@article {90, title = {dbMTS: A comprehensive database of putative human microRNA target site SNVs and their functional predictions.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 06}, pages = {1123-1130}, abstract = {

MicroRNAs (miRNA) are short noncoding RNAs that can repress the expression of protein-coding messenger RNAs (mRNAs) by binding to the 3{\textquoteright}-untranslated region (UTR) of the target. Genetic mutations such as single nucleotide variants (SNVs) in the 3{\textquoteright}-UTR of the mRNAs can disrupt miRNA regulation. In this study, we presented dbMTS, a database for miRNA target site (MTS) SNVs and their functional annotations. This database can help studies easily identify putative SNVs that affect miRNA targeting and facilitate the prioritization of their functional importance. dbMTS is freely available for academic use at http://database.liulab.science/dbMTS as a web service or a downloadable attached database of dbNSFP.

}, issn = {1098-1004}, doi = {10.1002/humu.24020}, author = {Li, Chang and Mou, Chengcheng and Swartz, Michael D and Yu, Bing and Bai, Yongsheng and Tu, Yicheng and Liu, Xiaoming} } @article {100, title = {Determinants of telomere length across human tissues.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.

}, keywords = {Aging, Genetic Markers, Genetic Variation, Humans, Organ Specificity, Telomere, Telomere Homeostasis, Telomere Shortening}, issn = {1095-9203}, doi = {10.1126/science.aaz6876}, author = {Demanelis, Kathryn and Jasmine, Farzana and Chen, Lin S and Chernoff, Meytal and Tong, Lin and Delgado, Dayana and Zhang, Chenan and Shinkle, Justin and Sabarinathan, Mekala and Lin, Hannah and Ramirez, Eduardo and Oliva, Meritxell and Kim-Hellmuth, Sarah and Stranger, Barbara E and Lai, Tsung-Po and Aviv, Abraham and Ardlie, Kristin G and Aguet, Fran{\c c}ois and Ahsan, Habibul and Doherty, Jennifer A and Kibriya, Muhammad G and Pierce, Brandon L} } @article {145, title = {Development and validation of the VISAGE AmpliSeq basic tool to predict appearance and ancestry from DNA.}, journal = {Forensic Sci Int Genet}, volume = {48}, year = {2020}, month = {2020 09}, pages = {102336}, abstract = {

Forensic DNA phenotyping is gaining interest as the number of applications increases within the forensic genetics community. The possibility of providing investigative leads in addition to conventional DNA profiling for human identification provides new insights into otherwise "cold" police investigations. The ability of reporting on the bio-geographical ancestry (BGA), appearance characteristics and age based on DNA obtained from a crime scene sample of an unknown donor makes the exploration of such markers and the development of new methods meaningful for criminal investigations. The VISible Attributes through GEnomics (VISAGE) Consortium aims to disseminate and broaden the use of predictive markers and develop fully optimized and validated prototypes for forensic casework implementation. Here, the first VISAGE appearance and ancestry tool development, performance and validation is reported. A total of 153 SNPs (96.84 \% assay conversion rate) were successfully incorporated into a single multiplex reaction using the AmpliSeq{\texttrademark} design pipeline, and applied for massively parallel sequencing with the Ion S5 platform. A collaborative effort involving six VISAGE laboratory partners was devised to perform all validation tests. An extensive validation plan was carefully organized to explore the assay{\textquoteright}s overall performance with optimum and low-input samples, as well as with challenging and casework mock samples. In addition, forensic validation studies such as concordance and mixture tests recurring to the Coriell sample set with known genotypes were performed. Finally, inhibitor tolerance and specificity were also evaluated. Results showed a robust, highly sensitive assay with good overall concordance between laboratories.

}, issn = {1878-0326}, doi = {10.1016/j.fsigen.2020.102336}, author = {Xavier, Catarina and de la Puente, Mar{\'\i}a and Mosquera-Miguel, Ana and Freire-Aradas, Ana and Kalamara, Vivian and Vidaki, Athina and E Gross, Theresa and Revoir, Andrew and Po{\'s}piech, Ewelina and Kartasi{\'n}ska, Ewa and Sp{\'o}lnicka, Magdalena and Branicki, Wojciech and E Ames, Carole and M Schneider, Peter and Hohoff, Carsten and Kayser, Manfred and Phillips, Christopher and Parson, Walther} } @article {110, title = {Discovery and population genomics of structural variation in a songbird genus.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 07 07}, pages = {3403}, abstract = {

