Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes.

Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human-specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD

Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing

Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (~1.5–5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing

Mutations causing medullary cystic kidney disease type 1 (MCKD1) lie in a large VNTR in MUC1 missed by massively parallel sequencing

While genetic lesions responsible for some Mendelian disorders can be rapidly discovered through massively parallel sequencing (MPS) of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple Mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing, and de novo assembly, we found that each of six MCKD1 families harbors an equivalent, but apparently independently arising, mutation in sequence dramatically underrepresented in MPS data: the insertion of a single C in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (~1.5-5 kb), GC-rich (>80%), coding VNTR in the mucin 1 gene. The results provide a cautionary tale about the challenges in identifying genes responsible for Mendelian, let alone more complex, disorders through MPS

J Biomed Inform

Geographically distributed environmental factors influence the burden of diseases such as asthma. Our objective was to identify sparse environmental variables associated with asthma diagnosis gathered from a large electronic health record (EHR) dataset while controlling for spatial variation. An EHR dataset from the University of Wisconsin's Family Medicine, Internal Medicine and Pediatrics Departments was obtained for 199,220 patients aged 5-50years over a three-year period. Each patient's home address was geocoded to one of 3456 geographic census block groups. Over one thousand block group variables were obtained from a commercial database. We developed a Sparse Spatial Environmental Analysis (SASEA). Using this method, the environmental variables were first dimensionally reduced with sparse principal component analysis. Logistic thin plate regression spline modeling was then used to identify block group variables associated with asthma from sparse principal components. The addresses of patients from the EHR dataset were distributed throughout the majority of Wisconsin's geography. Logistic thin plate regression spline modeling captured spatial variation of asthma. Four sparse principal components identified via model selection consisted of food at home, dog ownership, household size, and disposable income variables. In rural areas, dog ownership and renter occupied housing units from significant sparse principal components were associated with asthma. Our main contribution is the incorporation of sparsity in spatial modeling. SASEA sequentially added sparse principal components to Logistic thin plate regression spline modeling. This method allowed association of geographically distributed environmental factors with asthma using EHR and environmental datasets. SASEA can be applied to other diseases with environmental risk factors.UL1 TR000427/TR/NCATS NIH HHS/United StatesU58 CD001316/CD/ODCDC CDC HHS/United StatesT32 GM008692/GM/NIGMS NIH HHS/United StatesTL1 TR000429/TR/NCATS NIH HHS/United StatesF30HL112491/HL/NHLBI NIH HHS/United StatesUL1 RR025011/RR/NCRR NIH HHS/United StatesU38 EH000951/EH/NCEH CDC HHS/United StatesF30 HL112491/HL/NHLBI NIH HHS/United States1UL1RR025011/RR/NCRR NIH HHS/United States9U54TR000021/TR/NCATS NIH HHS/United States2016-02-01T00:00:00Z25533437PMC435508

Mutations causing medullary cystic kidney disease type 1 (MCKD1) lie in a large VNTR in MUC1 missed by massively parallel sequencing

While genetic lesions responsible for some Mendelian disorders can be rapidly discovered through massively parallel sequencing (MPS) of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple Mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing, and de novo assembly, we found that each of six MCKD1 families harbors an equivalent, but apparently independently arising, mutation in sequence dramatically underrepresented in MPS data: the insertion of a single C in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (~1.5-5 kb), GC-rich (>80%), coding VNTR in the mucin 1 gene. The results provide a cautionary tale about the challenges in identifying genes responsible for Mendelian, let alone more complex, disorders through MPS

Development of a Novel \u3cem\u3ein vivo\u3c/em\u3e Corneal Fibrosis Model in the Dog

The aim of this study was to develop a novel in vivo corneal model of fibrosis in dogs utilizing alkali burn and determine the ability of suberanilohydroxamic acid (SAHA) to inhibit corneal fibrosis using this large animal model. To accomplish this, we used seven research Beagle dogs. An axial corneal alkali burn in dogs was created using 1 N NaOH topically. Six dogs were randomly and equally assigned into 2 groups: A) vehicle (DMSO, 2 μL/mL); B) anti-fibrotic treatment (50 μM SAHA). The degree of corneal opacity, ocular health, and anti-fibrotic effects of SAHA were determined utilizing the Fantes grading scale, modified McDonald-Shadduck (mMS) scoring system, optical coherence tomography (OCT), corneal histopathology, immunohistochemistry (IHC), and transmission electron microscopy (TEM). The used alkali burn dose to produce corneal fibrosis was well tolerated as no significant difference in mMS scores between control and treatment groups (p=0.89) were detected. The corneas of alkali burned dogs showed significantly greater levels of α-smooth muscle actin, the fibrotic marker, than the controls (p=0.018). Total corneal thickness of all dogs post-burn was significantly greater than baseline OCT images irrespective of treatment (p=0.004); TEM showed that alkali burned corneas had significantly greater minimum and maximum interfibrillar distances than the controls (p=0.026, p=0.018). The tested topical corneal alkali burn dose generated significant opacity and fibrosis in dog corneas without damaging the limbus as evidenced by histopathology, IHC, TEM, and OCT findings, and represents a viable large animal corneal fibrosis in vivo model. Additional in vivo SAHA dosing studies with larger sample size are warranted

Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing

Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (~1.5–5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing

Tuberculosis (Edinb)

The emergence of whole genome sequencing (WGS) technologies as primary research tools has allowed for the detection of genetic diversity in Mycobacterium tuberculosis (Mtb) with unprecedented resolution. WGS has been used to address a broad range of topics, including the dynamics of evolution, transmission and treatment. Here, we have analyzed 55 publically available genomes to reconstruct the phylogeny of Mtb, and we have addressed complications that arise during the analysis of publically available WGS data. Additionally, we have reviewed the application of WGS to the study of Mtb and discuss those areas still to be addressed, moving from global (phylogeography), to local (transmission chains and circulating strain diversity), to the single patient (clonal heterogeneity) and to the bacterium itself (evolutionary studies). Finally, we discuss the current WGS approaches, their strengths and limitations.1DP20D001378/DP/NCCDPHP CDC HHS/United StatesU19 AI076217/AI/NIAID NIH HHS/United StatesDP2 OD001378/OD/NIH HHS/United StatesDP2 OD001378-01S1/OD/NIH HHS/United StatesDP2 OD001378-01/OD/NIH HHS/United StatesU19 AI076217-04/AI/NIAID NIH HHS/United States2013-05-01T00:00:00Z22218163PMC33236778873vault:734