Publications by authors named "Chad A Shaw"

151 Publications

Selection for or against escape from nonsense mediated decay is a novel signature for the detection of cancer genes.

Cancer Genet 2021 Sep 23;258-259:80-84. Epub 2021 Sep 23.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS225, Houston, TX 77030, United States; Baylor Genetics, Houston, TX, United States; Department of Statistics, Rice University, Houston, TX, United States. Electronic address:

Escape from nonsense mediated mRNA decay (NMD-) can produce activated or inactivated gene products, and bias in rates of escape can identify functionally important genes in germline disease. We hypothesized that the same would be true of cancer genes, and tested for NMD- bias within The Cancer Genome Atlas pan-cancer somatic mutation dataset. We identify 29 genes that show significantly elevated or suppressed rates of NMD-. This novel approach to cancer gene discovery reveals genes not previously cataloged as potentially tumorigenic, and identifies many potential driver mutations in known cancer genes for functional characterization.
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http://dx.doi.org/10.1016/j.cancergen.2021.09.003DOI Listing
September 2021

Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH.

J Med Genet 2021 Jan 18. Epub 2021 Jan 18.

Texas Children's Hospital, Houston, Texas, USA

Background: Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted.

Methods: We analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions.

Results: Among the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other cases (9%; 7/76). Four individuals had a diagnosis of Kabuki syndrome caused by frameshift variants in . Putatively deleterious variants in and were each found in two individuals, supporting their role in CDH development. We also identified individuals with de novo pathogenic variants in and , and compound heterozygous pathogenic variants in . The role of these genes in CDH development is supported by the expression of their mouse homologs in the developing diaphragm, their high CDH-specific pathogenicity scores generated using a previously validated algorithm for genome-scale knowledge synthesis and previously published case reports.

Conclusion: We conclude that ES should be ordered in cases of CDH+ when a specific diagnosis is not suspected and CNV analyses are negative. Our results also provide evidence in favour of phenotypic expansions involving CDH for genes associated with -congenital disorder of glycosylation, Rubinstein-Taybi syndrome, Fanconi anaemia, Coffin-Siris syndrome and -related disorders.
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http://dx.doi.org/10.1136/jmedgenet-2020-107317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286264PMC
January 2021

A joint modeling approach for longitudinal microbiome data improves ability to detect microbiome associations with disease.

PLoS Comput Biol 2020 12 14;16(12):e1008473. Epub 2020 Dec 14.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.

Changes in the composition of the microbiome over time are associated with myriad human illnesses. Unfortunately, the lack of analytic techniques has hindered researchers' ability to quantify the association between longitudinal microbial composition and time-to-event outcomes. Prior methodological work developed the joint model for longitudinal and time-to-event data to incorporate time-dependent biomarker covariates into the hazard regression approach to disease outcomes. The original implementation of this joint modeling approach employed a linear mixed effects model to represent the time-dependent covariates. However, when the distribution of the time-dependent covariate is non-Gaussian, as is the case with microbial abundances, researchers require different statistical methodology. We present a joint modeling framework that uses a negative binomial mixed effects model to determine longitudinal taxon abundances. We incorporate these modeled microbial abundances into a hazard function with a parameterization that not only accounts for the proportional nature of microbiome data, but also generates biologically interpretable results. Herein we demonstrate the performance improvements of our approach over existing alternatives via simulation as well as a previously published longitudinal dataset studying the microbiome during pregnancy. The results demonstrate that our joint modeling framework for longitudinal microbiome count data provides a powerful methodology to uncover associations between changes in microbial abundances over time and the onset of disease. This method offers the potential to equip researchers with a deeper understanding of the associations between longitudinal microbial composition changes and disease outcomes. This new approach could potentially lead to new diagnostic biomarkers or inform clinical interventions to help prevent or treat disease.
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http://dx.doi.org/10.1371/journal.pcbi.1008473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769610PMC
December 2020

Bayesian modelling of high-throughput sequencing assays with malacoda.

PLoS Comput Biol 2020 07 21;16(7):e1007504. Epub 2020 Jul 21.

Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.

NGS studies have uncovered an ever-growing catalog of human variation while leaving an enormous gap between observed variation and experimental characterization of variant function. High-throughput screens powered by NGS have greatly increased the rate of variant functionalization, but the development of comprehensive statistical methods to analyze screen data has lagged. In the massively parallel reporter assay (MPRA), short barcodes are counted by sequencing DNA libraries transfected into cells and the cell's output RNA in order to simultaneously measure the shifts in transcription induced by thousands of genetic variants. These counts present many statistical challenges, including overdispersion, depth dependence, and uncertain DNA concentrations. So far, the statistical methods used have been rudimentary, employing transformations on count level data and disregarding experimental and technical structure while failing to quantify uncertainty in the statistical model. We have developed an extensive framework for the analysis of NGS functionalization screens available as an R package called malacoda (available from github.com/andrewGhazi/malacoda). Our software implements a probabilistic, fully Bayesian model of screen data. The model uses the negative binomial distribution with gamma priors to model sequencing counts while accounting for effects from input library preparation and sequencing depth. The method leverages the high-throughput nature of the assay to estimate the priors empirically. External annotations such as ENCODE data or DeepSea predictions can also be incorporated to obtain more informative priors-a transformative capability for data integration. The package also includes quality control and utility functions, including automated barcode counting and visualization methods. To validate our method, we analyzed several datasets using malacoda and alternative MPRA analysis methods. These data include experiments from the literature, simulated assays, and primary MPRA data. We also used luciferase assays to experimentally validate several hits from our primary data, as well as variants for which the various methods disagree and variants detectable only with the aid of external annotations.
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http://dx.doi.org/10.1371/journal.pcbi.1007504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394446PMC
July 2020

Validation Studies for Single Circulating Trophoblast Genetic Testing as a Form of Noninvasive Prenatal Diagnosis.

