic metabolic enzyme alanine:glyoxylate aminotransferase (AGT) has changed on numerous occasions throughout the evolution of mammals. The AGT distribution in the livers of these species seems to show a relationship to diet. Thus AGT tends to be mitochondrial in carnivores, peroxisomal in herbivores and both mitochondrial and peroxisomal in omnivores. The archetypal mammalian AGT gene has the potential to encode an N-terminal mitchondrial targeting sequence (MTS) and a C-terminal peroxisomal targeting sequence type 1 (PTS1). The variable subcellular distribution of AGT results from the variable use of two alternative transcription and translation start sites which include or exclude the MTS from the open reading frame (ORF). The functionality and evolution of the targeting sequences of AGT are extraordinary. The MTS of AGT is often excluded from the ORF and the PTS1 is protein context dependent. This study further investigates the following: 1. The molecular mechanism for the variable distribution of AGT in different species 2. The selective pressure that acts on the targeting of AGT to cause its variable localization. The results presented in this thesis show the following: The molecular explanation for the unusual mitochondrial and cytosolic distribution of amphibian AGT was determined, using the xenopus as a representative species. It is the first AGT gene studied, which does not encode a peroxisomal targeting sequence. Xenopus AGT has the potential to encode two RNA transcripts. One of these includes the MTS and the other has no targeting information. Two novel molecular mechanisms for a solely peroxisomal distribution of AGT were suggested for certain primate species. These were the loss of a transcription start site excluding the MTS from the RNA transcript, and accumulation of mutations in the MTS that are incompatible with its function. The context specificity of PTS1s, in general, was explored by undertaking an extensive literature survey of C-terminal tripeptides that have some characteristics of PTS1s. This information was related to the peroxisomal targeting of AGT. Analysis of the relative number of synonymous and nonsynonymous mutations accumulated in the region of primate AGT genes, encoding the MTS, suggested that there has been recent strong, yet episodic, positive selection pressure to lose, or diminish, mitochondrial AGT targeting in anthropoid primates. The selection pressure is possibly connected to diet. Non-mammalian AGT homologues were identified from sequence databases. These, along with the xenopus AGT data, suggested a new hypothesis for the ancestral distribution of AGT. Stronger evidence for the theory of diet as the selective pressure driving the evolution of AGT subcellular targeting was acquired by comparative analysis of the distribution of AGT and diet, which showed a significant correlation

How to make DNA methylome wide association studies more powerful

Genome-wide association studies had a troublesome adolescence, while researchers increased statistical power, in part by increasing subject numbers. Interrogating the interaction of genetic and environmental influences raised new challenges of statistical power, which were not easily bested by the addition of subjects. Screening the DNA methylome offers an attractive alternative as methylation can be thought of as a proxy for the combined influences of genetics and environment. There are statistical challenges unique to DNA methylome data and also multiple features, which can be exploited to increase power. We anticipate the development of DNA methylome association study designs and new analytical methods, together with integration of data from other molecular species and other studies, which will boost statistical power and tackle causality. In this way, the molecular trajectories that underlie disease development will be uncovered

The role of positive selection in determining the molecular cause of species differences in disease

Related species, such as humans and chimpanzees, often experience the same disease with varying degrees of pathology, as seen in the cases of Alzheimer's disease, or differing symptomatology as in AIDS. Furthermore, certain diseases such as schizophrenia, epithelial cancers and autoimmune disorders are far more frequent in humans than in other species for reasons not associated with lifestyle. Genes that have undergone positive selection during species evolution are indicative of functional adaptations that drive species differences. Thus we investigate whether biomedical disease differences between species can be attributed to positively selected genes

Ethnic differences in effects of maternal prepregnancy and pregnancy adiposity on offspring size and adiposity

10.1210/jc.2015-1728The Journal of Clinical Endocrinology & Metabolism100103641–3650GUSTO (Growing up towards Healthy Outcomes

Manipulations of Amyloid Precursor Protein Cleavage Disrupt the Circadian Clock in Aging Drosophila

