Advances in genome sequencing technologies have created new opportunities for comparative primate genomics. Genome assemblies have been published for various primate species, and analyses of several ...others are underway. Whole-genome assemblies for the great apes provide remarkable new information about the evolutionary origins of the human genome and the processes involved. Genomic data for macaques and other non-human primates offer valuable insights into genetic similarities and differences among species that are used as models for disease-related research. This Review summarizes current knowledge regarding primate genome content and dynamics, and proposes a series of goals for the near future.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Genetic variants responsible for susceptibility to obesity and its comorbidities among Hispanic children have not been identified. The VIVA LA FAMILIA Study was designed to genetically map childhood ...obesity and associated biological processes in the Hispanic population. A genome-wide association study (GWAS) entailed genotyping 1.1 million single nucleotide polymorphisms (SNPs) using the Illumina Infinium technology in 815 children. Measured genotype analysis was performed between genetic markers and obesity-related traits i.e., anthropometry, body composition, growth, metabolites, hormones, inflammation, diet, energy expenditure, substrate utilization and physical activity. Identified genome-wide significant loci: 1) corroborated genes implicated in other studies (MTNR1B, ZNF259/APOA5, XPA/FOXE1 (TTF-2), DARC, CCR3, ABO); 2) localized novel genes in plausible biological pathways (PCSK2, ARHGAP11A, CHRNA3); and 3) revealed novel genes with unknown function in obesity pathogenesis (MATK , COL4A1). Salient findings include a nonsynonymous SNP (rs1056513) in INADL (p = 1.2E-07) for weight; an intronic variant in MTNR1B associated with fasting glucose (p = 3.7E-08); variants in the APOA5-ZNF259 region associated with triglycerides (p = 2.5-4.8E-08); an intronic variant in PCSK2 associated with total antioxidants (p = 7.6E-08); a block of 23 SNPs in XPA/FOXE1 (TTF-2) associated with serum TSH (p = 5.5E-08 to 1.0E-09); a nonsynonymous SNP (p = 1.3E-21), an intronic SNP (p = 3.6E-13) in DARC identified for MCP-1; an intronic variant in ARHGAP11A associated with sleep duration (p = 5.0E-08); and, after adjusting for body weight, variants in MATK for total energy expenditure (p = 2.7E-08) and in CHRNA3 for sleeping energy expenditure (p = 6.0E-08). Unprecedented phenotyping and high-density SNP genotyping enabled localization of novel genetic loci associated with the pathophysiology of childhood obesity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Of over 7000 patients referred to a diagnostic laboratory, 28% had diagnoses based on DNA sequencing, 5% of whom had two or more diagnoses. Their phenotypes could be better understood by considering ...whether the implicated genes affect independent biologic processes or organ systems.
Medical genetics focuses on the relationship between observed phenotypes and their underlying genotypes, modes of transmission, and risks of recurrence. Expected patterns of mendelian inheritance are often used to confirm the identification of disease genes, and deviations from mendelian expectations have led to the discovery of more complicated genetic underpinnings of disease (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).
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Multiple (or dual) molecular diagnoses involve more than one clinical diagnosis and more than one genetic locus (Figure 1), each segregating independently.
Diagnostic whole-exome sequencing affords opportunities for providing insights into relationships . . .
Thoracic endovascular repair (TEVAR) has recently been established as the preferred treatment option for complicated type B dissection. This procedure involves covering the primary entry tear to ...stimulate aortic remodelling and promote false lumen thrombosis thereby restoring true lumen flow. However, complications associated with incomplete false lumen thrombosis, such as aortic dilatation and stent graft induced new entry tears, can arise after TEVAR. This study presents the application and validation of a recently developed mathematical model for patient-specific prediction of thrombus formation and growth under physiologically realistic flow conditions. The model predicts thrombosis through the evaluation of shear rates, fluid residence time and platelet distribution, based on convection-diffusion-reaction transport equations. The model was applied to 3 type B aortic dissection patients: two TEVAR cases showing complete and incomplete false lumen thrombosis respectively, and one medically treated dissection with no signs of thrombosis. Predicted thrombus growth over time was validated against follow-up CT scans, showing good agreement with in vivo data in all cases with a maximum difference between predicted and measured false lumen reduction below 8%. Our results demonstrate that TEVAR-induced thrombus formation in type B aortic dissection can be predicted based on patient-specific anatomy and physiologically realistic boundary conditions. Our model can be used to identify anatomical or stent graft related factors that are associated with incomplete false lumen thrombosis following TEVAR, which may help clinicians develop personalised treatment plans for dissection patients in the future.
Whole exome capture sequencing allows researchers to cost-effectively sequence the coding regions of the genome. Although the exome capture sequencing methods have become routine and well ...established, there is currently a lack of tools specialized for variant calling in this type of data.
