@article {99, title = {Cell type-specific genetic regulation of gene expression across human tissues.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci in cis (QTLs) for the majority of genes across a wide range of human tissues. However, the functional characterization of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. We mapped interactions between computational estimates of cell type abundance and genotype to identify cell type-interaction QTLs for seven cell types and show that cell type-interaction expression QTLs (eQTLs) provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations with 87 complex traits show a contribution from cell type-interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue.

}, keywords = {Cells, Gene Expression Regulation, Humans, Organ Specificity, Quantitative Trait Loci, RNA, Long Noncoding, Transcriptome}, issn = {1095-9203}, doi = {10.1126/science.aaz8528}, author = {Kim-Hellmuth, Sarah and Aguet, Fran{\c c}ois and Oliva, Meritxell and Mu{\~n}oz-Aguirre, Manuel and Kasela, Silva and Wucher, Valentin and Castel, Stephane E and Hamel, Andrew R and Vi{\~n}uela, Ana and Roberts, Amy L and Mangul, Serghei and Wen, Xiaoquan and Wang, Gao and Barbeira, Alvaro N and Garrido-Mart{\'\i}n, Diego and Nadel, Brian B and Zou, Yuxin and Bonazzola, Rodrigo and Quan, Jie and Brown, Andrew and Martinez-Perez, Angel and Soria, Jos{\'e} Manuel and Getz, Gad and Dermitzakis, Emmanouil T and Small, Kerrin S and Stephens, Matthew and Xi, Hualin S and Im, Hae Kyung and Guigo, Roderic and Segr{\`e}, Ayellet V and Stranger, Barbara E and Ardlie, Kristin G and Lappalainen, Tuuli} } @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 {111, title = {Evaluation of the VISAGE Basic Tool for Appearance and Ancestry Prediction Using PowerSeq Chemistry on the MiSeq FGx System.}, journal = {Genes (Basel)}, volume = {11}, year = {2020}, month = {2020 06 26}, abstract = {

The study of DNA to predict externally visible characteristics (EVCs) and the biogeographical ancestry (BGA) from unknown samples is gaining relevance in forensic genetics. Technical developments in Massively Parallel Sequencing (MPS) enable the simultaneous analysis of hundreds of DNA markers, which improves successful Forensic DNA Phenotyping (FDP). The EU-funded VISAGE (VISible Attributes through GEnomics) Consortium has developed various targeted MPS-based lab tools to apply FDP in routine forensic analyses. Here, we present an evaluation of the VISAGE Basic tool for appearance and ancestry prediction based on PowerSeq chemistry (Promega) on a MiSeq FGx System (Illumina). The panel consists of 153 single nucleotide polymorphisms (SNPs) that provide information about EVCs (41 SNPs for eye, hair and skin color from HIrisPlex-S) and continental BGA (115 SNPs; three overlap with the EVCs SNP set). The assay was evaluated for sensitivity, repeatability and genotyping concordance, as well as its performance with casework-type samples. This targeted MPS assay provided complete genotypes at all 153 SNPs down to 125 pg of input DNA and 99.67\% correct genotypes at 50 pg. It was robust in terms of repeatability and concordance and provided useful results with casework-type samples. The results suggest that this MPS assay is a useful tool for basic appearance and ancestry prediction in forensic genetics for users interested in applying PowerSeq chemistry and MiSeq for this purpose.

}, keywords = {DNA Fingerprinting, Eye Color, Forensic Genetics, Genetic Markers, Genotype, Hair Color, High-Throughput Nucleotide Sequencing, Humans, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Skin Pigmentation, Software}, issn = {2073-4425}, doi = {10.3390/genes11060708}, author = {Palencia-Madrid, Leire and Xavier, Catarina and de la Puente, Mar{\'\i}a and Hohoff, Carsten and Phillips, Christopher and Kayser, Manfred and Parson, Walther} } @article {137, title = {Forensic evaluation of the Asia Pacific ancestry-informative MAPlex assay.}, journal = {Forensic Sci Int Genet}, volume = {48}, year = {2020}, month = {2020 09}, pages = {102344}, abstract = {