Structural variation~(SV) constitutes an important type of genetic mutations providing the raw material for evolution. Here, we uncover the genome-wide spectrum of intra- and interspecific SV segregating in natural populations of seven songbird species in the genus Corvus. Combining short-read (N = 127) and long-read re-sequencing (N = 31), as well as optical mapping (N = 16), we apply both assembly- and read mapping approaches to detect SV and characterize a total of 220,452 insertions, deletions and inversions. We exploit sampling across wide phylogenetic timescales to validate SV genotypes and assess the contribution of SV to evolutionary processes in an avian model of incipient speciation. We reveal an evolutionary young (~530,000 years) cis-acting 2.25-kb LTR retrotransposon insertion reducing expression of the NDP gene with consequences for premating isolation. Our results attest to the wealth and evolutionary significance of SV segregating in natural populations and highlight the need for reliable SV genotyping.

}, keywords = {Animals, Chromosome Inversion, Gene Deletion, Genetic Variation, Genetics, Population, Genome, Genomic Structural Variation, Genotype, Phylogeny, Polymorphism, Single Nucleotide, Retroelements, Sequence Analysis, DNA, Songbirds}, issn = {2041-1723}, doi = {10.1038/s41467-020-17195-4}, author = {Weissensteiner, Matthias H and Bunikis, Ignas and Catal{\'a}n, Ana and Francoijs, Kees-Jan and Knief, Ulrich and Heim, Wieland and Peona, Valentina and Pophaly, Saurabh D and Sedlazeck, Fritz J and Suh, Alexander and Warmuth, Vera M and Wolf, Jochen B W} } @article {53, title = {Differential NOVA2-Mediated Splicing in Excitatory and Inhibitory Neurons Regulates Cortical Development and Cerebellar Function.}, journal = {Neuron}, volume = {101}, year = {2019}, month = {2019 Feb 20}, pages = {707-720.e5}, abstract = {

RNA-binding proteins (RBPs) regulate genetic diversity, but the degree to which they do so in individual cell types in~vivo is unknown. We developed NOVA2 cTag-crosslinking and immunoprecipitation (CLIP) to generate functional RBP-RNA maps from different neuronal populations in the mouse brain. Combining cell type datasets from Nova2-cTag and Nova2 conditional knockout mice revealed differential NOVA2 regulatory actions on alternative splicing (AS) on the same transcripts expressed in different neurons. This includes functional differences in transcripts expressed in cortical and cerebellar excitatory versus inhibitory neurons, where we find NOVA2 is required for, respectively, development of laminar structure, motor coordination, and synapse formation. We also find that NOVA2-regulated AS is coupled to NOVA2 regulation of intron retention in hundreds of transcripts, which can sequester the trans-acting splicing factor PTBP2. In summary, cTag-CLIP complements single-cell RNA sequencing (RNA-seq) studies by providing a means for understanding RNA regulation of functional cell diversity.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2018.12.019}, author = {Saito, Yuhki and Yuan, Yuan and Zucker-Scharff, Ilana and Fak, John J and Jereb, Sa{\v s}a and Tajima, Yoko and Licatalosi, Donny D and Darnell, Robert B} } @article {81, title = {Drug-Resistant Juvenile Myoclonic Epilepsy: Misdiagnosis of Progressive Myoclonus Epilepsy.}, journal = {Front Neurol}, volume = {10}, year = {2019}, month = {2019}, pages = {946}, abstract = {

Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome characterized by bilateral myoclonic and tonic-clonic seizures typically starting in adolescence and responding well to medication. Misdiagnosis of a more severe progressive myoclonus epilepsy (PME) as JME has been suggested as a cause of drug-resistance. Medical records of the Epilepsy Center Hessen-Marburg between 2005 and 2014 were automatically selected using keywords and manually reviewed regarding the presence of a JME diagnosis at any timepoint. The identified patients were evaluated regarding seizure outcome and drug resistance according to ILAE criteria. 87/168 identified JME patients were seizure-free at last follow-up including 61 drug-responsive patients (group NDR). Seventy-eight patients were not seizure-free including 26 drug-resistant patients (group DR). Valproate was the most efficacious AED. The JME diagnosis was revised in 7 patients of group DR including 6 in whom the diagnosis had already been questioned or revised during clinical follow-up. One of these was finally diagnosed with PME (genetically confirmed Lafora disease) based on genetic testing. She was initially reviewed at age 29 yrs and considered to be inconsistent with PME. Intellectual disability ( = 0.025), cognitive impairment ( < 0.001), febrile seizures in first-degree relatives ( = 0.023) and prominent dialeptic seizures ( = 0.009) where significantly more frequent in group DR. Individuals with PME are rarely found among drug-resistant alleged JME patients in a tertiary epilepsy center. Even a very detailed review by experienced epileptologists may not identify the presence of PME before the typical features evolve underpinning the need for early genetic testing in drug-resistant JME patients.

