New Implications on Genomic Adaptation Derived from the Helicobacter pylori Genome Comparison

BACKGROUND: Helicobacter pylori has a reduced genome and lives in a tough environment for long-term persistence. It evolved with its particular characteristics for biological adaptation. Because several H. pylori genome sequences are available, comparative analysis could help to better understand genomic adaptation of this particular bacterium. PRINCIPAL FINDINGS: We analyzed nine H. pylori genomes with emphasis on microevolution from a different perspective. Inversion was an important factor to shape the genome structure. Illegitimate recombination not only led to genomic inversion but also inverted fragment duplication, both of which contributed to the creation of new genes and gene family, and further, homological recombination contributed to events of inversion. Based on the information of genomic rearrangement, the first genome scaffold structure of H. pylori last common ancestor was produced. The core genome consists of 1186 genes, of which 22 genes could particularly adapt to human stomach niche. H. pylori contains high proportion of pseudogenes whose genesis was principally caused by homopolynucleotide (HPN) mutations. Such mutations are reversible and facilitate the control of gene expression through the change of DNA structure. The reversible mutations and a quasi-panmictic feature could allow such genes or gene fragments frequently transferred within or between populations. Hence, pseudogenes could be a reservoir of adaptation materials and the HPN mutations could be favorable to H. pylori adaptation, leading to HPN accumulation on the genomes, which corresponds to a special feature of Helicobacter species: extremely high HPN composition of genome. CONCLUSION: Our research demonstrated that both genome content and structure of H. pylori have been highly adapted to its particular life style

The Intensity of IUGR-Induced Transcriptome Deregulations Is Inversely Correlated with the Onset of Organ Function in a Rat Model

A low-protein diet applied during pregnancy in the rat results in intrauterine growth restricted (IUGR) fetuses. In humans, IUGR is associated with increased perinatal morbidity, higher incidence of neuro-developmental defects and increased risk of adult metabolic anomalies, such as diabetes and cardiovascular disease. Development and function of many organs are affected by environmental conditions such as those inducing fetal and early postnatal growth restriction. This phenomenon, termed “fetal programming” has been studied unconnectedly in some organs, but very few studies (if any) have investigated at the same time several organs, on a more comparative basis. However, it is quite probable that IUGR affects differentially most organ systems, with possible persistent changes in gene expression. In this study we address transcriptional alterations induced by IUGR in a multi-organ perspective, by systematic analysis of 20-days rat fetuses. We show that (1) expressional alterations are apparently stronger in organs functioning late in foetal or postnatal life than in organs that are functioning early (2) hierarchical classification of the deregulations put together kidney and placenta in one cluster, liver, lungs and heart in another; (3) the epigenetic machinery is set up especially in the placenta, while its alterations are rather mild in other organs; (4) the genes appear deregulated in chromosome clusters; (5) the altered expression cascades varies from organ to organ, with noticeably a very significant modification of the complement and coagulation cascades in the kidney; (6) we found a significant increase in TF binding site for HNF4 proteins specifically for liver genes that are down-regulated in IUGR, suggesting that this decrease is achieved through the action of HNF transcription factors, that are themselves transcriptionnally induced in the liver by IUGR (x 1.84 fold). Altogether, our study suggests that a combination of tissue-specific mechanisms contributes to bring about tissue-driven modifications of gene cascades. The question of these cascades being activated to adapt the organ to harsh environmental condition, or as an endpoint consequence is still raised

Rare Copy Number Deletions Predict Individual Variation in Intelligence

Phenotypic variation in human intellectual functioning shows substantial heritability, as demonstrated by a long history of behavior genetic studies. Many recent molecular genetic studies have attempted to uncover specific genetic variations responsible for this heritability, but identified effects capture little variance and have proven difficult to replicate. The present study, motivated an interest in “mutation load” emerging from evolutionary perspectives, examined the importance of the number of rare (or infrequent) copy number variations (CNVs), and the total number of base pairs included in such deletions, for psychometric intelligence. Genetic data was collected using the Illumina 1MDuoBeadChip Array from a sample of 202 adult individuals with alcohol dependence, and a subset of these (N = 77) had been administered the Wechsler Abbreviated Scale of Intelligence (WASI). After removing CNV outliers, the impact of rare genetic deletions on psychometric intelligence was investigated in 74 individuals. The total length of the rare deletions significantly and negatively predicted intelligence (r = −.30, p = .01). As prior studies have indicated greater heritability in individuals with relatively higher parental socioeconomic status (SES), we also examined the impact of ethnicity (Anglo/White vs. Other), as a proxy measure of SES; these groups did not differ on any genetic variable. This categorical variable significantly moderated the effect of length of deletions on intelligence, with larger effects being noted in the Anglo/White group. Overall, these results suggest that rare deletions (between 5% and 1% population frequency or less) adversely affect intellectual functioning, and that pleotropic effects might partly account for the association of intelligence with health and mental health status. Significant limitations of this research, including issues of generalizability and CNV measurement, are discussed