Am J Hum Genet 2019 12 27;105(6):1262-1273. Epub 2019 Nov 27.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address:

It has long been appreciated that genetic analysis of fetal or trophoblast cells in maternal blood could revolutionize prenatal diagnosis. We implemented a protocol for single circulating trophoblast (SCT) testing using positive selection by magnetic-activated cell sorting and single-cell low-coverage whole-genome sequencing to detect fetal aneuploidies and copy-number variants (CNVs) at ∼1 Mb resolution. In 95 validation cases, we identified on average 0.20 putative trophoblasts/mL, of which 55% were of high quality and scorable for both aneuploidy and CNVs. We emphasize the importance of analyzing individual cells because some cells are apoptotic, in S-phase, or otherwise of poor quality. When two or more high-quality trophoblast cells were available for singleton pregnancies, there was complete concordance between all trophoblasts unless there was evidence of confined placental mosaicism. SCT results were highly concordant with available clinical data from chorionic villus sampling (CVS) or amniocentesis procedures. Although determining the exact sensitivity and specificity will require more data, this study further supports the potential for SCT testing to become a diagnostic prenatal test.
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http://dx.doi.org/10.1016/j.ajhg.2019.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904821PMC
December 2019

Increased Moraxella and Streptococcus species abundance after severe bronchiolitis is associated with recurrent wheezing.

J Allergy Clin Immunol 2020 02 15;145(2):518-527.e8. Epub 2019 Nov 15.

Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

Background: The role of the airway microbiome in the development of recurrent wheezing and asthma remains uncertain, particularly in the high-risk group of infants hospitalized for bronchiolitis.

Objective: We sought to examine the relation of the nasal microbiota at bronchiolitis-related hospitalization and 3 later points to the risk of recurrent wheezing by age 3 years.

Methods: In 17 US centers researchers collected clinical data and nasal swabs from infants hospitalized for bronchiolitis. Trained parents collected nasal swabs 3 weeks after hospitalization and, when healthy, during the summer and 1 year after hospitalization. We applied 16S rRNA gene sequencing to all nasal swabs. We used joint modeling to examine the relation of longitudinal nasal microbiota abundances to the risk of recurrent wheezing.

Results: Among 842 infants hospitalized for bronchiolitis, there was 88% follow-up at 3 years, and 31% had recurrent wheezing. The median age at enrollment was 3.2 months (interquartile range, 1.7-5.8 months). In joint modeling analyses adjusting for 16 covariates, including viral cause, a 10% increase in relative abundance of Moraxella or Streptococcus species 3 weeks after day 1 of hospitalization was associated with an increased risk of recurrent wheezing (hazard ratio [HR] of 1.38 and 95% high-density interval [HDI] of 1.11-1.85 and HR of 1.76 and 95% HDI of 1.13-3.19, respectively). Increased Streptococcus species abundance the summer after hospitalization was also associated with a greater risk of recurrent wheezing (HR, 1.76; 95% HDI, 1.15-3.27).

Conclusions: Enrichment of Moraxella or Streptococcus species after bronchiolitis hospitalization was associated with recurrent wheezing by age 3 years, possibly providing new avenues to ameliorate the long-term respiratory outcomes of infants with severe bronchiolitis.
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http://dx.doi.org/10.1016/j.jaci.2019.10.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010548PMC
February 2020

Functionalization of CD36 cardiovascular disease and expression associated variants by interdisciplinary high throughput analysis.

PLoS Genet 2019 07 25;15(7):e1008287. Epub 2019 Jul 25.

Cardeza Foundation for Hematologic Research/Department of Medicine, Sidney Kimmel Medical School, Thomas Jefferson University, Philadelphia, PA, United States of America.

CD36 is a platelet membrane glycoprotein whose engagement with oxidized low-density lipoprotein (oxLDL) results in platelet activation. The CD36 gene has been associated with platelet count, platelet volume, as well as lipid levels and CVD risk by genome-wide association studies. Platelet CD36 expression levels have been shown to be associated with both the platelet oxLDL response and an elevated risk of thrombo-embolism. Several genomic variants have been identified as associated with platelet CD36 levels, however none have been conclusively demonstrated to be causative. We screened 81 expression quantitative trait loci (eQTL) single nucleotide polymorphisms (SNPs) associated with platelet CD36 expression by a Massively Parallel Reporter Assay (MPRA) and analyzed the results with a novel Bayesian statistical method. Ten eQTLs located 13kb to 55kb upstream of the CD36 transcriptional start site of transcript ENST00000309881 and 49kb to 92kb upstream of transcript ENST00000447544, demonstrated significant transcription shifts between their minor and major allele in the MPRA assay. Of these, rs2366739 and rs1194196, separated by only 20bp, were confirmed by luciferase assay to alter transcriptional regulation. In addition, electromobility shift assays demonstrated differential DNA:protein complex formation between the two alleles of this locus. Furthermore, deletion of the genomic locus by CRISPR/Cas9 in K562 and Meg-01 cells results in upregulation of CD36 transcription. These data indicate that we have identified a variant that regulates expression of CD36, which in turn affects platelet function. To assess the clinical relevance of our findings we used the PhenoScanner tool, which aggregates large scale GWAS findings; the results reinforce the clinical relevance of our variants and the utility of the MPRA assay. The study demonstrates a generalizable paradigm for functional testing of genetic variants to inform mechanistic studies, support patient management and develop precision therapies.
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http://dx.doi.org/10.1371/journal.pgen.1008287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684090PMC
July 2019

