Biology subjects

Zwick, M. E.

Publications and source records attributed to Zwick, M. E..

8 recordsLinked to original sources

bioRxiv2022

Outcome of Crash Course Training on Protein Structure Prediction with Artificial Intelligence

Protein structure predictions have broad impact on several science disciplines such as biology, bioengineering, and medical science. AlphaFold2[1] and RoseTTAFold[2] are the current state-of-the-art AI methods to predict the structures of proteins with an accuracy comparable to lower-resolution experimental methods. In its 2021 year review, both these methods were recognized as "breakthrough of the year" by Science magazine[3] and "method of the year" by Nature magazine [4]. It is timely and important to provide training and support on these emerging methods. Our crash course "Enabling Protein Structure Prediction with Artificial Intelligence "was conducted in collaboration with domain experts and research computing professionals. The crash course was well received by the community as there were 750 registrants from all over the world. Here we provide the summary of the crash course, describe our findings in organizing the crash course, and explain what preparation steps helped us with the hands-on training. CCS CONCEPTSComputing methodologies a Machine learning a Machine learning approaches a Bio-inspired approaches

scientific communication and education↗

bioRxiv2022

Loss-of-function of OTUD7A in the schizophrenia-associated 15q13.3 deletion impairs synapse development and function in human neurons

Identifying causative gene(s) within disease-associated large genomic regions of copy number variants (CNVs) is challenging. Here, by targeted sequencing of genes within schizophrenia (SZ)-associated CNVs in 1,779 SZ cases and 1,418 controls, we identified three rare putative loss-of-function (LoF) mutations in OTU deubiquitinase 7A (OTUD7A) within the 15q13.3 deletion in cases, but none in controls. To tie OTUD7A LoF with any SZ-relevant cellular phenotypes, we modeled the OTUD7A LoF mutation, rs757148409, in human induced pluripotent stem cell (hiPSC)-derived induced excitatory neurons (iNs) by CRISPR/Cas9 engineering. The mutant iNs showed a [~]50% decrease in OTUD7A expression without undergoing nonsense-mediated mRNA decay. The mutant iNs also exhibited marked reduction of dendritic complexity, density of synaptic proteins GluA1 and PSD-95, and neuronal network activity. Congruent with the neuronal phenotypes in mutant iNs, our transcriptomic analysis showed that the set of OTUD7A LoF-downregulated genes was enriched for those relating to synapse development and function, and was associated with SZ and other neuropsychiatric disorders. These results suggest that OTUD7A LoF impairs synapse development and neuronal function in human neurons, providing mechanistic insight into the possible role of OTUD7A in driving neuropsychiatric phenotypes associated with the 15q13.3 deletion.

neuroscience↗

bioRxiv2020

Metabolic effects of the schizophrenia-associated 3q29 deletion are sex-specific and uncoupled from behavioral phenotypes

The 1.6 Mb 3q29 deletion is associated with developmental and psychiatric phenotypes. Reduced birthweight and a high prevalence of feeding disorders in patients suggest underlying metabolic dysregulation. We investigated 3q29 deletion-induced metabolic changes using the B6.Del16+/Bdh1-Tfrc mouse model. We found that B6.Del16+/Bdh1-Tfrc animals preferentially use dietary lipids as an energy source. Untargeted metabolomics showed a strong sex-dependent effect of the 3q29 deletion on fat metabolism. A high-fat diet (HFD) partially rescued the 3q29 deletion-associated weight deficit in females, but not males. Untargeted metabolomics after HFD revealed persistent fat metabolism alterations in females. The HFD did not affect B6.Del16+/Bdh1-Tfrc behavioral phenotypes, suggesting that 3q29 deletion-associated metabolic and behavioral outcomes are uncoupled. Our data indicate a HFD intervention in 3q29 deletion syndrome may improve weight phenotypes without exacerbating behavioral manifestations. Our study also highlights the importance of assessing sex in metabolic studies and suggests mechanisms underlying 3q29 deletion-associated metabolic phenotypes are sex-specific.

genetics↗

bioRxiv2020

Sex-specific recombination predicts parent of origin for recurrent genomic disorders

Genomic disorders are caused by structural rearrangements of the genome that generally occur during meiosis1. Often the rearrangements result in large-scale (> 1 kb) copy number variants (CNV; deletions or duplications [≥] 1 kb)2,3. Recurrent pathogenic CNVs harbor similar breakpoints in multiple unrelated individuals and are primarily formed via non-allelic homologous recombination (NAHR)3,4. Several pathogenic NAHR-mediated recurrent CNV loci demonstrate biases for parental origin of de novo CNVs5-9. However, the mechanism underlying these biases is not well understood. Here we have curated parent of origin data for multiple pathogenic CNV loci and demonstrate a significant association between sex-specific differences in meiotic recombination and parental origin biases at these loci. Our results suggest that parental-origin of CNVs is largely controlled by sex-specific recombination rates and bring into light the need to consider these differences when seeking to determine the factors underlying risk for structural variation.

genetics↗

bioRxiv2019

Systematic Description of 3q29 Duplication Syndrome Reveals New Syndromic Phenotypes: Results from the 3q29 Registry

