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Machine learning reveals bilateral distribution of somatic L1 insertions in human neurons and glia

Zhu, Xiaowei; Zhou, Bo; Pattni, Reenal; Gleason, Kelly; Tan, Chunfeng; Kalinowski, Agnieszka; Sloan, Steven; Fiston-Lavier, Anna-Sophie; Mariani, Jessica; Petrov, Dmitri; Barres, Ben A; Duncan, Laramie; Abyzov, Alexej; Vogel, Hannes; Moran, John V; Vaccarino, Flora M; Tamminga, Carol A; Levinson, Douglas F; Urban, Alexander E
Retrotransposons can cause somatic genome variation in the human nervous system, which is hypothesized to have relevance to brain development and neuropsychiatric disease. However, the detection of individual somatic mobile element insertions presents a difficult signal-to-noise problem. Using a machine-learning method (RetroSom) and deep whole-genome sequencing, we analyzed L1 and Alu retrotransposition in sorted neurons and glia from human brains. We characterized two brain-specific L1 insertions in neurons and glia from a donor with schizophrenia. There was anatomical distribution of the L1 insertions in neurons and glia across both hemispheres, indicating retrotransposition occurred during early embryogenesis. Both insertions were within the introns of genes (CNNM2 and FRMD4A) inside genomic loci associated with neuropsychiatric disorders. Proof-of-principle experiments revealed these L1 insertions significantly reduced gene expression. These results demonstrate that RetroSom has broad applications for studies of brain development and may provide insight into the possible pathological effects of somatic retrotransposition.
PMID: 33432196
ISSN: 1546-1726
CID: 4913632

Using postmortem formalin fixed paraffin-embedded tissues for molecular testing of sudden cardiac death: A cautionary tale of utility and limitations

Lin, Ying; Gryazeva, Tatyana; Wang, Dawei; Zhou, Bo; Um, Sung Yon; Eng, Lucy S; Ruiter, Kevin; Rojas, Lisa; Williams, Nori; Sampson, Barbara A; Tang, Yingying
For archived cases of previously young healthy individuals where cause of sudden death remains undetermined, formalin fixed paraffin-embedded tissues (FFPE) samples are often the only biological resource available for molecular testing. We aim to ascertain the validity of postmortem molecular analysis of 95 cardiac genes using the FFPE samples routinely processed in the offices of medical examiners - typical fixation time in formalin ranges from days to months. The study was conducted in the College of American Pathologists accredited Molecular Genetics Laboratory within the City of New York Office of Chief Medical Examiner. Twelve cases, with FFPE samples and corresponding non-formalin fixed samples (RNAlater-preserved tissues or bloodstain card), were chosen for testing results comparison. The methods of extracting DNA from FFPE samples using Covaris, Qiagen, and Promega products showed comparable results. The quality of the extracted DNA, the target-enriched DNA libraries of 95 cardiac genes using HaloPlex Target Enrichment system by Agilent Technologies, and sequencing results using Illumina Miseq instrument were evaluated. Compared to the sequencing results of the nonfixed samples, the FFPE samples were categorized into three groups: 1) Group 1 samples fixed in formalin 2-6 days, had greater than 55 % sequencing regions ≥30x and 94%-100% variant concordance. 2) Group 2 samples fixed in formalin for 8 days, showed intra-sample sequencing variations: the surface tissues showed 25%-27% extra variants (false positive) and 8.1%-9.7% missing variants (false negative), whereas the repeated core tissues showed reduced extra variants to 1.6 % and the false negative error was unchanged. 3) Group 3 samples fixed in formalin 29-136 days, had 2-55 % sequencing regions ≥30x, up to 52.2 % missed variants and up to 6.3 % extra variants. All reportable variants (pathogenic, likely pathogenic or variant of uncertain significance) identified in the nonfixed samples were also identified in FFPE, albeit three variants had low confidence variant calling. In summary, our study showed that postmortem molecular diagnostic testing using FFPE samples routinely processed by the medical examiners should be cautioned, as they are replete with false positive and negative results, particularly when sample fixation time is longer than 8 days. Saving non-formalin fixed samples for high fidelity molecular analysis is strongly encouraged.
PMID: 32155531
ISSN: 1872-6283
CID: 4348962

