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  1. Article ; Online: MiDAS-Meaningful Immunogenetic Data at Scale.

    Maciej Migdal / Dan Fu Ruan / William F Forrest / Amir Horowitz / Christian Hammer

    PLoS Computational Biology, Vol 17, Iss 7, p e

    2021  Volume 1009131

    Abstract: Human immunogenetic variation in the form of HLA and KIR types has been shown to be strongly associated with a multitude of immune-related phenotypes. However, association studies involving immunogenetic loci most commonly involve simple analyses of ... ...

    Abstract Human immunogenetic variation in the form of HLA and KIR types has been shown to be strongly associated with a multitude of immune-related phenotypes. However, association studies involving immunogenetic loci most commonly involve simple analyses of classical HLA allelic diversity, resulting in limitations regarding the interpretability and reproducibility of results. We here present MiDAS, a comprehensive R package for immunogenetic data transformation and statistical analysis. MiDAS recodes input data in the form of HLA alleles and KIR types into biologically meaningful variables, allowing HLA amino acid fine mapping, analyses of HLA evolutionary divergence as well as experimentally validated HLA-KIR interactions. Further, MiDAS enables comprehensive statistical association analysis workflows with phenotypes of diverse measurement scales. MiDAS thus closes the gap between the inference of immunogenetic variation and its efficient utilization to make relevant discoveries related to immune and disease biology. It is freely available under a MIT license.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Multiple-gene targeting and mismatch tolerance can confound analysis of genome-wide pooled CRISPR screens

    Jean-Philippe Fortin / Jenille Tan / Karen E. Gascoigne / Peter M. Haverty / William F. Forrest / Michael R. Costa / Scott E. Martin

    Genome Biology, Vol 20, Iss 1, Pp 1-

    2019  Volume 25

    Abstract: Abstract Background Genome-wide loss-of-function screens using the CRISPR/Cas9 system allow the efficient discovery of cancer cell vulnerabilities. While several studies have focused on correcting for DNA cleavage toxicity biases associated with copy ... ...

    Abstract Abstract Background Genome-wide loss-of-function screens using the CRISPR/Cas9 system allow the efficient discovery of cancer cell vulnerabilities. While several studies have focused on correcting for DNA cleavage toxicity biases associated with copy number alterations, the effects of sgRNAs co-targeting multiple genomic loci in CRISPR screens have not been discussed. Results In this work, we analyze CRISPR essentiality screen data from 391 cancer cell lines to characterize biases induced by multi-target sgRNAs. We investigate two types of multi-targets: on-targets predicted through perfect sequence complementarity and off-targets predicted through sequence complementarity with up to two nucleotide mismatches. We find that the number of on-targets and off-targets both increase sgRNA activity in a cell line-specific manner and that existing additive models of gene knockout effects fail at capturing genetic interactions that may occur between co-targeted genes. We use synthetic lethality between paralog genes to show that genetic interactions can introduce biases in essentiality scores estimated from multi-target sgRNAs. We further show that single-mismatch tolerant sgRNAs can confound the analysis of gene essentiality and lead to incorrect co-essentiality functional networks. Lastly, we also find that single nucleotide polymorphisms located in protospacer regions can impair on-target activity as a result of mismatch tolerance. Conclusion We show the impact of multi-target effects on estimating cancer cell dependencies and the impact of off-target effects caused by mismatch tolerance in sgRNA-DNA binding.
    Keywords CRISPR/Cas9 ; Functional genomics ; Gene essentiality ; Cancer vulnerability ; Synthetic lethality ; Achilles ; Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
    Subject code 612
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Identifying and mitigating batch effects in whole genome sequencing data

    Jennifer A. Tom / Jens Reeder / William F. Forrest / Robert R. Graham / Julie Hunkapiller / Timothy W. Behrens / Tushar R. Bhangale

    BMC Bioinformatics, Vol 18, Iss 1, Pp 1-

    2017  Volume 12

    Abstract: Abstract Background Large sample sets of whole genome sequencing with deep coverage are being generated, however assembling datasets from different sources inevitably introduces batch effects. These batch effects are not well understood and can be due to ...

