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Amazon Web Services in action
\"The largest and most mature of the cloud platforms, AWS offers over 100 prebuilt services, practically limitless compute resources, bottomless secure storage, as well as top-notch automation capabilities. This book shows you how to develop, host, and manage applications on AWS. Amazon Web Services in Action, Second Edition is a comprehensive introduction to deploying web applications in the AWS cloud. You'll find clear, relevant coverage of all essential AWS services, with a focus on automation, security, high availability, and scalability. This thoroughly revised edition covers the latest additions to AWS, including serverless infrastructure with AWS Lambda, sharing data with EFS, and in-memory storage with ElastiCache.\"--Back cover.
Book
Genome-wide association study in 8,956 German individuals identifies influence of ABO histo-blood groups on gut microbiome
The intestinal microbiome is implicated as an important modulating factor in multiple inflammatory
1
,
2
, neurologic
3
and neoplastic diseases
4
. Recent genome-wide association studies yielded inconsistent, underpowered and rarely replicated results such that the role of human host genetics as a contributing factor to microbiome assembly and structure remains uncertain
5
–
11
. Nevertheless, twin studies clearly suggest host genetics as a driver of microbiome composition
11
. In a genome-wide association analysis of 8,956 German individuals, we identified 38 genetic loci to be associated with single bacteria and overall microbiome composition. Further analyses confirm the identified associations of ABO histo-blood groups and FUT2 secretor status with
Bacteroides
and
Faecalibacterium
spp. Mendelian randomization analysis suggests causative and protective effects of gut microbes, with clade-specific effects on inflammatory bowel disease. This holistic investigative approach of the host, its genetics and its associated microbial communities as a ‘metaorganism’ broaden our understanding of disease etiology, and emphasize the potential for implementing microbiota in disease treatment and management.
Genome-wide association analysis of 8,956 German individuals identifies 38 genetic loci associated with single bacteria and overall microbiome composition.
Journal Article
Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism
X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset (
p
< 5 × 10
−8
). The lead single nucleotide polymorphisms collectively account for 25.6% of the remaining variance not explained by the hexanucleotide repeat and 13.0% of the overall variance in age at onset in X-linked dystonia-parkinsonism with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to
MSH3
and
PMS2
, the genes that were recently implicated in modifying age at onset in Huntington’s disease, likely through a common pathway influencing repeat instability. Our work indicates the existence of three modifiers of age at onset in X-linked dystonia-parkinsonism that likely affect the DNA mismatch repair pathway.
Age at onset of X-linked dystonia-parkinsonism is 50% explained by the length of a repeat in an
SVA
insert. The authors perform a GWAS for genetic modifiers and discover three more loci, accounting for another 13% of variability in age at onset with the protective alleles delaying onset by seven years.
Journal Article
Ancient DNA study reveals HLA susceptibility locus for leprosy in medieval Europeans
Leprosy, a chronic infectious disease caused by
Mycobacterium leprae
(
M. leprae
), was very common in Europe till the 16th century. Here, we perform an ancient DNA study on medieval skeletons from Denmark that show lesions specific for lepromatous leprosy (LL). First, we test the remains for
M. leprae
DNA to confirm the infection status of the individuals and to assess the bacterial diversity. We assemble 10 complete
M. leprae
genomes that all differ from each other. Second, we evaluate whether the human leukocyte antigen allele DRB1*15:01, a strong LL susceptibility factor in modern populations, also predisposed medieval Europeans to the disease. The comparison of genotype data from 69
M. leprae
DNA-positive LL cases with those from contemporary and medieval controls reveals a statistically significant association in both instances. In addition, we observe that DRB1*15:01 co-occurs with DQB1*06:02 on a haplotype that is a strong risk factor for inflammatory diseases today.
Leprosy, caused by infection with
Mycobacterium leprae
, was common in Europe in the Middle Ages. Here, Krause-Kyora et al. analyze ancient DNA from a medieval Danish leprosarium to assemble 10 complete bacterial genomes and perform association analysis of the DRB1*15:01 allele with risk of leprosy infection.
Journal Article
A structure-based in silico analysis of the Kell blood group system
Kell is one of the most complex blood group systems, with a highly polymorphic genetic background. Extensive allelic variations in the KEL gene affect the encoded erythrocyte surface protein Kell. Genetic variants causing aberrant splicing, premature termination of protein translation, or specific amino acid exchanges lead to a variety of different phenotypes with altered Kell expression levels or changes in the antigenic properties of the Kell protein. Using an in silico structural model of the Kell protein, we analyzed the biophysical and structural context of all full-length Kell variants of known phenotype. The results provided insights regarding the 3D co-localization of antigenic Kell variants and led us to suggest several conformational epitopes on the Kell protein surface. We found a number of correlations between the properties of individual genetic variants in the Kell protein and their respective serological phenotypes, which we used as a search filter to predict potentially new immunogenic Kell variants from an in-house whole exome sequencing dataset of 19,772 exomes. Our analysis workflow and results aid blood group serologists in predicting whether a newly identified Kell genetic variant may result in a specific phenotype.