Copy number variant and runs of homozygosity detection by microarrays enabled more precise molecular diagnoses in 11,020 clinical exome cases.

Genome Med 2019 05 17;11(1):30. Epub 2019 May 17.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030-3411, USA.

Background: Exome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains challenging. The purpose of this study is to understand the contribution of CNVs and copy neutral runs of homozygosity (ROH) in molecular diagnosis of patients referred for ES.

Methods: In a cohort of 11,020 consecutive ES patients, an Illumina SNP array analysis interrogating mostly coding SNPs was performed as a quality control (QC) measurement and for CNV/ROH detection. Among these patients, clinical chromosomal microarray analysis (CMA) was performed at Baylor Genetics (BG) on 3229 patients, either before, concurrently, or after ES. We retrospectively analyzed the findings from CMA and the QC array.

Results: The QC array can detect ~ 70% of pathogenic/likely pathogenic CNVs (PCNVs) detectable by CMA. Out of the 11,020 ES cases, the QC array identified PCNVs in 327 patients and uniparental disomy (UPD) disorder-related ROH in 10 patients. The overall PCNV/UPD detection rate was 5.9% in the 3229 ES patients who also had CMA at BG; PCNV/UPD detection rate was higher in concurrent ES and CMA than in ES with prior CMA (7.2% vs 4.6%). The PCNVs/UPD contributed to the molecular diagnoses in 17.4% (189/1089) of molecularly diagnosed ES cases with CMA and were estimated to contribute in 10.6% of all molecularly diagnosed ES cases. Dual diagnoses with both PCNVs and SNVs were detected in 38 patients. PCNVs affecting single recessive disorder genes in a compound heterozygous state with SNVs were detected in 4 patients, and homozygous deletions (mostly exonic deletions) were detected in 17 patients. A higher PCNV detection rate was observed for patients with syndromic phenotypes and/or cardiovascular abnormalities.

Conclusions: Our clinical genomics study demonstrates that detection of PCNV/UPD through the QC array or CMA increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses. Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and therefore is recommended especially in time-sensitive clinical situations.
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http://dx.doi.org/10.1186/s13073-019-0639-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525387PMC
May 2019

Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome.

Genome Med 2019 04 23;11(1):25. Epub 2019 Apr 23.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room 604B, Houston, TX, 77030-3498, USA.

Background: Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation. Recently, post-zygotic de novo triplications adjacent to copy-number neutral genomic intervals with runs of homozygosity (ROH) have been shown to result in uniparental isodisomy (UPD). The genomic structure of these complex genomic rearrangements (CGRs) shows a consistent pattern of an inverted triplication flanked by duplications (DUP-TRP/INV-DUP) formed by an iterative DNA replisome template-switching mechanism during replicative repair of a single-ended, double-stranded DNA (seDNA), the ROH results from an interhomolog or nonsister chromatid template switch. It has been postulated that these CGRs may lead to genetic abnormalities in carriers due to dosage-sensitive genes mapping within the copy-number variant regions, homozygosity for alleles at a locus causing an autosomal recessive (AR) disease trait within the ROH region, or imprinting-associated diseases.

Methods: Here, we report a family wherein the affected subject carries a de novo 2.2-Mb TRP followed by 42.2 Mb of ROH and manifests clinical features overlapping with those observed in association with chromosome 14 maternal UPD (UPD(14)mat). UPD(14)mat can cause clinical phenotypic features enabling a diagnosis of Temple syndrome. This CGR was then molecularly characterized by high-density custom aCGH, genome-wide single-nucleotide polymorphism (SNP) and methylation arrays, exome sequencing (ES), and the Oxford Nanopore long-read sequencing technology.

Results: We confirmed the postulated DUP-TRP/INV-DUP structure by multiple orthogonal genomic technologies in the proband. The methylation status of known differentially methylated regions (DMRs) on chromosome 14 revealed that the subject shows the typical methylation pattern of UPD(14)mat. Consistent with these molecular findings, the clinical features overlap with those observed in Temple syndrome, including speech delay.

Conclusions: These data provide experimental evidence that, in humans, triplication can lead to segmental UPD and imprinting disease. Importantly, genotype/phenotype analyses further reveal how a post-zygotically generated complex structural variant, resulting from a replication-based mutational mechanism, contributes to expanding the clinical phenotype of known genetic syndromes. Mechanistically, such events can distort transmission genetics resulting in homozygosity at a locus for which only one parent is a carrier as well as cause imprinting diseases.
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http://dx.doi.org/10.1186/s13073-019-0633-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480824PMC
April 2019

Megabase Length Hypermutation Accompanies Human Structural Variation at 17p11.2.

