Genome-wide Characterization of Shared and Distinct Genetic Components that Influence Blood Lipid Levels in Ethnically Diverse Human Populations

Blood lipid concentrations are heritable risk factors associated with atherosclerosis and cardiovascular diseases. Lipid traits exhibit considerable variation among populations of distinct ancestral origin as well as between individuals within a population. We performed association analyses to identify genetic loci influencing lipid concentrations in African American and Hispanic American women in the Women’s Health Initiative SNP Health Association Resource. We validated one African-specific high-density lipoprotein cholesterol locus at CD36 as well as 14 known lipid loci that have been previously implicated in studies of European populations. Moreover, we demonstrate striking similarities in genetic architecture (loci influencing the trait, direction and magnitude of genetic effects, and proportions of phenotypic variation explained) of lipid traits across populations. In particular, we found that a disproportionate fraction of lipid variation in African Americans and Hispanic Americans can be attributed to genomic loci exhibiting statistical evidence of association in Europeans, even though the precise genes and variants remain unknown. At the same time, we found substantial allelic heterogeneity within shared loci, characterized both by population-specific rare variants and variants shared among multiple populations that occur at disparate frequencies. The allelic heterogeneity emphasizes the importance of including diverse populations in future genetic association studies of complex traits such as lipids; furthermore, the overlap in lipid loci across populations of diverse ancestral origin argues that additional knowledge can be gleaned from multiple populations.     

Additive Genetic Variation in Schizophrenia Risk Is Shared by Populations of African and European Descent

To investigate the extent to which the proportion of schizophrenia’s additive genetic variation tagged by SNPs is shared by populations of European and African descent, we analyzed the largest combined African descent (AD [n = 2,142]) and European descent (ED [n = 4,990]) schizophrenia case-control genome-wide association study (GWAS) data set available, the Molecular Genetics of Schizophrenia (MGS) data set. We show how a method that uses genomic similarities at measured SNPs to estimate the additive genetic correlation (SNP correlation [SNP-r_g]) between traits can be extended to estimate SNP-r_g for the same trait between ethnicities. We estimated SNP-r_g for schizophrenia between the MGS ED and MGS AD samples to be 0.66 (SE = 0.23), which is significantly different from 0 (p_{(SNP-rg = 0)} = 0.0003), but not 1 (p_{(SNP-rg = 1)} = 0.26). We re-estimated SNP-r_g between an independent ED data set (n = 6,665) and the MGS AD sample to be 0.61 (SE = 0.21, p_{(SNP-rg = 0)} = 0.0003, p_{(SNP-rg = 1)} = 0.16). These results suggest that many schizophrenia risk alleles are shared across ethnic groups and predate African-European divergence.     

肠道微生物与人体健康研究进展

人类肠道中定居着许多对宿主有益的微生物,包括细菌、病毒、真核生物等,它们在肠道内能与其他微生物及免疫系统相互作用,对人体健康具有重要影响,被称为"被遗忘的器官",它们的基因组也被誉为人类的"第二基因组",与人体的能量代谢及物质代谢有关。本文总结了人体肠道中病毒、真核生物、细菌和宿主免疫系统的相互作用,微生物群的失衡可能导致的疾病如肥胖和克罗恩病等,以及微生物环境在人体内的成熟过程,期望有助于诊断和治疗与肠道微生物失衡相关的疾病。     

Cholinergic Neuron-Specific Expression of the Human Choline Acetyltransferase Gene Is Controlled by Silencer Elements

Abstract: Choline acetyltransferase (ChAT) is specifically expressed in Cholinergic neurons. To identify control mechanisms regulating the cell-specific expression of the gene encoding ChAT, transient expression of the luciferase gene driven by human ChAT gene 5' flanking sequences was compared in cholinergic and noncholinergic cell lines. Analysis of the gene indicated the presence of two regulatory elements with selective silencing activity. These elements, located between nucleotides −2043 to −3347 and nucleotides −3347 to −6550, act cooperatively to repress promoter activity > 10-fold in a human adrenergic neuroblastoma cell line, SHSY5Y, and a human osteosarcoma cell line, 143 TK, while exhibiting less than a two-fold effect in Cholinergic cell lines. Deletion of either nucleotides −2043 to −3347 or nucleotides −3348 to −6550 reduced cell-specific repression by approximately half. Such differential repression appears to be responsible for the selective expression of the ChAT component of the Cholinergic phenotype.     