3q29 duplication syndrome (3q29Dup) is a rare genomic disorder caused by the reciprocal duplication of the 1.6 Mb 3q29 deletion syndrome region. Case reports indicate the 3q29Dup is likely to be pathogenic, but because no systematic study of the syndrome exists, the full range of manifestations is not well-understood. To develop a better understanding of 3q29 duplication syndrome, we used the 3q29 registry (https://3q29deletion.patientcrossroads.org/) to ascertain 31 individuals with 3q29Dup, the largest cohort ever surveyed in a systematic way. For comparison, we ascertained 117 individuals with the reciprocal 3q29 deletion syndrome (3q29Del) and 64 typically developing controls. We used a custom medical and demographic questionnaire to assess physical and developmental phenotypes, and two standardized instruments, the Social Responsiveness Scale (SRS) and Achenbach Behavior Checklists (CBCL/ABCL), to assess social disability. We find that our 3q29Dup participants report a high rate of problems in the first year of life (80.6%), including feeding problems (58%), failure to gain weight (42%), hypotonia (39%), and respiratory distress (29%). In early childhood, learning problems (87.1%) and seizures (25.8%) are common. Additionally, we find a rate of self-reported ASD diagnoses (39%) similar to that previously identified in 3q29Del (29%), and the granular characteristics of social disability measured using the SRS and CBCL/ABCL are comparable between 3q29Dup and 3q29Del. This is the most comprehensive description of 3q29Dup to date. Our findings can be used to develop evidence-based strategies for early intervention and management of 3q29 duplication syndrome.

genetics↗

bioRxiv2018

Neuropsychiatric Phenotypes in 3q29 Deletion Syndrome

BackgroundThe 1.6 Mb 3q29 deletion is associated with neurodevelopmental and psychiatric phenotypes, including increased risk for autism spectrum disorder (ASD) and a 20-40-fold increased risk for schizophrenia. However, the phenotypic spectrum of the deletion, particularly with respect to ASD, remains poorly described.\n\nMethodsWe ascertained individuals with 3q29 deletion syndrome (3q29Del, \"cases\", n=93, 58.1% male) and typically developing controls (n=64, 51.6% male) through the 3q29 registry (https://3q29deletion.patientcrossroads.org). Self-report of neuropsychiatric illness was evaluated for 93 cases. Subsets of participants were evaluated with the Social Responsiveness Scale (SRS, n=48 cases, 56 controls), Social Communication Questionnaire (SCQ, n=33 cases, 46 controls), Autism Spectrum Screening Questionnaire (ASSQ, n=24 cases, 35 controls), and Achenbach Behavior Checklists (n=48 cases, 57 controls).\n\nResults3q29Del cases report a higher prevalence of autism diagnoses versus the general population (29.0% vs. 1.47%, p<2.2E-16). Notably, 3q29 deletion confers a greater influence on risk for ASD in females (OR=41.8, p=4.78E-05) than in males (OR=24.6, p=6.06E-09); this is aligned with the reduced male:female bias from 4:1 in the general population to 2:1 in our study sample. Although 71% of cases do not report a diagnosis of ASD, there is evidence of significant social disability (3q29Del SRS T-score=71.8, control SRS T-score=45.9, p=2.16E-13). Cases also report increased frequency of generalized anxiety disorder compared to controls (28.0% vs. 6.2%, p=0.001), which is mirrored by elevated mean scores on the Achenbach DSM-oriented sub-scales (p<0.001). Finally, cases show a distinct constellation of ASD features on the SRS as compared to idiopathic ASD, with substantially elevated Restricted Interests and Repetitive Behaviors, but only mild impairment in Social Motivation.\n\nConclusionsOur sample of 3q29Del is significantly enriched for ASD diagnosis, especially among females, and features of autism may be present even when an ASD diagnosis is not reported. Further, the constellation of ASD features in this population is distinct from idiopathic ASD, with substantially less impaired social motivation. Our study implies that ASD evaluation should be the standard of care for individuals with 3q29Del. From a research perspective, the distinct ASD subtype present in 3q29Del is an ideal entry point for expanding understanding of ASD.

genetics↗

bioRxiv2017

SeqAnt 2.0: Whole-Genome Annotation and Natural-Language Searching in the Cloud

Accurately selecting relevant alleles in large sequencing experiments remains technically challenging. Bystro (https://bystro.io/) is the first online, cloud-based application that makes variant annotation and filtering accessible to all researchers for terabyte-sized whole-genome experiments containing thousands of samples. Its key innovation is a general-purpose, natural-language search engine that enables users to identify and export alleles of interest in milliseconds. The search engine dramatically simplifies complex filtering tasks that previously required programming experience or specialty command-line programs. Critically, Bystro annotation and filtering capabilities are orders of magnitude faster than previous solutions, saving weeks of processing time for large experiments.

bioinformatics↗

bioRxiv2016

Analysis of copy number variants on chromosome 21 in Down syndrome-associated congenital heart defects

One in five people with Down syndrome (DS) are born with an atrioventricular septal defect (AVSD), an incidence 2,000 times higher than in the euploid population. The genetic loci that contribute to this risk are poorly understood. In this study, we tested two hypotheses: 1) individuals with DS carrying chromosome 21 copy number variants (CNVs) that interrupt exons may be protected from AVSD, because these CNVs return AVSD susceptibility loci back to disomy, and 2) individuals with DS carrying chromosome 21 genes spanned by microduplications are at greater risk for AVSD because these microduplications boost the dosage of AVSD susceptibility loci beyond a tolerable threshold. We tested 198 case individuals with DS+AVSD and 211 control individuals with DS and a normal heart using a custom microarray with dense probes tiled on chromosome 21 for array CGH. We found that neither an individual chromosome 21 CNV nor any individual gene intersected by a CNV was associated with AVSD in DS. Burden analyses revealed that African American controls had more bases covered by rare deletions than did African American cases. Inversely, we found that Caucasian cases had more genes intersected by rare duplications than did Caucasian controls. Pathway analyses indicated copy number perturbations of genes involved in protein heterotrimerization and histone methylating proteins. Finally, we showed that previously DS+AVSD-associated common CNVs on chromosome 21 are likely false positives. This research adds to the swell of evidence indicating that DS-associated AVSD is similarly heterogeneous, as is AVSD in the euploid population.

genomics↗