Cell 2019 03 28;176(6):1310-1324.e10. Epub 2019 Feb 28.

Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Human Genome Sequencing Center, BCM, Houston, TX 77030, USA; Department of Pediatrics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, BCM, Houston, TX 77030, USA. Electronic address:

DNA rearrangements resulting in human genome structural variants (SVs) are caused by diverse mutational mechanisms. We used long- and short-read sequencing technologies to investigate end products of de novo chromosome 17p11.2 rearrangements and query the molecular mechanisms underlying both recurrent and non-recurrent events. Evidence for an increased rate of clustered single-nucleotide variant (SNV) mutation in cis with non-recurrent rearrangements was found. Indel and SNV formation are associated with both copy-number gains and losses of 17p11.2, occur up to ∼1 Mb away from the breakpoint junctions, and favor C > G transversion substitutions; results suggest that single-stranded DNA is formed during the genesis of the SV and provide compelling support for a microhomology-mediated break-induced replication (MMBIR) mechanism for SV formation. Our data show an additional mutational burden of MMBIR consisting of hypermutation confined to the locus and manifesting as SNVs and indels predominantly within genes.
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http://dx.doi.org/10.1016/j.cell.2019.01.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438178PMC
March 2019

Publisher Correction: Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA.

Nat Med 2019 Apr;25(4):701-702

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

In the version of this article originally published, some cases that were presented in Fig. 3 should have been underlined but were not. The appropriate cases have now been underlined. The error has been corrected in the print, PDF and HTML versions of the article.
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http://dx.doi.org/10.1038/s41591-019-0391-9DOI Listing
April 2019

Identification of the Regulatory Elements and Target Genes of Megakaryopoietic Transcription Factor MEF2C.

Thromb Haemost 2019 May 7;119(5):716-725. Epub 2019 Feb 7.

Department of Medicine, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical School at Thomas Jefferson University, Philadelphia, Pennsylvania, United States.

Megakaryopoiesis produces specialized haematopoietic stem cells in the bone marrow that give rise to megakaryocytes which ultimately produce platelets. Defects in megakaryopoiesis can result in altered platelet counts and physiology, leading to dysfunctional haemostasis and thrombosis. Additionally, dysregulated megakaryopoiesis is also associated with myeloid pathologies. Transcription factors play critical roles in cell differentiation by regulating the temporal and spatial patterns of gene expression which ultimately decide cell fate. Several transcription factors have been described as regulating megakaryopoiesis including myocyte enhancer factor 2C (MEF2C); however, the genes regulated by MEF2C that influence megakaryopoiesis have not been reported. Using chromatin immunoprecipitation-sequencing and Gene Ontology data we identified five candidate genes that are bound by MEF2C and regulate megakaryopoiesis: , , , and . To study expression of these genes, we silenced gene expression in the Meg01 megakaryocytic cell line and in induced pluripotent stem cells by CRISPR/Cas9 editing. We also knocked down expression in cord blood-derived haematopoietic stem cells by siRNA. We found that absent or reduced expression resulted in defects in megakaryocytic differentiation and reduced levels of the candidate target genes. Luciferase assays confirmed that genomic sequences within the target genes are regulated by MEF2C levels. Finally, we demonstrate that small deletions linked to a platelet count-associated single nucleotide polymorphism alter transcriptional activity, suggesting a mechanism by which genetic variation in alters platelet production. These data help elucidate the mechanism behind MEF2C regulation of megakaryopoiesis and genetic variation driving platelet production.
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http://dx.doi.org/10.1055/s-0039-1678694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932631PMC
May 2019

Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA.

Nat Med 2019 03 28;25(3):439-447. Epub 2019 Jan 28.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Current non-invasive prenatal screening is targeted toward the detection of chromosomal abnormalities in the fetus. However, screening for many dominant monogenic disorders associated with de novo mutations is not available, despite their relatively high incidence. Here we report on the development and validation of, and early clinical experience with, a new approach for non-invasive prenatal sequencing for a panel of causative genes for frequent dominant monogenic diseases. Cell-free DNA (cfDNA) extracted from maternal plasma was barcoded, enriched, and then analyzed by next-generation sequencing (NGS) for targeted regions. Low-level fetal variants were identified by a statistical analysis adjusted for NGS read count and fetal fraction. Pathogenic or likely pathogenic variants were confirmed by a secondary amplicon-based test on cfDNA. Clinical tests were performed on 422 pregnancies with or without abnormal ultrasound findings or family history. Follow-up studies on cases with available outcome results confirmed 20 true-positive, 127 true-negative, zero false-positive, and zero-false negative results. The initial clinical study demonstrated that this non-invasive test can provide valuable molecular information for the detection of a wide spectrum of dominant monogenic diseases, complementing current screening for aneuploidies or carrier screening for recessive disorders.
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http://dx.doi.org/10.1038/s41591-018-0334-xDOI Listing
March 2019

Prioritization of Candidate Genes for Congenital Diaphragmatic Hernia in a Critical Region on Chromosome 4p16 using a Machine-Learning Algorithm.

J Pediatr Genet 2018 Dec 30;7(4):164-173. Epub 2018 May 30.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.