Diversified Microbiota of Meconium Is Affected by Maternal Diabetes Status

Objectives

This study was aimed to assess the diversity of the meconium microbiome and determine if the bacterial community is affected by maternal diabetes status.

Methods

The first intestinal discharge (meconium) was collected from 23 newborns stratified by maternal diabetes status: 4 mothers had pre-gestational type 2 diabetes mellitus (DM) including one mother with dizygotic twins, 5 developed gestational diabetes mellitus (GDM) and 13 had no diabetes. The meconium microbiome was profiled using multi-barcode 16S rRNA sequencing followed by taxonomic assignment and diversity analysis.

Results

All meconium samples were not sterile and contained diversified microbiota. Compared with adult feces, the meconium showed a lower species diversity, higher sample-to-sample variation, and enrichment of Proteobacteria and reduction of Bacteroidetes. Among the meconium samples, the taxonomy analyses suggested that the overall bacterial content significantly differed by maternal diabetes status, with the microbiome of the DM group showing higher alpha-diversity than that of no-diabetes or GDM groups. No global difference was found between babies delivered vaginally versus via Cesarean-section. Regression analysis showed that the most robust predictor for the meconium microbiota composition was the maternal diabetes status that preceded pregnancy. Specifically, Bacteroidetes (phyla) and Parabacteriodes (genus) were enriched in the meconium in the DM group compared to the no-diabetes group.

Conclusions

Our study provides evidence that meconium contains diversified microbiota and is not affected by the mode of delivery. It also suggests that the meconium microbiome of infants born to mothers with DM is enriched for the same bacterial taxa as those reported in the fecal microbiome of adult DM patients.     

The Microbiota,Chemical Symbiosis,and Human Disease

Our understanding of mammalian–microbial mutualism has expanded by combing microbial sequencing with evolving molecular and cellular methods, as well as unique model systems. Here, the recent literature linking the microbiota to diseases of three of the key mammalian mucosal epithelial compartments—nasal, lung, and gastrointestinal tract—is reviewed with a focus on new knowledge about the taxa, species, proteins, and chemistry that promote health and impact progression toward disease. The information presented is further organized by specific diseases now associated with the microbiota: Staphylococcus aureus infection and rhinosinusitis in the nasal-sinus mucosa, as well as cystic fibrosis, chronic obstructive pulmonary disorder, and asthma in the pulmonary tissues. For the vast and microbially dynamic gastrointestinal compartment, several disorders are considered, including obesity, atherosclerosis, Crohn's disease, ulcerative colitis, drug toxicity, and even autism. Our appreciation of the chemical symbiosis ongoing between human systems and the microbiota continues to grow and suggests new opportunities for modulating this symbiosis using designed interventions.     

三江白猪与其他5个品种猪的群体遗传关系的分析

应用100条RAPD引物对三江白猪及其杂交亲本长白猪和东北民猪,以及大约克夏、圣特西和法系大白猪进行亲缘关系的DNA多态分析。其中15条引物的扩增结果具有明显的多态,将其扩增结果进行聚类分析,发现三江白猪与长白猪(遗传距离d=0.090)、与东北民猪(d=0.175)的亲缘关系较近,与大约克夏(d=0.263)、法系大白(d=0.223)、圣特西猪(d=0.580)的亲缘关系较远。     

A Macrophage Subversion Factor Is Shared by Intracellular and Extracellular Pathogens