Phenotypic variations in carriers of predicted protein-truncating genetic variants in MYBPC3: an autopsy-based case series

Williams, Nori; Marion, Robert; McDonald, Thomas V; Wang, Dawei; Zhou, Bo; Eng, Lucy S; Um, Sung Yon; Lin, Ying; Ruiter, Kevin; Rojas, Lisa; Sampson, Barbara A; Tang, Yingying
Our aim is to characterize predicted protein-truncating variants (PTVs) in MYBPC3, the gene most commonly associated with hypertrophic cardiomyopathy (HCM), found in a series of autopsied HCM cases after sudden unexpected cardiac death. All cases underwent death scene investigation, gross and microscopic autopsies, toxicological testing, a review of medical records, and a molecular analysis of 95 cardiac genes. We found four pathogenic PTVs in MYBPC3 among male decedents. All variants were previously submitted to ClinVar without phenotype details. Two PTVs were located in the cardiac-specific myosin S2-binding (M) motif at the N-terminus of the MYBPC3-encoded cMyBP-C protein, and two PTVs were in the non-cardiac-specific C-terminus of the protein. The carriers of two cardiac-specific M-motif PTVs died at age 38 years; their heart weight (HW, g) and body mass index (BMI, kg/m2) ratio were 34.90 (890/25.5) and 23.56 (980/41.6), respectively. In contrast, the carriers of two non-cardiac-specific C-terminal PTVs died at age 57 and 67 years, respectively; their HW and BMI ratio were 14.71 (450/30.6) and 13.98 (600/42.9), respectively. A detailed three-generation family study was conducted in one case. This study showed age-at-death variations among MYBPC3 PTVs carriers in adult males.
PMID: 30282064
ISSN: 1879-1336
CID: 3328102

Facile target validation in an animal model with intracellularly expressed monobodies

Gupta, Ankit; Xu, Jing; Lee, Shirley; Tsai, Steven T; Zhou, Bo; Kurosawa, Kohei; Werner, Michael S; Koide, Akiko; Ruthenburg, Alexander J; Dou, Yali; Koide, Shohei
Rapidly determining the biological effect of perturbing a site within a potential drug target could guide drug discovery efforts, but it remains challenging. Here, we describe a facile target validation approach that exploits monobodies, small synthetic binding proteins that can be fully functionally expressed in cells. We developed a potent and selective monobody to WDR5, a core component of the mixed lineage leukemia (MLL) methyltransferase complex. The monobody bound to the MLL interaction site of WDR5, the same binding site for small-molecule inhibitors whose efficacy has been demonstrated in cells but not in animals. As a genetically encoded reagent, the monobody inhibited proliferation of an MLL-AF9 cell line in vitro, suppressed its leukemogenesis and conferred a survival benefit in an in vivo mouse leukemia model. The capacity of this approach to readily bridge biochemical, structural, cellular characterization and tests in animal models may accelerate discovery and validation of druggable sites.
PMCID:6103845
PMID: 30013062
ISSN: 1552-4469
CID: 3202082

Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths

Lin, Ying; Williams, Nori; Wang, Dawei; Coetzee, William; Zhou, Bo; Eng, Lucy S; Um, Sung Yon; Bao, Ruijun; Devinsky, Orrin; McDonald, Thomas V; Sampson, Barbara A; Tang, Yingying
BACKGROUND:Genetic variant interpretation contributes to testing yield differences reported for sudden unexplained death. Adapting a high-resolution variant interpretation framework, which considers disease prevalence, reduced penetrance, genetic heterogeneity, and allelic contribution to determine the maximum tolerated allele count in gnomAD, we report an evaluation of cardiac channelopathy and cardiomyopathy genes in a large, demographically diverse sudden unexplained death cohort that underwent thorough investigation in the United States' largest medical examiner's office. METHODS AND RESULTS/RESULTS:The cohort has 296 decedents: 147 Blacks, 64 Hispanics, 49 Whites, 22 Asians, and 14 mixed ethnicities; 142 infants (1 to 11 months), 39 children (1 to 17 years), 74 young adults (18 to 34 years), and 41 adults (35 to 55 years). Eighty-nine cardiac disease genes were evaluated. Using a high-resolution variant interpretation workflow, we classified 17 variants as pathogenic or likely pathogenic (2 of which were incidental findings and excluded in testing yield analysis), 46 novel variants of uncertain significance, and 130 variants of uncertain significance. Nine pathogenic or likely pathogenic variants in ClinVar were reclassified to likely benign and excluded in testing yield analysis. The yields of positive cases by ethnicity and age were 21.4% in mixed ethnicities, 10.2% Whites, 4.5% Asians, 3.1% Hispanics, and 2% Blacks; 7.7% children, 7.3% in adults, 5.4% young adults, and 2.8% infants. The percentages of uncertain cases with variants of uncertain significance by ethnicity were 45.5% in Asians, 45.3% Hispanics, 44.20% Blacks, 36.7% Whites, and 14.3% in mixed ethnicities. CONCLUSIONS:High-resolution variant interpretation provides diagnostic accuracy and healthcare efficiency. Under-represented populations warrant greater inclusion in future studies.
PMID: 29247119
ISSN: 1942-3268
CID: 2892682

Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network

McConnell, Michael J; Moran, John V; Abyzov, Alexej; Akbarian, Schahram; Bae, Taejeong; Cortes-Ciriano, Isidro; Erwin, Jennifer A; Fasching, Liana; Flasch, Diane A; Freed, Donald; Ganz, Javier; Jaffe, Andrew E; Kwan, Kenneth Y; Kwon, Minseok; Lodato, Michael A; Mills, Ryan E; Paquola, Apua C M; Rodin, Rachel E; Rosenbluh, Chaggai; Sestan, Nenad; Sherman, Maxwell A; Shin, Joo Heon; Song, Saera; Straub, Richard E; Thorpe, Jeremy; Weinberger, Daniel R; Urban, Alexander E; Zhou, Bo; Gage, Fred H; Lehner, Thomas; Senthil, Geetha; Walsh, Christopher A; Chess, Andrew; Courchesne, Eric; Gleeson, Joseph G; Kidd, Jeffrey M; Park, Peter J; Pevsner, Jonathan; Vaccarino, Flora M
Neuropsychiatric disorders have a complex genetic architecture. Human genetic population-based studies have identified numerous heritable sequence and structural genomic variants associated with susceptibility to neuropsychiatric disease. However, these germline variants do not fully account for disease risk. During brain development, progenitor cells undergo billions of cell divisions to generate the ~80 billion neurons in the brain. The failure to accurately repair DNA damage arising during replication, transcription, and cellular metabolism amid this dramatic cellular expansion can lead to somatic mutations. Somatic mutations that alter subsets of neuronal transcriptomes and proteomes can, in turn, affect cell proliferation and survival and lead to neurodevelopmental disorders. The long life span of individual neurons and the direct relationship between neural circuits and behavior suggest that somatic mutations in small populations of neurons can significantly affect individual neurodevelopment. The Brain Somatic Mosaicism Network has been founded to study somatic mosaicism both in neurotypical human brains and in the context of complex neuropsychiatric disorders.
PMCID:5558435
PMID: 28450582
ISSN: 1095-9203
CID: 2892182

A trabecular plate-like phenotype is overrepresented in Chinese-American versus Caucasian women