Wolf-Hirschhorn syndrome (WHS) is caused by partial deletion of the short arm of chromosome 4 and is characterized by dysmorphic facies, congenital heart defects, intellectual/developmental disability, and increased risk for congenital diaphragmatic hernia (CDH). In this report, we describe a stillborn girl with WHS and a large CDH. A literature review revealed 15 cases of WHS with CDH, which overlap a 2.3-Mb CDH critical region. We applied a machine-learning algorithm that integrates large-scale genomic knowledge to genes within the 4p16.3 CDH critical region and identified , , , , , , , and as genes whose haploinsufficiency may contribute to the development of CDH.
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http://dx.doi.org/10.1055/s-0038-1655755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234038PMC
December 2018

Publisher Correction: EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells.

Nat Commun 2018 11 12;9(1):4720. Epub 2018 Nov 12.

Department of Pharmacology, University of Colorado-Denver, 12800 East 19th Avenue, Room P18-6115, Aurora, Colorado, 80045, USA.

This Article contains an error in Figure 2. In panel a, the second lane of the western blot should have been labelled 'siNT'. A correct version of Figure 2a appears in the Author Correction associated with this Article; the error has not been fixed in the original Article.
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http://dx.doi.org/10.1038/s41467-018-07168-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232083PMC
November 2018

Design tools for MPRA experiments.

Bioinformatics 2018 08;34(15):2682-2683

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Motivation: Genetic reporter assays are a convenient, relatively inexpensive method for studying the regulation of gene expression. Massively Parallel Reporter Assays (MPRA) are high-throughput functionalization assays that interrogate the transcriptional activity of many genetic variants at once using a library of synthetic barcoded constructs. Despite growing interest in this area, there are few computational tools to design and execute MPRA studies.

Results: We designed an online web-tool and R package that allows for interactive MPRA experimental design encompassing both power analysis and design of constructs. Our tool is tuned using data from real MPRA studies. Users can adjust experimental parameters to examine the predicted effect on assay power as well as upload VCFs for automated construct sequence generation.

Availability And Implementation: The MPRA Design Tools web application is available here: https://andrewghazi.shinyapps.io/designmpra/, https://github.com/andrewGhazi/designMPRA and https://github.com/andrewGhazi/mpradesigntools.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/bty150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454564PMC
August 2018

Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles.

Am J Hum Genet 2018 08 19;103(2):171-187. Epub 2018 Jul 19.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Premature termination codon (PTC)-bearing transcripts are often degraded by nonsense-mediated decay (NMD) resulting in loss-of-function (LoF) alleles. However, not all PTCs result in LoF mutations, i.e., some such transcripts escape NMD and are translated to truncated peptide products that result in disease due to gain-of-function (GoF) effects. Since the location of the PTC is a major factor determining transcript fate, we hypothesized that depletion of protein-truncating variants (PTVs) within the gene region predicted to escape NMD in control databases could provide a rank for genic susceptibility for disease through GoF versus LoF. We developed an NMD escape intolerance score to rank genes based on the depletion of PTVs that would render them able to escape NMD using the Atherosclerosis Risk in Communities Study (ARIC) and the Exome Aggregation Consortium (ExAC) control databases, which was further used to screen the Baylor-Center for Mendelian Genomics disease database. This analysis revealed 1,996 genes significantly depleted for PTVs that are predicted to escape from NMD, i.e., PTVesc; further studies provided evidence that revealed a subset as candidate genes underlying Mendelian phenotypes. Importantly, these genes have characteristically low pLI scores, which can cause them to be overlooked as candidates for dominant diseases. Collectively, we demonstrate that this NMD escape intolerance score is an effective and efficient tool for gene discovery in Mendelian diseases due to production of truncated or altered proteins. More importantly, we provide a complementary analytical tool to aid identification of genes associated with dominant traits through a mechanism distinct from LoF.
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http://dx.doi.org/10.1016/j.ajhg.2018.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081281PMC
August 2018

Predicting human genes susceptible to genomic instability associated with /-mediated rearrangements.

Genome Res 2018 08 15;28(8):1228-1242. Epub 2018 Jun 15.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.

elements, the short interspersed element numbering more than 1 million copies per human genome, can mediate the formation of copy number variants (CNVs) between substrate pairs. These /-mediated rearrangements (AAMRs) can result in pathogenic variants that cause diseases. To investigate the impact of AAMR on gene variation and human health, we first characterized s that are involved in mediating CNVs (CNV-s) and observed that these s tend to be evolutionarily younger. We then computationally generated, with the assistance of a supercomputer, a test data set consisting of 78 million pairs and predicted ∼18% of them are potentially susceptible to AAMR. We further determined the relative risk of AAMR in 12,074 OMIM genes using the count of predicted CNV- pairs and experimentally validated the predictions with 89 samples selected by correlating predicted hotspots with a database of CNVs identified by clinical chromosomal microarrays (CMAs) on the genomes of approximately 54,000 subjects. We fine-mapped 47 duplications, 40 deletions, and two complex rearrangements and examined a total of 52 breakpoint junctions of simple CNVs. Overall, 94% of the candidate breakpoints were at least partially mediated. We successfully predicted all (100%) of pairs that mediated deletions ( = 21) and achieved an 87% positive predictive value overall when including AAMR-generated deletions and duplications. We provided a tool, AluAluCNVpredictor, for assessing AAMR hotspots and their role in human disease. These results demonstrate the utility of our predictive model and provide insights into the genomic features and molecular mechanisms underlying AAMR.
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http://dx.doi.org/10.1101/gr.229401.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071635PMC
August 2018

Early-onset epileptic encephalopathy and severe developmental delay in an association with de novo double mutations in and .