Pathogenic bacteria have developed strategies to adapt to host environment and resist host immune response. Several intracellular bacterial pathogens, including Salmonella enterica and Mycobacterium tuberculosis, share the horizontally-acquired MgtC virulence factor that is important for multiplication inside macrophages. MgtC is also found in pathogenic Pseudomonas species. Here we investigate for the first time the role of MgtC in the virulence of an extracellular pathogen, Pseudomonas aeruginosa. A P. aeruginosa mgtC mutant is attenuated in the systemic infection model of zebrafish embryos, and strikingly, the attenuated phenotype is dependent on the presence of macrophages. In ex vivo experiments, the P. aeruginosa mgtC mutant is more sensitive to macrophage killing than the wild-type strain. However, wild-type and mutant strains behave similarly toward macrophage killing when macrophages are treated with an inhibitor of the vacuolar proton ATPase. Importantly, P. aeruginosa mgtC gene expression is strongly induced within macrophages and phagosome acidification contributes to an optimal expression of the gene. Thus, our results support the implication of a macrophage intracellular stage during P. aeruginosa acute infection and suggest that Pseudomonas MgtC requires phagosome acidification to play its intracellular role. Moreover, we demonstrate that P. aeruginosa MgtC is required for optimal growth in Mg²⁺ deprived medium, a property shared by MgtC factors from intracellular pathogens and, under Mg²⁺ limitation, P. aeruginosa MgtC prevents biofilm formation. We propose that MgtC shares a similar function in intracellular and extracellular pathogens, which contributes to macrophage resistance and fine-tune adaptation to host immune response in relation to the different bacterial lifestyles. In addition, the phenotypes observed with the mgtC mutant in infection models can be mimicked in wild-type P. aeruginosa strain by producing a MgtC antagonistic peptide, thus highlighting MgtC as a promising new target for anti-virulence strategies.     

三江白猪与其他5个品种猪的群体遗传关系的分析

应用100条RAPD引物对三江白猪及其杂交亲本长白猪和东北民猪,以及大约克夏、圣特西和法系大白猪进行亲缘关系的DNA多态分析。其中15条引物的扩增结果具有明显的多态,将其扩增结果进行聚类分析,发现三江白猪与长白猪（遗传距离d = 0.090）、与东北民猪（d = 0.175）的亲缘关系较近,与大约克夏(d = 0.263)、法系大白(d = 0.223)、圣特西猪(d = 0.580)的亲缘关系较远。Abstract: One hundred primers were used to analyze the polymorphism of kinship of Sanjiang White pig and its parents, Landrace and Dongbei Min pig, Yorkshire, French Hybrids(Fh 019 strain),French Yorkshire by RAPD. Amplification results of 15 primers showed obvious polymorphisms, which were analyzed by clustering. The results indicate that the genetic relationship of Sanjiang White Pig, and Landrace, and Dongbei Min pig are respectively closer(d=0.090,,0.175), and that of Sanjiang White pig and Yorkshive(d=0.263), French Yorkshire(d = 0.223), Fh 019strain (d = 0.580) are respectively further.     

The Proteome of Pig Spermatozoa Is Remodeled During Ejaculation

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Highlights

• •Proteome of mature boar spermatozoa from cauda epididymal and ejaculated sources were analyzed by iTRAQ-based LC-MS/MS.
• •1,723 sperm proteins identified (974 of Sus scrofa taxonomy).
• •1,602 sperm proteins quantified (960 of Sus scrofa taxonomy).
• •32 Sus scrofa sperm proteins were differentially expressed among sperm sources.
• •The proteome of boar spermatozoa is remodelled during ejaculation.

     

Cohesin's DNA Exit Gate Is Distinct from Its Entrance Gate and Is Regulated by Acetylation

Sister chromatid cohesion is mediated by entrapment of sister DNAs by a tripartite ring composed of cohesin's Smc1, Smc3, and α-kleisin subunits. Cohesion requires acetylation of Smc3 by Eco1, whose role is to counteract an inhibitory (antiestablishment) activity associated with cohesin's Wapl subunit. We show that mutations abrogating antiestablishment activity also reduce turnover of cohesin on pericentric chromatin. Our results reveal?a "releasing" activity inherent to cohesin complexes transiently associated with Wapl that catalyzes their dissociation from chromosomes. Fusion of Smc3's nucleotide binding domain to α-kleisin's N-terminal domain also reduces cohesin turnover within pericentric chromatin and permits establishment of Wapl-resistant cohesion in the absence of Eco1. We suggest that releasing activity opens the Smc3/α-kleisin interface, creating a DNA exit gate distinct from its proposed entry gate at the Smc1/3 interface. According to this notion, the function of Smc3 acetylation is to block its dissociation from α-kleisin. The functional implications of regulated ring opening are discussed.     