Journal Article
Single base-pair substitutions in exon-intron junctions of human genes: nature, distribution, and consequences for mRNA splicing
Although single base‐pair substitutions in splice junctions constitute at least 10% of all mutations causing human inherited disease, the factors that determine their phenotypic consequences at the RNA level remain to be fully elucidated. Employing a neural network for splice‐site recognition, we performed a meta‐analysis of 478 disease‐associated splicing mutations, in 38 different genes, for which detailed laboratory‐based mRNA phenotype assessment had been performed. Inspection of the ±50‐bp DNA sequence context of the mutations revealed that exon skipping was the preferred phenotype when the immediate vicinity of the affected exon–intron junctions was devoid of alternative splice‐sites. By contrast, in the presence of at least one such motif, cryptic splice‐site utilization, became more prevalent. This association was, however, confined to donor splice‐sites. Outside the obligate dinucleotide, the spatial distribution of pathological mutations was found to differ significantly from that of SNPs. Whereas disease‐associated lesions clustered at positions –1 and +3 to +6 for donor sites and –3 for acceptor sites, SNPs were found to be almost evenly distributed over all sequence positions considered. When all putative missense mutations in the vicinity of splice‐sites were extracted from the Human Gene Mutation Database for the 38 studied genes, a significantly higher proportion of changes at donor sites (37/152; 24.3%) than at acceptor splice‐sites (1/142; 0.7%) was found to reduce the neural network signal emitted by the respective splice‐site. Based upon these findings, we estimate that some 1.6% of disease‐causing missense substitutions in human genes are likely to affect the mRNA splicing phenotype. Taken together, our results are consistent with correct donor splice‐site recognition being a key step in exon recognition. Hum Mutat 28(2), 150–158, 2007. © 2006 Wiley‐Liss, Inc.
Journal Article
Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL)
Andre Franke and colleagues report results of a genome-wide association and replication study of ulcerative colitis. They identify two new regions of association at 7q22 and at 22q13 in
IL17REL
.
We performed a genome-wide association analysis of 1,897,764 SNPs in 1,043 German ulcerative colitis (UC) cases and 1,703 controls. We discovered new associations at chromosome 7q22 (rs7809799) and at chromosome 22q13 in
IL17REL
(rs5771069) and confirmed these associations in six replication panels (2,539 UC cases and 5,428 controls) from different regions of Europe (overall study sample
P
rs7809799
= 8.81 × 10
−11
and
P
rs5771069
= 4.21 × 10
−8
, respectively).
Journal Article
A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease
With an overall prevalence of 10–20%, gallstone disease (cholelithiasis) represents one of the most frequent and economically relevant health problems of industrialized countries
1
,
2
. We performed an association scan of >500,000 SNPs in 280 individuals with gallstones and 360 controls. A follow-up study of the 235 most significant SNPs in 1,105 affected individuals and 873 controls replicated the disease association of SNP A-1791411 in
ABCG8
(allelic
P
value
P
CCA
= 4.1 × 10
−9
), which was subsequently attributed to coding variant rs11887534 (D19H). Additional replication was achieved in 728 German (
P
= 2.8 × 10
−7
) and 167 Chilean subjects (
P
= 0.02). The overall odds ratio for D19H carriership was 2.2 (95% confidence interval: 1.8–2.6,
P
= 1.4 × 10
−14
) in the full German sample. Association was stronger in subjects with cholesterol gallstones (odds ratio = 3.3), suggesting that His19 might be associated with a more efficient transport of cholesterol into the bile.
Journal Article
Identification of two novel bullous pemphigoid- associated alleles, HLA-DQA105:05 and -DRB107:01, in Germans
Bullous pemphigoid (BP) is the most common autoimmune skin blistering disease characterized by autoimmunity against the hemidesmosomal proteins BP180, type XVII collagen, and BP230. To elucidate the genetic basis of susceptibility to BP, we performed the first genome-wide association study (GWAS) in Germans. This GWAS was combined with HLA locus targeted sequencing in an additional independent BP cohort. The strongest association with BP in Germans tested in this study was observed in the two HLA loci, HLA-DQA1*05:05 and HLA-DRB1*07:01. Further studies with increased sample sizes and complex studies integrating multiple pathogenic drivers will be conducted.
Journal Article
A post-GWAS analysis of predicted regulatory variants and tuberculosis susceptibility
Utilizing data from published tuberculosis (TB) genome-wide association studies (GWAS), we use a bioinformatics pipeline to detect all polymorphisms in linkage disequilibrium (LD) with variants previously implicated in TB disease susceptibility. The probability that these variants had a predicted regulatory function was estimated using RegulomeDB and Ensembl's Variant Effect Predictor. Subsequent genotyping of these 133 predicted regulatory polymorphisms was performed in 400 admixed South African TB cases and 366 healthy controls in a population-based case-control association study to fine-map the causal variant. We detected associations between tuberculosis susceptibility and six intronic polymorphisms located in MARCO, IFNGR2, ASHAS2, ACACA, NISCH and TLR10. Our post-GWAS approach demonstrates the feasibility of combining multiple TB GWAS datasets with linkage information to identify regulatory variants associated with this infectious disease.
Journal Article