Epilepsia Open 2018 03 23;3(1):81-85. Epub 2017 Nov 23.

Department of Pediatrics Graduate School of Medical Sciences Kyushu University Fukuoka Japan.

Advance in the exome-wide sequencing analysis contributes to identifying hundreds of genes that are associated with early-onset epileptic encephalopathy and neurodevelopmental disorders. On the basis of massive sequencing data, functional interactions among different genes are suggested to explain the common molecular pathway underlying the pathogenic process of these disorders. However, the relevance of such interactions with the phenotypic severity or variety in an affected individual remains elusive. In this report, we present a 45-year-old woman with neurofibromatosis type 1 (NF1), infantile-onset epileptic encephalopathy, and severe developmental delay. Whole-exome sequencing identified de novo pathogenic mutations in and the Schaaf-Yang syndrome-associated gene, . Literature-curated interaction data predicted that NF1 and MAGEL2 proteins were closely connected in this network via their common interacting proteins. Direct conversion of fibroblasts into neurons in vitro showed that neuronal cells from 9 patients with NF1 expressed significantly lower levels of (54%, p = 0.0047) than those from healthy individuals. These data provide the first evidence that pathogenic mutations of deregulate the expression of other neurodevelopmental disease-associated genes. De novo mutations in multiple genes may lead to severe developmental phenotypes through their cumulative effects or synergistic interactions.
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http://dx.doi.org/10.1002/epi4.12085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839317PMC
March 2018

Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer.

Nat Med 2018 05 26;24(4):505-511. Epub 2018 Mar 26.

Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer diagnosed in more than 200,000 women each year and is recalcitrant to targeted therapies. Although TNBCs harbor multiple hyperactive receptor tyrosine kinases (RTKs), RTK inhibitors have been largely ineffective in TNBC patients thus far. We developed a broadly effective therapeutic strategy for TNBC that is based on combined inhibition of receptors that share the negative regulator PTPN12. Previously, we and others identified the tyrosine phosphatase PTPN12 as a tumor suppressor that is frequently inactivated in TNBC. PTPN12 restrains several RTKs, suggesting that PTPN12 deficiency leads to aberrant activation of multiple RTKs and a co-dependency on these receptors. This in turn leads to the therapeutic hypothesis that PTPN12-deficient TNBCs may be responsive to combined RTK inhibition. However, the repertoire of RTKs that are restrained by PTPN12 in human cells has not been systematically explored. By methodically identifying the suite of RTK substrates (MET, PDGFRβ, EGFR, and others) inhibited by PTPN12, we rationalized a combination RTK-inhibitor therapy that induced potent tumor regression across heterogeneous models of TNBC. Orthogonal approaches revealed that PTPN12 was recruited to and inhibited these receptors after ligand stimulation, thereby serving as a feedback mechanism to limit receptor signaling. Cancer-associated mutation of PTPN12 or reduced PTPN12 protein levels diminished this feedback mechanism, leading to aberrant activity of these receptors. Restoring PTPN12 protein levels restrained signaling from RTKs, including PDGFRβ and MET, and impaired TNBC survival. In contrast with single agents, combined inhibitors targeting the PDGFRβ and MET receptors induced the apoptosis in TNBC cells in vitro and in vivo. This therapeutic strategy resulted in tumor regressions in chemo-refractory patient-derived TNBC models. Notably, response correlated with PTPN12 deficiency, suggesting that impaired receptor feedback may establish a combined addiction to these proto-oncogenic receptors. Taken together, our data provide a rationale for combining RTK inhibitors in TNBC and other malignancies that lack receptor-activating mutations.
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http://dx.doi.org/10.1038/nm.4507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675908PMC
May 2018

The association between anterior nares and nasopharyngeal microbiota in infants hospitalized for bronchiolitis.

Microbiome 2018 01 3;6(1). Epub 2018 Jan 3.

Department of Medicine, Boston Children's Hospital, Boston, MA, USA.

Background: The airway microbiome is a subject of great interest for the study of respiratory disease. Anterior nare samples are more accessible than samples from deeper within the nasopharynx. However, the correlation between the microbiota found in the anterior nares and the microbiota found within the nasopharynx is unknown. We assessed the anterior nares and nasopharyngeal microbiota to determine (1) the relation of the microbiota from these two upper airway sites and (2) if associations were maintained between the microbiota from these two sites and two bronchiolitis severity outcomes.