DNA intelligence, and particularly the inference of biogeographical ancestry (BGA) is increasing in interest, and relevance within the forensic genetics community. The majority of current MPS-based forensic ancestry-informative assays focus on the differentiation of major global populations. The recently published MAPlex (Multiplex for the Asia Pacific) panel contains 144 SNPs and 20 microhaplotypes and aims to improve the differentiation of populations in the Asia Pacific region. This study reports the first forensic evaluation of the MAPlex panel using AmpliSeq technology and Ion S5 sequencing. This study reports on the overall performance of MAPlex including the assay{\textquoteright}s sequence coverage distribution and stability, baseline noise and description of problematic SNPs. Dilution series, artificially degraded and mixed DNA samples were also analysed to evaluate the sensitivity of the panel with challenging or compromised forensic samples. As the first panel to combine biallelic SNPs, multiple-allele SNPs and microhaplotypes, the MAPlex assay demonstrated an enhanced capacity for mixture detection, not easily performed with common binary SNPs. This performance evaluation indicates that MAPlex is a robust, stable and highly sensitive assay that is applicable to forensic casework for the prediction of BGA.

}, issn = {1878-0326}, doi = {10.1016/j.fsigen.2020.102344}, author = {Xavier, C and de la Puente, M and Phillips, C and Eduardoff, M and Heidegger, A and Mosquera-Miguel, A and Freire-Aradas, A and Lagace, R and Wootton, S and Power, D and Parson, W and Lareu, M V and Daniel, R} } @article {93, title = {Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.}, journal = {Cell}, volume = {180}, year = {2020}, month = {2020 02 06}, pages = {568-584.e23}, abstract = {

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n~= 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

}, keywords = {Autistic Disorder, Case-Control Studies, Cell Lineage, Cerebral Cortex, Cohort Studies, Exome, Female, Gene Expression Regulation, Developmental, Gene Frequency, Genetic Predisposition to Disease, Humans, Male, Mutation, Missense, Neurobiology, Neurons, Phenotype, Sex Factors, Single-Cell Analysis, Whole Exome Sequencing}, issn = {1097-4172}, doi = {10.1016/j.cell.2019.12.036}, author = {Satterstrom, F Kyle and Kosmicki, Jack A and Wang, Jiebiao and Breen, Michael S and De Rubeis, Silvia and An, Joon-Yong and Peng, Minshi and Collins, Ryan and Grove, Jakob and Klei, Lambertus and Stevens, Christine and Reichert, Jennifer and Mulhern, Maureen S and Artomov, Mykyta and Gerges, Sherif and Sheppard, Brooke and Xu, Xinyi and Bhaduri, Aparna and Norman, Utku and Brand, Harrison and Schwartz, Grace and Nguyen, Rachel and Guerrero, Elizabeth E and Dias, Caroline and Betancur, Catalina and Cook, Edwin H and Gallagher, Louise and Gill, Michael and Sutcliffe, James S and Thurm, Audrey and Zwick, Michael E and B{\o}rglum, Anders D and State, Matthew W and Cicek, A Ercument and Talkowski, Michael E and Cutler, David J and Devlin, Bernie and Sanders, Stephan J and Roeder, Kathryn and Daly, Mark J and Buxbaum, Joseph D} } @article {118, title = {Lung Function in African American Children with Asthma Is Associated with Novel Regulatory Variants of the KIT Ligand and Gene-By-Air-Pollution Interaction.}, journal = {Genetics}, volume = {215}, year = {2020}, month = {2020 07}, pages = {869-886}, abstract = {

Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV), is a standard diagnostic criterion used by clinicians to identify and classify lung diseases. Using whole-genome sequencing data from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine project, we identified a novel genetic association with FEV on chromosome 12 in 867 African American children with asthma ( = 1.26 {\texttimes} 10, β = 0.302). Conditional analysis within 1 Mb of the tag signal (rs73429450) yielded one major and two other weaker independent signals within this peak. We explored statistical and functional evidence for all variants in linkage disequilibrium with the three independent signals and yielded nine variants as the most likely candidates responsible for the association with FEV Hi-C data and expression QTL analysis demonstrated that these variants physically interacted with (KIT ligand, also known as ), and their minor alleles were associated with increased expression of the gene in nasal epithelial cells. Gene-by-air-pollution interaction analysis found that the candidate variant rs58475486 interacted with past-year ambient sulfur dioxide exposure ( = 0.003, β = 0.32). This study identified a novel protective genetic association with FEV, possibly mediated through , in African American children with asthma. This is the first study that has identified a genetic association between lung function and , which has established a role in orchestrating allergic inflammation in asthma.