Walker, M D; Shi, S; Russo, J J; Liu, X S; Zhou, B; Zhang, C; Liu, G; McMahon, D J; Bilezikian, J P; Guo, X E
UNLABELLED:This study used extreme phenotype selection to define two trabecular bone phenotypes in a cohort of Chinese-American and Caucasian women. A trabecular plate-predominant phenotype is more common in Chinese-Americans while the rod-predominant phenotype is more typical of Caucasians. The robustness of these phenotypic associations with respect to lifestyle factors suggests that this trait may have a genetic basis and that these phenotypes can be utilized in future genetic studies. INTRODUCTION/BACKGROUND:Compared to Caucasians, Chinese-Americans have more plate-like trabecular bone when measured by individual trabecula segmentation (ITS). These findings suggest a phenotypic difference between the races, which may be amenable to genetic analysis. We sought to identify a single ITS plate trait to pursue in genetic studies by conducting an extreme phenotype selection strategy to numerically define two distinct phenotypes-plate-like and rod-like-and determine whether the selected phenotypic associations were independent of lifestyle factors in order to conduct future genetic studies. METHODS:A previously described cohort of 146 Chinese-American and Caucasian women with high-resolution peripheral quantitative computed tomography imaging and ITS analyses were studied with logistic regression and receiver operator characteristic analyses. RESULTS:The tibial plate-to-rod (TPR) ratio was the best ITS discriminator of race. Using extreme phenotypic selection, two TPR ratio phenotypes were defined numerically: plate-like as a TPR ratio value in the highest quartile (≥1.336) and rod-like as a TPR ratio value in the lowest quartile (≤0.621). Women with a plate-like phenotype were 25.7 times more likely (95 % CI 7.3-90.1) to be Chinese-American than women with rod-like morphology. After controlling for constitutional and lifestyle covariates, women in the highest vs. lowest TPR ratio quartile were 85.0 times more likely (95 % CI 12.7-568.0) to be Chinese-American. CONCLUSION/CONCLUSIONS:Using extreme phenotype selection, we defined a plate- and rod-like trabecular bone phenotype for the TPR ratio trait. The former phenotype is more common in Chinese-American women, while the latter is more typical of Caucasian women. The robustness of these phenotypic associations after controlling for differences in constitution and lifestyle suggest that the TPR ratio may have a genetic basis and that the extreme phenotypes defined in this analysis can be utilized for future studies.
PMID: 25069706
ISSN: 1433-2965
CID: 5213352

Prevalence and causes of decreased visual acuity in Singaporean Chinese preschoolers

Dirani, M; Zhou, B; Hornbeak, D; Chang, B C; Gazzard, G; Chia, A; Ling, Y; Selvaraj, P; Young, T L; Varma, R; Wong, T Y; Saw, S M
AIMS/OBJECTIVE:To describe the prevalence and causes of decreased visual acuity (VA) in Singaporean Chinese children. METHODS:A population-based survey of Singaporean Chinese children aged 6 to 72 months was conducted. Participants underwent an orthoptic evaluation, cycloplegic refraction and biometric measurements. A sub-group of children aged 30 to 72 months with presenting logMAR VA were included in this analysis. Retesting was performed on the same day or another day by predefined criteria with best refractive correction. Decreased VA was defined as worse than 20/50 (0.4 logMAR) for ages 30 to 47 months and worse than 20/40 (0.3 logMAR) for ages 48 to 72 months. RESULTS:The study examined 3009 children (participation rate 72.3%) of which 2017 children aged 30 to 72 months were eligible for VA testing and completed in 1684 (83.5%). In children aged 30-47 months, the prevalence of decreased presenting VA was 2.1%, and in children 48-72 months, it was 2.05%, with no significant difference between boys and girls in both age groups (p=0.15 and p=0.85). Causes for decreased presenting VA in those 30-47 months were refractive error (7/11, 63.6%), amblyopia (1/11, 9.1%) and "no explanation" (3/11, 27.3%), and 17/24 (70.8%), 5/24 (20.8%) and 2/24 (8.3%), respectively, for those aged 48-72 months. The types of refractive error were astigmatism (15/24, 62.5%), myopia (6/24, 25.0%), hyperopia (2/24, 8.3%) and hyperopia with astigmatism (1/24, 4.2%). CONCLUSIONS:The prevalence of decreased VA among Singaporean Chinese preschoolers is low, with uncorrected refractive error being the main cause in both children 30-47 and 48-72 months.
PMID: 20576782
ISSN: 1468-2079
CID: 5498472