    Abstract Abstract Background Large sample sets of whole genome sequencing with deep coverage are being generated, however assembling datasets from different sources inevitably introduces batch effects. These batch effects are not well understood and can be due to changes in the sequencing protocol or bioinformatics tools used to process the data. No systematic algorithms or heuristics exist to detect and filter batch effects or remove associations impacted by batch effects in whole genome sequencing data. Results We describe key quality metrics, provide a freely available software package to compute them, and demonstrate that identification of batch effects is aided by principal components analysis of these metrics. To mitigate batch effects, we developed new site-specific filters that identified and removed variants that falsely associated with the phenotype due to batch effect. These include filtering based on: a haplotype based genotype correction, a differential genotype quality test, and removing sites with missing genotype rate greater than 30% after setting genotypes with quality scores less than 20 to missing. This method removed 96.1% of unconfirmed genome-wide significant SNP associations and 97.6% of unconfirmed genome-wide significant indel associations. We performed analyses to demonstrate that: 1) These filters impacted variants known to be disease associated as 2 out of 16 confirmed associations in an AMD candidate SNP analysis were filtered, representing a reduction in power of 12.5%, 2) In the absence of batch effects, these filters removed only a small proportion of variants across the genome (type I error rate of 3%), and 3) in an independent dataset, the method removed 90.2% of unconfirmed genome-wide SNP associations and 89.8% of unconfirmed genome-wide indel associations. Conclusions Researchers currently do not have effective tools to identify and mitigate batch effects in whole genome sequencing data. We developed and validated methods and filters to address this deficiency.
    Keywords Whole genome sequencing ; Genotyping ; Genome-wide association studies ; Batch effects ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2017-07-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Ocular phenotypes in a mouse model of impaired glucocerebrosidase activity

    Martin Weber / Sang-Won Min / Tom Truong / Jeffrey Hung / Stephanie Dale / Mike Reichelt / Savita Ubhayakar / Carol Cain-Hom / Miriam Baca / Zhiyu Jiang / Qingling Li / Robert Brendza / Han Lin / Chung Kung / William F. Forrest / Cristine Quiason-Huynh / Wendy Sandoval / Buyun Chen / Yuzhong Deng /
    Amy Easton / Oded Foreman / Abdoulaye Sene / Baris Bingol

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 17

    Abstract: Abstract Mutations in the GBA1 gene encoding glucocerebrosidase (GCase) are linked to Gaucher (GD) and Parkinson’s Disease (PD). Since some GD and PD patients develop ocular phenotypes, we determined whether ocular phenotypes might result from impaired ... ...

    Abstract Abstract Mutations in the GBA1 gene encoding glucocerebrosidase (GCase) are linked to Gaucher (GD) and Parkinson’s Disease (PD). Since some GD and PD patients develop ocular phenotypes, we determined whether ocular phenotypes might result from impaired GCase activity and the corresponding accumulation of glucosylceramide (GluCer) and glucosylsphingosine (GluSph) in the Gba1 D409V/D409V knock-in (Gba KI/KI; “KI”) mouse. Gba KI mice developed age-dependent pupil dilation deficits to an anti-muscarinic agent; histologically, the iris covered the anterior part of the lens with adhesions between the iris and the anterior surface of the lens (posterior synechia). This may prevent pupil dilation in general, beyond an un-responsiveness of the iris to anti-muscarinics. Gba KI mice displayed atrophy and pigment dispersion of the iris, and occlusion of the iridocorneal angle by pigment-laden cells, reminiscent of secondary open angle glaucoma. Gba KI mice showed progressive thinning of the retina consistent with retinal degeneration. GluSph levels were increased in the anterior and posterior segments of the eye, suggesting that accumulation of lipids in the eye may contribute to degeneration in this compartment. We conclude that the Gba KI model provides robust and reproducible eye phenotypes which may be used to test for efficacy and establish biomarkers for GBA1-related therapies.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: A whole genome sequencing study of moderate to severe asthma identifies a lung function locus associated with asthma risk