Using statistical models trained on validated whole-exome capture sequencing data, the Atlas2 Suite is an integrative variant analysis pipeline optimized for variant discovery on all three of the widely used next generation sequencing platforms (SOLiD, Illumina, and Roche 454). The suite employs logistic regression models in conjunction with user-adjustable cutoffs to accurately separate true SNPs and INDELs from sequencing and mapping errors with high sensitivity (96.7%).
We have implemented the Atlas2 Suite and applied it to 92 whole exome samples from the 1000 Genomes Project. The Atlas2 Suite is available for download at http://sourceforge.net/projects/atlas2/. In addition to a command line version, the suite has been integrated into the Genboree Workbench, allowing biomedical scientists with minimal informatics expertise to remotely call, view, and further analyze variants through a simple web interface. The existing genomic databases displayed via the Genboree browser also streamline the process from variant discovery to functional genomics analysis, resulting in an off-the-shelf toolkit for the broader community.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The development of the microbiome from infancy to childhood is dependent on a range of factors, with microbial-immune crosstalk during this time thought to be involved in the pathobiology of later ...life diseases
such as persistent islet autoimmunity and type 1 diabetes
. However, to our knowledge, no studies have performed extensive characterization of the microbiome in early life in a large, multi-centre population. Here we analyse longitudinal stool samples from 903 children between 3 and 46 months of age by 16S rRNA gene sequencing (n = 12,005) and metagenomic sequencing (n = 10,867), as part of the The Environmental Determinants of Diabetes in the Young (TEDDY) study. We show that the developing gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3-14), a transitional phase (months 15-30), and a stable phase (months 31-46). Receipt of breast milk, either exclusive or partial, was the most significant factor associated with the microbiome structure. Breastfeeding was associated with higher levels of Bifidobacterium species (B. breve and B. bifidum), and the cessation of breast milk resulted in faster maturation of the gut microbiome, as marked by the phylum Firmicutes. Birth mode was also significantly associated with the microbiome during the developmental phase, driven by higher levels of Bacteroides species (particularly B. fragilis) in infants delivered vaginally. Bacteroides was also associated with increased gut diversity and faster maturation, regardless of the birth mode. Environmental factors including geographical location and household exposures (such as siblings and furry pets) also represented important covariates. A nested case-control analysis revealed subtle associations between microbial taxonomy and the development of islet autoimmunity or type 1 diabetes. These data determine the structural and functional assembly of the microbiome in early life and provide a foundation for targeted mechanistic investigation into the consequences of microbial-immune crosstalk for long-term health.
Uncomplicated acute type B aortic dissections are usually treated medically, but they can become acutely complicated by rapid expansion, rupture and malperfusion syndromes and in the longer term by ...chronic dilatation and aortic aneurysm formation. The objective of this study is to use computational fluid dynamics reconstructions of type B aortic dissections to compare geometric and haemodynamic factors between the cases selected for medical treatment and the cases selected for thoracic endovascular aortic repair (TEVAR), and to examine whether any of these factors are associated with the outcome of the medically treated group. This study includes eight type B dissection cases, with four in each group. Aortic flow analyses were carried out based on patient-specific anatomy at initial presentation before treatment. Comparisons between the two groups show that the false lumen to true lumen volume ratio is considerably higher in patients selected for TEVAR. Results from the four medically treated cases indicate that the size of the primary entry tear is the key determinant of the false lumen flow rate, which may influence the long-term outcome of medically treated patients. Potential relations between flow related parameters based on initial anatomy and subsequent anatomical changes in the medically treatment group were examined. Our initial findings based on the limited cases are that high relative residence time is a strong predictor of subsequent false lumen thrombosis, whereas pressure difference between the true and false lumen as well as the location of the largest pressure difference may be associated with the likelihood of subsequent aortic expansion.
Following the "finished," euchromatic, haploid human reference genome sequence, the rapid development of novel, faster, and cheaper sequencing technologies is making possible the era of personalized ...human genomics. Personal diploid human genome sequences have been generated, and each has contributed to our better understanding of variation in the human genome. We have consequently begun to appreciate the vastness of individual genetic variation from single nucleotide to structural variants. Translation of genome-scale variation into medically useful information is, however, in its infancy. This review summarizes the initial steps undertaken in clinical implementation of personal genome information, and describes the application of whole-genome and exome sequencing to identify the cause of genetic diseases and to suggest adjuvant therapies. Better analysis tools and a deeper understanding of the biology of our genome are necessary in order to decipher, interpret, and optimize clinical utility of what the variation in the human genome can teach us. Personal genome sequencing may eventually become an instrument of common medical practice, providing information that assists in the formulation of a differential diagnosis. We outline herein some of the remaining challenges.
We derive three new tests that can be applied to a Kalman filter to check for inconsistencies. The Filter Residual Test can detect observations that are outliers but would be missed by a basic ...residual test because the uncertainty of the expected observation is large relative to the uncertainty of the observation. The Smoother Residual Test uses the output from a Modified Bryson–Frazier (MBF) smoother to detect observations that are outliers. The Smoother State Test compares the state estimates from the filter and MBF smoother to detect model inconsistencies, in particular insufficient process noise.
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