Identifying a Window of Vulnerability during Fetal Development in a Maternal Iron Restriction Model

It is well acknowledged from observations in humans that iron deficiency during pregnancy can be associated with a number of developmental problems in the newborn and developing child. Due to the obvious limitations of human studies, the stage during gestation at which maternal iron deficiency causes an apparent impairment in the offspring remains elusive. In order to begin to understand the time window(s) during pregnancy that is/are especially susceptible to suboptimal iron levels, which may result in negative effects on the development of the fetus, we developed a rat model in which we were able to manipulate and monitor the dietary iron intake during specific stages of pregnancy and analyzed the developing fetuses. We established four different dietary-feeding protocols that were designed to render the fetuses iron deficient at different gestational stages. Based on a functional analysis that employed Auditory Brainstem Response measurements, we found that maternal iron restriction initiated prior to conception and during the first trimester were associated with profound changes in the developing fetus compared to iron restriction initiated later in pregnancy. We also showed that the presence of iron deficiency anemia, low body weight, and changes in core body temperature were not defining factors in the establishment of neural impairment in the rodent offspring

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Ethnic inequalities in the incidence of diagnosis of severe mental illness in England: a systematic review and new meta-analyses for non-affective and affective psychoses.

This is a post-peer-review, pre-copyedit version of an article published in Social Psychiatry and Psychiatric Epidemiology. The final authenticated version is available online at: https://doi.org/10.1007/s00127-019-01758-yPURPOSE: Although excess risks particularly for a diagnosis of schizophrenia have been identified for ethnic minority people in England and other contexts, we sought to identify and synthesise up-to-date evidence (2018) for affective in addition to non-affective psychoses by specific ethnic groups in England. METHODS: Systematic review and meta-analysis of ethnic differences in diagnosed incidence of psychoses in England, searching nine databases for reviews (citing relevant studies up to 2009) and an updated search in three databases for studies between 2010 and 2018. Studies from both searches were combined in meta-analyses allowing coverage of more specific ethnic groups than previously. RESULTS: We included 28 primary studies. Relative to the majority population, significantly higher risks of diagnosed schizophrenia were found in Black African (Relative risk, RR 5.72, 95% CI 3.87-8.46, n = 9); Black Caribbean (RR 5.20, 95% CI 4.33-6.24, n = 21); South Asian (RR 2.27, 95% CI 1.63-3.16, n = 14); White Other (RR 2.24, 95% CI 1.59-3.14, n = 9); and Mixed Ethnicity people (RR 2.24, 95% CI 1.32-3.80, n = 4). Significantly higher risks for diagnosed affective psychoses were also revealed: Black African (RR 4.07, 95% CI 2.27-7.28, n = 5); Black Caribbean (RR 2.91, 95% CI 1.78-4.74, n = 16); South Asian (RR 1.71, 95% CI 1.07-2.72, n = 8); White Other (RR 1.55, 95% CI 1.32-1.83, n = 5); Mixed Ethnicity (RR 6.16, 95% CI 3.99-9.52, n = 4). CONCLUSIONS: The risk for a diagnosis of non-affective and affective psychoses is particularly elevated for Black ethnic groups, but is higher for all ethnic minority groups including those previously not assessed through meta-analyses (White Other, Mixed Ethnicity). This calls for further research on broader disadvantages affecting ethnic minority people.Lankelly Chase Foundatio

Virtual human as a new diagnostic tool, a proof of concept study in the field of major depressive disorders

Embodied Conversational Agents (ECAs) are promising software to communicate with patients but no study has tested them in the diagnostic field of mental disorders. The aim of this study was 1) to test the performance of a diagnostic system for major depressive disorders (MDD), based on the identification by an ECA of specific symptoms (the MDD DSM 5 criteria) in outpatients; 2) to evaluate the acceptability of such an ECA. Patients completed two clinical interviews in a randomized order (ECA versus psychiatrist) and filled in the Acceptability E-scale (AES) to quantify the acceptability of the ECA. 179 outpatients were included in this study (mean age 46.5 ± 12.9 years, 57.5% females). Among the 35 patients diagnosed with MDD by the psychiatrist, 14 (40%) patients exhibited mild, 12 (34.3%) moderate and 9 (25.7%) severe depressive symptoms. Sensitivity increased across the severity level of depressive symptoms and reached 73% for patients with severe depressive symptoms, while specificity remained above 95% for all three severity levels. The acceptability of the ECA evaluated by the AES was very good (25.4). We demonstrate here the validity and acceptability of an ECA to diagnose major depressive disorders. ECAs are promising tools to conduct standardized and well-accepted clinical interviews