Alzheimer's disease (AD) is a neurodegenerative disease characterized by severe cognitive deterioration. While causes of AD pathology are debated, a large body of evidence suggests that increased cleavage of Amyloid Precursor Protein (APP) producing the neurotoxic Amyloid-β (Aβ) peptide plays a fundamental role in AD pathogenesis. One of the detrimental behavioral symptoms commonly associated with AD is the fragmentation of sleep-activity cycles with increased nighttime activity and daytime naps in humans. Sleep-activity cycles, as well as physiological and cellular rhythms, which may be important for neuronal homeostasis, are generated by a molecular system known as the circadian clock. Links between AD and the circadian system are increasingly evident but not well understood. Here we examined whether genetic manipulations of APP-like (APPL) protein cleavage in Drosophila melanogaster affect rest-activity rhythms and core circadian clock function in this model organism. We show that the increased β-cleavage of endogenous APPL by the β-secretase (dBACE) severely disrupts circadian behavior and leads to reduced expression of clock protein PER in central clock neurons of aging flies. Our data suggest that behavioral rhythm disruption is not a product of APPL-derived Aβ production but rather may be caused by a mechanism common to both α and β-cleavage pathways. Specifically, we show that increased production of the endogenous Drosophila Amyloid Intracellular Domain (dAICD) caused disruption of circadian rest-activity rhythms, while flies overexpressing endogenous APPL maintained stronger circadian rhythms during aging. In summary, our study offers a novel entry point toward understanding the mechanism of circadian rhythm disruption in Alzheimer's disease.Keywords: period gene, Amyloid precursor protein, Amyloid intracellular domain, Drosophila, Alzheimer's disease, Circadian rhythms, BAC

Effects of Antenatal Maternal Depressive Symptoms and Socio-Economic Status on Neonatal Brain Development are Modulated by Genetic Risk

This study included 168 and 85 mother-infant dyads from Asian and United States of America cohorts to examine whether a genomic profile risk score for major depressive disorder (GPRSMDD) moderates the association between antenatal maternal depressive symptoms (or socio-economic status, SES) and fetal neurodevelopment, and to identify candidate biological processes underlying such association. Both cohorts showed a significant interaction between antenatal maternal depressive symptoms and infant GPRSMDD on the right amygdala volume. The Asian cohort also showed such interaction on the right hippocampal volume and shape, thickness of the orbitofrontal and ventromedial prefrontal cortex. Likewise, a significant interaction between SES and infant GPRSMDD was on the right amygdala and hippocampal volumes and shapes. After controlling for each other, the interaction effect of antenatal maternal depressive symptoms and GPRSMDD was mainly shown on the right amygdala, while the interaction effect of SES and GPRSMDD was mainly shown on the right hippocampus. Bioinformatic analyses suggested neurotransmitter/neurotrophic signaling, SNAp REceptor complex, and glutamate receptor activity as common biological processes underlying the influence of antenatal maternal depressive symptoms on fetal cortico-limbic development. These findings suggest gene-environment interdependence in the fetal development of brain regions implicated in cognitive-emotional function. Candidate biological mechanisms involve a range of brain region-specific signaling pathways that converge on common processes of synaptic development

Relationships between the Circadian System and Alzheimer’s Disease-Like Symptoms in Drosophila

Circadian clocks coordinate physiological, neurological, and behavioral functions into circa 24 hour rhythms, and the molecular mechanisms underlying circadian clock oscillations are conserved from Drosophila to humans. Clock oscillations and clock-controlled rhythms are known to dampen during aging; additionally, genetic or environmental clock disruption leads to accelerated aging and increased susceptibility to age-related pathologies. Neurodegenerative diseases, such as Alzheimer’s disease (AD), are associated with a decay of circadian rhythms, but it is not clear whether circadian disruption accelerates neuronal and motor decline associated with these diseases. To address this question, we utilized transgenic Drosophila expressing various Amyloid-β (Aβ) peptides, which are prone to form aggregates characteristic of AD pathology in humans. We compared development of AD-like symptoms in adult flies expressing Aβ peptides in the wild type background and in flies with clocks disrupted via a null mutation in the clock gene period (per[superscript 01]). No significant differences were observed in longevity, climbing ability and brain neurodegeneration levels between control and clock-deficient flies, suggesting that loss of clock function does not exacerbate pathogenicity caused by human-derived Aβ peptides in flies. However, AD-like pathologies affected the circadian system in aging flies. We report that rest/activity rhythms were impaired in an age-dependent manner. Flies expressing the highly pathogenic arctic Aβ peptide showed a dramatic degradation of these rhythms in tune with their reduced longevity and impaired climbing ability. At the same time, the central pacemaker remained intact in these flies providing evidence that expression of Aβ peptides causes rhythm degradation downstream from the central clock mechanism