}, issn = {1943-2631}, doi = {10.1534/genetics.120.303231}, author = {Mak, Angel C Y and Sajuthi, Satria and Joo, Jaehyun and Xiao, Shujie and Sleiman, Patrick M and White, Marquitta J and Lee, Eunice Y and Saef, Benjamin and Hu, Donglei and Gui, Hongsheng and Keys, Kevin L and Lurmann, Fred and Jain, Deepti and Abecasis, Gon{\c c}alo and Kang, Hyun Min and Nickerson, Deborah A and Germer, Soren and Zody, Michael C and Winterkorn, Lara and Reeves, Catherine and Huntsman, Scott and Eng, Celeste and Salazar, Sandra and Oh, Sam S and Gilliland, Frank D and Chen, Zhanghua and Kumar, Rajesh and Mart{\'\i}nez, Fernando D and Wu, Ann Chen and Ziv, Elad and Hakonarson, Hakon and Himes, Blanca E and Williams, L Keoki and Seibold, Max A and Burchard, Esteban G} } @article {47, title = {Cell type-specific CLIP reveals that NOVA regulates cytoskeleton interactions in motoneurons.}, journal = {Genome Biol}, volume = {19}, year = {2018}, month = {2018 08 15}, pages = {117}, abstract = {

BACKGROUND: Alternative RNA processing plays an essential role in shaping cell identity and connectivity in the central nervous system. This is believed to involve differential regulation of RNA processing in various cell types. However, in vivo study of cell type-specific post-transcriptional regulation has been a challenge. Here, we describe a sensitive and stringent method combining genetics and CLIP (crosslinking and immunoprecipitation) to globally identify regulatory interactions between NOVA and RNA in the mouse spinal cord motoneurons.

RESULTS: We developed a means of undertaking motoneuron-specific CLIP to explore motoneuron-specific protein-RNA interactions relative to studies of the whole spinal cord in mouse. This allowed us to pinpoint differential RNA regulation specific to motoneurons, revealing a major role for NOVA in regulating cytoskeleton interactions in motoneurons. In particular, NOVA specifically promotes the palmitoylated isoform of the cytoskeleton protein Septin 8 in motoneurons, which enhances dendritic arborization.

CONCLUSIONS: Our study demonstrates that cell type-specific RNA regulation is important for fine tuning motoneuron physiology and highlights the value of defining RNA processing regulation at single cell type resolution.

}, keywords = {Alternative Splicing, Amino Acid Sequence, Animals, Cercopithecus aethiops, Chromosomes, Artificial, Bacterial, COS Cells, Cross-Linking Reagents, Cytoskeleton, Dendrites, Exons, Immunoprecipitation, Lipoylation, Mice, Mice, Transgenic, Motor Neurons, Nerve Tissue Proteins, NIH 3T3 Cells, Pseudopodia, RNA, RNA-Binding Proteins, Septins, Transcriptome}, issn = {1474-760X}, doi = {10.1186/s13059-018-1493-2}, author = {Yuan, Yuan and Xie, Shirley and Darnell, Jennifer C and Darnell, Andrew J and Saito, Yuhki and Phatnani, Hemali and Murphy, Elisabeth A and Zhang, Chaolin and Maniatis, Tom and Darnell, Robert B} } @article {45, title = {Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 10 02}, pages = {4038}, abstract = {

Hundreds of thousands of human whole genome sequencing (WGS) datasets will be generated over the next few years. These data are more valuable in aggregate: joint analysis of genomes from many sources increases sample size and statistical power. A central challenge for joint analysis is that different WGS data processing pipelines cause substantial differences in variant calling in combined datasets, necessitating computationally expensive reprocessing. This approach is no longer tenable given the scale of current studies and data volumes. Here, we define WGS data processing standards that allow different groups to produce functionally equivalent (FE) results, yet still innovate on data processing pipelines. We present initial FE pipelines developed at five genome centers and show that they yield similar variant calling results and produce significantly less variability than sequencing replicates. This work alleviates a key technical bottleneck for genome aggregation and helps lay the foundation for community-wide human genetics studies.