    Diana Chang / Julie Hunkapiller / Tushar Bhangale / Jens Reeder / Kiran Mukhyala / Jennifer Tom / Amy Cowgill / Jan Vogel / William F. Forrest / Zia Khan / Amy Stockwell / Mark I. McCarthy / Tracy L. Staton / Julie Olsson / Cecile T. J. Holweg / Dorothy S. Cheung / Hubert Chen / Matthew J. Brauer / Robert R. Graham /
    Timothy Behrens / Mark S. Wilson / Joseph R. Arron / David F. Choy / Brian L. Yaspan

    Scientific Reports, Vol 12, Iss 1, Pp 1-

    2022  Volume 11

    Abstract: Abstract Genome-wide association studies (GWAS) have identified many common variant loci associated with asthma susceptibility, but few studies investigate the genetics underlying moderate-to-severe asthma risk. Here, we present a whole-genome sequencing ...

    Abstract Abstract Genome-wide association studies (GWAS) have identified many common variant loci associated with asthma susceptibility, but few studies investigate the genetics underlying moderate-to-severe asthma risk. Here, we present a whole-genome sequencing study comparing 3181 moderate-to-severe asthma patients to 3590 non-asthma controls. We demonstrate that asthma risk is genetically correlated with lung function measures and that this component of asthma risk is orthogonal to the eosinophil genetics that also contribute to disease susceptibility. We find that polygenic scores for reduced lung function are associated with younger asthma age of onset. Genome-wide, seven previously reported common asthma variant loci and one previously reported lung function locus, near THSD4, reach significance. We replicate association of the lung function locus in a recently published GWAS of moderate-to-severe asthma patients. We additionally replicate the association of a previously reported rare (minor allele frequency < 1%) coding variant in IL33 and show significant enrichment of rare variant burden in genes from common variant allergic disease loci. Our findings highlight the contribution of lung function genetics to moderate-to-severe asthma risk, and provide initial rare variant support for associations with moderate-to-severe asthma risk at several candidate genes from common variant loci.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Reactive-site-centric chemoproteomics identifies a distinct class of deubiquitinase enzymes

    David S. Hewings / Johanna Heideker / Taylur P. Ma / Andrew P. AhYoung / Farid El Oualid / Alessia Amore / Gregory T. Costakes / Daniel Kirchhofer / Bradley Brasher / Thomas Pillow / Nataliya Popovych / Till Maurer / Carsten Schwerdtfeger / William F. Forrest / Kebing Yu / John Flygare / Matthew Bogyo / Ingrid E. Wertz

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 17

    Abstract: Deubiquitinases are proteases that cleave after the C-terminus of ubiquitin to hydrolyze ubiquitin chains and cleave ubiquitin from substrates. Here the authors describe a reactive-site-centric chemoproteomics approach to studying deubiquitinase activity, ...

    Abstract Deubiquitinases are proteases that cleave after the C-terminus of ubiquitin to hydrolyze ubiquitin chains and cleave ubiquitin from substrates. Here the authors describe a reactive-site-centric chemoproteomics approach to studying deubiquitinase activity, and expand the repertoire of known deubiquitinases.
    Keywords Science ; Q
    Language English
    Publishing date 2018-03-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Reactive-site-centric chemoproteomics identifies a distinct class of deubiquitinase enzymes

    David S. Hewings / Johanna Heideker / Taylur P. Ma / Andrew P. AhYoung / Farid El Oualid / Alessia Amore / Gregory T. Costakes / Daniel Kirchhofer / Bradley Brasher / Thomas Pillow / Nataliya Popovych / Till Maurer / Carsten Schwerdtfeger / William F. Forrest / Kebing Yu / John Flygare / Matthew Bogyo / Ingrid E. Wertz

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 17

    Abstract: Deubiquitinases are proteases that cleave after the C-terminus of ubiquitin to hydrolyze ubiquitin chains and cleave ubiquitin from substrates. Here the authors describe a reactive-site-centric chemoproteomics approach to studying deubiquitinase activity, ...

    Abstract Deubiquitinases are proteases that cleave after the C-terminus of ubiquitin to hydrolyze ubiquitin chains and cleave ubiquitin from substrates. Here the authors describe a reactive-site-centric chemoproteomics approach to studying deubiquitinase activity, and expand the repertoire of known deubiquitinases.
    Keywords Science ; Q
    Language English
    Publishing date 2018-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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