Epigenetic age acceleration in adolescence associates with BMI, inflammation and risk score for middle age cardiovascular disease

BACKGROUND: 'Accelerated ageing', assessed by adult DNA methylation predicts cardiovascular disease (CVD). Adolescent accelerated aging might predict CVD earlier. We investigated whether epigenetic age acceleration (assessed age 17-years) associated with adiposity/CVD-risk measured (ages 17, 20, 22-years), and projected CVD by middle-age. METHODS: DNA methylation measured in peripheral blood provided 2 estimates of epigenetic age acceleration; intrinsic (IEAA, (preserved across cell types) and extrinsic (EEAA, dependent on cell admixture and methylation levels within each cell type).Adiposity was assessed by anthropometry, ultrasound and DEXA (ages 17, 20, 22 years). CVD-risk factors (lipids, HOMA-IR, blood pressure, inflammatory markers) were assessed at age 17-years. CVD development by age 47 years was calculated by Framingham algorithms. Results are presented as regression coefficients/5-year epigenetic age acceleration (IEAA/EEAA) for adiposity, CVD-risk factors and CVD development. RESULTS: In 995 participants (49.6% female, age 17.3+/-0.6 years), EEAA (/5-years) was associated with increased BMI of 2.4% (95%CI 1.2-3.6%) and 2.4% (0.8-3.9%) at 17 and 22 years, respectively. EEAA was associated with increases of 23% (3-33%) in hsCRP, 10% (4-17%) in interferon-gamma induced protein (IP-10) and 4% (2-6%) in tumour necrosis factor receptor 2 (sTNFR2), adjusted for BMI and HOMA-IR. EEAA(/5-years) results in a 4% increase in hard endpoints of CVD by 47 years old and a 3% increase, after adjustment for conventional risk factors. CONCLUSIONS: Accelerated epigenetic age in adolescence was associated with inflammation, BMI measured 5 years later, and probability of middle-age CVD. Irrespective whether this is cause or effect, assessing epigenetic age might refine disease prediction

Interrogating resilience: toward a typology to improve its operationalization

In the context of accelerated global change, the concept of resilience, with its roots in ecological theory and complex adaptive systems, has emerged as the favored framework for understanding and responding to the dynamics of change. Its transfer from ecological to social contexts, however, has led to the concept being interpreted in multiple ways across numerous disciplines causing significant challenges for its practical application. The aim of this paper is to improve conceptual clarity within resilience thinking so that resilience can be interpreted and articulated in ways that enhance its utility and explanatory power, not only theoretically but also operationally. We argue that the current confusion and ambiguity within resilience thinking is problematic for operationalizing the concept within policy making. To achieve our aim, we interrogate resilience interpretations used within a number of academic and practice domains in the forefront of contending with the disruptive and sometimes catastrophic effects of global change (primarily due to climate change) on ecological and human-nature systems. We demonstrate evolution and convergence among disciplines in the interpretations and theoretical underpinnings of resilience and in engagement with cross-scale considerations. From our analysis, we identify core conceptual elements to be considered in policy responses if resilience is to fulfill its potential in improving decision making for change. We offer an original classification of resilience definitions in current use and a typology of resilience interpretations. We conclude that resilience thinking must be open to alternative traditions and interpretations if it is to become a theoretically and operationally powerful paradigm

Association of maternal Vitamin D status with glucose tolerance and caesarean section in a multi-ethnic Asian cohort: the growing up in Singapore towards healthy outcomes study

10.1371/journal.pone.0142239PLoS ONE10111-16GUSTO (Growing up towards Healthy Outcomes