Results: Among 815 infants hospitalized at 17 US centers for bronchiolitis with optimal 16S rRNA gene sequence reads from both nasal swab and nasopharyngeal aspirate samples, there were strong intra-individual correlations in the microbial communities between the two sample types, especially relating to Haemophilus and Moraxella genera. By contrast, we found a high abundance of Staphylococcus genus in the nasal swabs-a pattern not found in the nasopharyngeal samples and not informative when predicting the dominant nasopharyngeal genera. While these disparities may have been due to sample processing differences (i.e., nasal swabs were mailed at ambient temperature to emulate processing of future parent collected swabs while nasopharyngeal aspirates were mailed on dry ice), a previously reported association between Haemophilus-dominant nasopharyngeal microbiota and the increased severity of bronchiolitis was replicated utilizing the nasal swab microbiota and the same outcome measures: intensive care use (adjusted OR 6.43; 95% CI 2.25-20.51; P < 0.001) and hospital length-of-stay (adjusted OR 4.31; 95% CI, 1.73-11.11; P = 0.002). Additionally, Moraxella-dominant nasopharyngeal microbiota was previously identified as protective against intensive care use, a result that was replicated when analyzing the nasal swab microbiota (adjusted OR 0.30; 95% CI, 0.11-0.64; P = 0.01).

Conclusions: While the microbiota of the anterior nares and the nasopharynx are distinct, there is considerable overlap between the bacterial community compositions from these two anatomic sites. Despite processing differences between the samples, these results indicate that microbiota severity associations from the nasopharynx are recapitulated in the anterior nares, suggesting that nasal swab samples not only are effective sample types, but also can be used to detect microbial risk markers.
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http://dx.doi.org/10.1186/s40168-017-0385-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751828PMC
January 2018

Sustained endocrine profiles of a girl with WAGR syndrome.

BMC Med Genet 2017 10 23;18(1):117. Epub 2017 Oct 23.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.

Background: Wilms tumor, aniridia, genitourinary anomalies and mental retardation (WAGR) syndrome is a rare genetic disorder caused by heterozygous deletions of WT1 and PAX6 at chromosome 11p13. Deletion of BDNF is known eto be associated with hyperphagia and obesity in both humans and animal models; however, neuroendocrine and epigenetic profiles of individuals with WAGR syndrome remain to be determined.

Case Presentation: We report a 5-year-old girl with the typical phenotype of WAGR syndrome. She showed profound delays in physical growth, motor and cognitive development without signs of obesity. Array comparative genome hybridization (CGH) revealed that she carried a 14.4 Mb deletion at 11p14.3p12, encompassing the WT1, PAX6 and BDNF genes. She experienced recurrent hypoglycemic episodes at 5 years of age. Insulin tolerance and hormonal loading tests showed normal hypothalamic responses to the hypoglycemic condition and other stimulations. Methylation analysis for freshly prepared DNA from peripheral lymphocytes using the pyro-sequencing-based system showed normal patterns of methylation at known imprinting control regions.

Conclusions: Children with WAGR syndrome may manifest profound delay in postnatal growth through unknown mechanisms. Epigenetic factors and growth-associated genes in WAGR syndrome remain to be characterized.
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http://dx.doi.org/10.1186/s12881-017-0477-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654094PMC
October 2017

Identification of novel candidate disease genes from de novo exonic copy number variants.

Genome Med 2017 09 21;9(1):83. Epub 2017 Sep 21.

St. Luke's Children's Hospital, Boise, ID, 83702, USA.

Background: Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery.

Methods: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association.

Results: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses.

Conclusions: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.
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http://dx.doi.org/10.1186/s13073-017-0472-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607840PMC
September 2017

EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells.

Nat Commun 2017 06 12;8:15773. Epub 2017 Jun 12.

Department of Pharmacology, University of Colorado-Denver, 12800 East 19th Avenue, Room P18-6115, Aurora, Colorado 80045, USA.

Recent fate-mapping studies concluded that EMT is not required for metastasis of carcinomas. Here we challenge this conclusion by showing that these studies failed to account for possible crosstalk between EMT and non-EMT cells that promotes dissemination of non-EMT cells. In breast cancer models, EMT cells induce increased metastasis of weakly metastatic, non-EMT tumour cells in a paracrine manner, in part by non-cell autonomous activation of the GLI transcription factor. Treatment with GANT61, a GLI1/2 inhibitor, but not with IPI 926, a Smoothened inhibitor, blocks this effect and inhibits growth in PDX models. In human breast tumours, the EMT-transcription factors strongly correlate with activated Hedgehog/GLI signalling but not with the Hh ligands. Our findings indicate that EMT contributes to metastasis via non-cell autonomous effects that activate the Hh pathway. Although all Hh inhibitors may act against tumours with canonical Hh/GLI signalling, only GLI inhibitors would act against non-canonical EMT-induced GLI activation.
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http://dx.doi.org/10.1038/ncomms15773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472791PMC
June 2017

HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2 Breast Cancer.

Clin Cancer Res 2017 Sep 9;23(17):5123-5134. Epub 2017 May 9.

Department of Biomedical Engineering and Oregon Center for Spatial Systems Biomedicine, Oregon Health & Science University, Portland, Oregon.