}, keywords = {Genome, Human, Human Genetics, Humans, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-018-06159-4}, author = {Regier, Allison A and Farjoun, Yossi and Larson, David E and Krasheninina, Olga and Kang, Hyun Min and Howrigan, Daniel P and Chen, Bo-Juen and Kher, Manisha and Banks, Eric and Ames, Darren C and English, Adam C and Li, Heng and Xing, Jinchuan and Zhang, Yeting and Matise, Tara and Abecasis, Goncalo R and Salerno, Will and Zody, Michael C and Neale, Benjamin M and Hall, Ira M} } @article {48, title = {The phenotypic spectrum of Xia-Gibbs syndrome.}, journal = {Am J Med Genet A}, volume = {176}, year = {2018}, month = {2018 06}, pages = {1315-1326}, abstract = {

Xia-Gibbs syndrome (XGS: OMIM $\#$ 615829) results from de novo truncating mutations within the AT-Hook DNA Binding Motif Containing 1 gene (AHDC1). To further define the phenotypic and molecular spectrum of this disorder, we established an XGS Registry and recruited patients from a worldwide pool of approximately 60 probands. Additional de novo truncating mutations were observed among 25 individuals, extending both the known number of mutation sites and the range of positions within the coding region that were sensitive to alteration. Detailed phenotypic examination of 20 of these patients via clinical records review and data collection from additional surveys showed a wider age range than previously described. Data from developmental milestones showed evidence for delayed speech and that males were more severely affected. Neuroimaging from six available patients showed an associated thinning of the corpus callosum and posterior fossa cysts. An increased risk of both scoliosis and seizures relative to the population burden was also observed. Data from a modified autism screening tool revealed that XGS shares significant overlap with autism spectrum disorders. These details of the phenotypic heterogeneity of XGS implicate specific genotype/phenotype correlations and suggest potential clinical management guidelines.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38699}, author = {Jiang, Yunyun and Wangler, Michael F and McGuire, Amy L and Lupski, James R and Posey, Jennifer E and Khayat, Michael M and Murdock, David R and Sanchez-Pulido, Luis and Ponting, Chris P and Xia, Fan and Hunter, Jill V and Meng, Qingchang and Murugan, Mullai and Gibbs, Richard A} } @article {9, title = {Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation.}, journal = {N Engl J Med}, volume = {376}, year = {2017}, month = {2017 Jan 05}, pages = {21-31}, abstract = {

BACKGROUND: Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes.

METHODS: We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology.

RESULTS: A molecular diagnosis was rendered for 2076 of 7374 patients (28.2\%); among these patients, 101 (4.9\%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8\% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7\% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7\% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9\%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P=1.77{\texttimes}10).

CONCLUSIONS: In our study, we found multiple molecular diagnoses in 4.9\% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.).

}, keywords = {Exome, Genetic Diseases, Inborn, Genetic Variation, Genotyping Techniques, High-Throughput Nucleotide Sequencing, Humans, Phenotype, Retrospective Studies, Sequence Analysis, DNA}, issn = {1533-4406}, doi = {10.1056/NEJMoa1516767}, author = {Posey, Jennifer E and Harel, Tamar and Liu, Pengfei and Rosenfeld, Jill A and James, Regis A and Coban Akdemir, Zeynep H and Walkiewicz, Magdalena and Bi, Weimin and Xiao, Rui and Ding, Yan and Xia, Fan and Beaudet, Arthur L and Muzny, Donna M and Gibbs, Richard A and Boerwinkle, Eric and Eng, Christine M and Sutton, V Reid and Shaw, Chad A and Plon, Sharon E and Yang, Yaping and Lupski, James R} }