}, issn = {1664-2295}, doi = {10.3389/fneur.2019.00946}, author = {Martin, Sarah and Strzelczyk, Adam and Lindlar, Silvia and Krause, Kristina and Reif, Philipp S and Menzler, Katja and Chiocchetti, Andreas G and Rosenow, Felix and Knake, Susanne and Klein, Karl Martin} } @article {39, title = {Differential 3{\textquoteright} Processing of Specific Transcripts Expands Regulatory and Protein Diversity Across Neuronal Cell Types.}, journal = {Elife}, volume = {7}, year = {2018}, month = {2018 Mar 26}, abstract = {

Alternative polyadenylation (APA) regulates mRNA translation, stability, and protein localization. However, it is unclear to what extent APA regulates these processes uniquely in specific cell types. Using a new technique, cTag-PAPERCLIP, we discovered significant differences in APA between the principal types of mouse cerebellar neurons, the Purkinje and granule cells, as well as between proliferating and differentiated granule cells. Transcripts that differed in APA in these comparisons were enriched in key neuronal functions and many differed in coding sequence in addition to 3{\textquoteright}UTR length. We characterize , a transcript that shifted from expressing a short 3{\textquoteright}UTR isoform to a longer one during granule cell differentiation. We show that regulates granule cell precursor proliferation and that its long 3{\textquoteright}UTR isoform is targeted by miR-124, contributing to its downregulation during development. Our findings provide insight into roles for APA in specific cell types and establish a platform for further functional studies.

}, issn = {2050-084X}, doi = {10.7554/eLife.34042}, author = {Jereb, Sa{\v s}a and Hwang, Hun-Way and Van Otterloo, Eric and Govek, Eve-Ellen and Fak, John J and Yuan, Yuan and Hatten, Mary E and Darnell, Robert B} } @article {14, title = {Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Apr}, pages = {527-536}, abstract = {

Gain-of-function mutations in some genes underlie neurodegenerative conditions, whereas loss-of-function mutations in the same genes have distinct phenotypes. This appears to be the case with the protein ataxin 1 (ATXN1), which forms a transcriptional repressor complex with capicua (CIC). Gain of function of the complex leads to neurodegeneration, but ATXN1-CIC is also essential for survival. We set out to understand the functions of the ATXN1-CIC complex in the developing forebrain and found that losing this complex results in hyperactivity, impaired learning and memory, and abnormal maturation and maintenance of upper-layer cortical neurons. We also found that CIC activity in the hypothalamus and medial amygdala modulates social interactions. Informed by these neurobehavioral features in mouse mutants, we identified five individuals with de novo heterozygous truncating mutations in CIC who share similar clinical features, including intellectual disability, attention deficit/hyperactivity disorder (ADHD), and autism spectrum disorder. Our study demonstrates that loss of ATXN1-CIC complexes causes a spectrum of neurobehavioral phenotypes.

}, keywords = {Animals, Ataxin-1, Autism Spectrum Disorder, Cerebellum, Female, Humans, Intellectual Disability, Interpersonal Relations, Male, Mice, Nerve Tissue Proteins, Neurodegenerative Diseases, Nuclear Proteins, Phenotype, Repressor Proteins}, issn = {1546-1718}, doi = {10.1038/ng.3808}, author = {Lu, Hsiang-Chih and Tan, Qiumin and Rousseaux, Maxime W C and Wang, Wei and Kim, Ji-Yoen and Richman, Ronald and Wan, Ying-Wooi and Yeh, Szu-Ying and Patel, Jay M and Liu, Xiuyun and Lin, Tao and Lee, Yoontae and Fryer, John D and Han, Jing and Chahrour, Maria and Finnell, Richard H and Lei, Yunping and Zurita-Jimenez, Maria E and Ahimaz, Priyanka and Anyane-Yeboa, Kwame and Van Maldergem, Lionel and Lehalle, Daphne and Jean-Marcais, Nolwenn and Mosca-Boidron, Anne-Laure and Thevenon, Julien and Cousin, Margot A and Bro, Della E and Lanpher, Brendan C and Klee, Eric W and Alexander, Nora and Bainbridge, Matthew N and Orr, Harry T and Sillitoe, Roy V and Ljungberg, M Cecilia and Liu, Zhandong and Schaaf, Christian P and Zoghbi, Huda Y} }