Resistance to anti-HER2 therapies in HER2 breast cancer can occur through activation of alternative survival pathways or reactivation of the HER signaling network. Here we employed BT474 parental and treatment-resistant cell line models to investigate a mechanism by which HER2 breast cancer can reactivate the HER network under potent HER2-targeted therapies. Resistant derivatives to lapatinib (L), trastuzumab (T), or the combination (LR/TR/LTR) were developed independently from two independent estrogen receptor ER/HER2 BT474 cell lines (AZ/ATCC). Two derivatives resistant to the lapatinib-containing regimens (BT474/AZ-LR and BT474/ATCC-LTR lines) that showed HER2 reactivation at the time of resistance were subjected to massive parallel sequencing and compared with parental lines. Ectopic expression and mutant-specific siRNA interference were applied to analyze the mutation functionally. and experiments were performed to test alternative therapies for mutant HER2 inhibition. Genomic analyses revealed that the L755S mutation was the only common somatic mutation gained in the BT474/AZ-LR and BT474/ATCC-LTR lines. Ectopic expression of L755S induced acquired lapatinib resistance in the BT474/AZ, SK-BR-3, and AU565 parental cell lines. L755S-specific siRNA knockdown reversed the resistance in BT474/AZ-LR and BT474/ATCC-LTR lines. The HER1/2-irreversible inhibitors afatinib and neratinib substantially inhibited both resistant cell growth and the HER2 and downstream AKT/MAPK signaling driven by L755S and HER2 reactivation through acquisition of the L755S mutation was identified as a mechanism of acquired resistance to lapatinib-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762201PMC
September 2017

Sequence variability of the respiratory syncytial virus (RSV) fusion gene among contemporary and historical genotypes of RSV/A and RSV/B.

PLoS One 2017 17;12(4):e0175792. Epub 2017 Apr 17.

Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America.

Background: The fusion (F) protein of RSV is the major vaccine target. This protein undergoes a conformational change from pre-fusion to post-fusion. Both conformations share antigenic sites II and IV. Pre-fusion F has unique antigenic sites p27, ø, α2α3β3β4, and MPE8; whereas, post-fusion F has unique antigenic site I. Our objective was to determine the antigenic variability for RSV/A and RSV/B isolates from contemporary and historical genotypes compared to a historical RSV/A strain.

Methods: The F sequences of isolates from GenBank, Houston, and Chile (N = 1,090) were used for this analysis. Sequences were compared pair-wise to a reference sequence, a historical RSV/A Long strain. Variability (calculated as %) was defined as changes at each amino acid (aa) position when compared to the reference sequence. Only aa at antigenic sites with variability ≥5% were reported.

Results: A total of 1,090 sequences (822 RSV/A and 268 RSV/B) were analyzed. When compared to the reference F, those domains with the greatest number of non-synonymous changes included the signal peptide, p27, heptad repeat domain 2, antigenic site ø, and the transmembrane domain. RSV/A subgroup had 7 aa changes in the antigenic sites: site I (N = 1), II (N = 1), p27 (N = 4), α2α3β3β4(AM14) (N = 1), ranging in frequency from 7-91%. In comparison, RSV/B had 19 aa changes in antigenic sites: I (N = 3), II (N = 1), p27 (N = 9), ø (N = 4), α2α3β3β4(AM14) (N = 1), and MPE8 (N = 1), ranging in frequency from 79-100%.

Discussion: Although antigenic sites of RSV F are generally well conserved, differences are observed when comparing the two subgroups to the reference RSV/A Long strain. Further, these discrepancies are accented in the antigenic sites in pre-fusion F of RSV/B isolates, often occurring with a frequency of 100%. This could be of importance if a monovalent F protein from the historical GA1 genotype of RSV/A is used for vaccine development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175792PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393888PMC
May 2017

Identification of a functional genetic variant driving racially dimorphic platelet gene expression of the thrombin receptor regulator, PCTP.

Thromb Haemost 2017 05 2;117(5):962-970. Epub 2017 Mar 2.

Leonard C. Edelstein, Department of Medicine Sidney Kimmel Medical College, Thomas Jefferson University, 1020 Locust Street, Suite 394, Philadelphia, PA 19107, USA, Tel.: +1 215 955 1797, Fax: +1 215 955 9170,

Platelet activation in response to stimulation of the Protease Activated Receptor 4 (PAR4) receptor differs by race. One factor that contributes to this difference is the expression level of Phosphatidylcholine Transfer Protein (PCTP), a regulator of platelet PAR4 function. We have conducted an expression Quantitative Trait Locus (eQTL) analysis that identifies single nucleotide polymorphisms (SNPs) linked to the expression level of platelet genes. This analysis revealed 26 SNPs associated with the expression level of PCTP at genome-wide significance (p < 5×10). Using annotation from ENCODE and other public data we prioritised one of these SNPs, rs2912553, for functional testing. The allelic frequency of rs2912553 is racially-dimorphic, in concordance with the racially differential expression of PCTP. Reporter gene assays confirmed that the single nucleotide change caused by rs2912553 altered the transcriptional potency of the surrounding genomic locus. Electromobility shift assays, luciferase assays, and overexpression studies indicated a role for the megakaryocytic transcription factor GATA1. In summary, we have integrated multi-omic data to identify and functionalise an eQTL. This, along with the previously described relationship between PCTP and PAR4 function, allows us to characterise a genotype-phenotype relationship through the mechanism of gene expression.
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http://dx.doi.org/10.1160/TH16-09-0692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512274PMC
May 2017

An Organismal CNV Mutator Phenotype Restricted to Early Human Development.

Cell 2017 02;168(5):830-842.e7

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.

De novo copy number variants (dnCNVs) arising at multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient perizygotic period. We propose that a defect in the CNV formation process is responsible for the "CNV-mutator state," and this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution, and cancer biology.
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http://dx.doi.org/10.1016/j.cell.2017.01.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407901PMC
February 2017
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