S Phase Progression in Human Cells Is Dictated by the Genetic Continuity of DNA Foci

DNA synthesis must be performed with extreme precision to maintain genomic integrity. In mammalian cells, different genomic regions are replicated at defined times, perhaps to preserve epigenetic information and cell differentiation status. However, the molecular principles that define this S phase program are unknown. By analyzing replication foci within discrete chromosome territories during interphase, we show that foci which are active during consecutive intervals of S phase are maintained as spatially adjacent neighbors throughout the cell cycle. Using extended DNA fibers, we demonstrate that this spatial continuity of replication foci correlates with the genetic continuity of adjacent replicon clusters along chromosomes. Finally, we used bioinformatic tools to compare the structure of DNA foci with DNA domains that are seen to replicate during discrete time intervals of S phase using genome-wide strategies. Data presented show that a major mechanism of S phase progression involves the sequential synthesis of regions of the genome because of their genetic continuity along the chromosomal fiber.     

Myf-6基因在不同猪种中的PCR-RFLP遗传多态性及其遗传效应分析

作为生肌调节因子家族的一个成员,Myf-6基因在肌形成的过程中发挥着重要的作用。实验采用PCR-RFLP技术分析了Myf-6基因在12个中外猪种及部分杂交群体中的分布情况,并分析了Myf-6基因对肌纤维、胴体品质、胴体等级性状和肉质性状的遗传效应。结果表明：Myf-6基因内含子1内的Ava I酶切位点多态性不丰富,多数中国地方猪种群体中A等位基因已经完全固定,B等位基因仅以较低的频率存在于外种猪或含外种猪血缘的杂交群体中。尽管没有检测到BB纯合个体,但AB杂合子的平均瘦肉率为50.344 %,极显著地高于AA纯合子的45.875 %(P<0.01)。AB杂合子的眼肌面积为27.097 cm2,极显著地大于AA纯合子的22.572 cm2(P<0.01)。AB杂合子的皮脂率（39.889 %）极显著地低于AA纯合子（44.503 %）(P<0.01)。上述结果说明本次试验群体中的B等位基因具有增加胴体瘦肉率和眼肌面积,降低胴体脂肪含量从而改善胴体品质的遗传效应。此外,Myf-6基因对肌纤维生长性状、FOM肉脂仪测定的胴体等级性状以及肉质性状等都没有显著影响(P>0.05)。     

The Microbiota Is Essential for the Generation of Black Tea Theaflavins-Derived Metabolites

Background

Theaflavins including theaflavin (TF), theaflavin-3-gallate (TF3G), theaflavin-3′-gallate (TF3′G), and theaflavin-3,3′-digallate (TFDG), are the most important bioactive polyphenols in black tea. Because of their poor systemic bioavailability, it is still unclear how these compounds can exert their biological functions. The objective of this study is to identify the microbial metabolites of theaflavins in mice and in humans.

Methods and Findings

In the present study, we gavaged specific pathogen free (SPF) mice and germ free (GF) mice with 200 mg/kg TFDG and identified TF, TF3G, TF3′G, and gallic acid as the major fecal metabolites of TFDG in SPF mice. These metabolites were absent in TFDG- gavaged GF mice. The microbial bioconversion of TFDG, TF3G, and TF3′G was also investigated in vitro using fecal slurries collected from three healthy human subjects. Our results indicate that TFDG is metabolized to TF, TF3G, TF3′G, gallic acid, and pyrogallol by human microbiota. Moreover, both TF3G and TF3′G are metabolized to TF, gallic acid, and pyrogallol by human microbiota. Importantly, we observed interindividual differences on the metabolism rate of gallic acid to pyrogallol among the three human subjects. In addition, we demonstrated that Lactobacillus plantarum 299v and Bacillus subtilis have the capacity to metabolize TFDG.

Conclusions

The microbiota is important for the metabolism of theaflavins in both mice and humans. The in vivo functional impact of microbiota-generated theaflavins-derived metabolites is worthwhile of further study.