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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 62,745 bioRxiv papers from 278,406 authors.

Most downloaded bioRxiv papers, since beginning of last month

in category genetics

3,479 results found. For more information, click each entry to expand.

1: The GTEx Consortium atlas of genetic regulatory effects across human tissues
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Posted to bioRxiv 03 Oct 2019

The GTEx Consortium atlas of genetic regulatory effects across human tissues
2,250 downloads genetics

Francois Aguet, Alvaro N Barbeira, Rodrigo Bonazzola, Andrew Brown, Stephane E Castel, Brian Jo, Silva Kasela, Sarah Kim-Hellmuth, Yanyu Liang, Meritxell Oliva, Princy E Parsana, Elise Flynn, Laure Fresard, Eric R Gaamzon, Andrew R Hamel, Yuan He, Farhad Hormozdiari, Pejman Mohammadi, Manuel Muñoz-Aguirre, YoSon Park, Ashis Saha, Ayellet V Segrć, Benjamin J. Strober, Xiaoquan Wen, Valentin Wucher, Sayantan Das, Diego Garrido-Martín, Nicole R Gay, Robert E Handsaker, Paul J. Hoffman, Seva Kashin, Alan Kwong, Xiao Li, Daniel MacArthur, John M Rouhana, Matthew Stephens, Ellen Todres, Ana Viñuela, Gao Wang, Yuxin Zou, The GTEx Consortium, Christopher D Brown, Nancy Cox, Emmanouil Dermitzakis, Barbara E Engelhardt, Gad Getz, Roderic Guigo, Stephen B. Montgomery, Barbara E. Stranger, Hae Kyung Im, Alexis Battle, Kristin Ardlie, Tuuli Lappalainen

The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues, and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue-specificity of genetic effects, and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.

2: Genetic “General Intelligence,” Objectively Determined and Measured
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Posted to bioRxiv

Genetic “General Intelligence,” Objectively Determined and Measured
1,176 downloads genetics

Javier de la Fuente, Gail Davies, Andrew D Grotzinger, Elliot M Tucker-Drob, Ian J Deary

It has been known for 115 years that, in humans, diverse cognitive traits are positively intercorrelated; this forms the basis for the general factor of intelligence ( g ). We directly test for a genetic basis for g using data from seven different cognitive tests (N = 11,263 to N = 331,679) and genome-wide autosomal single nucleotide polymorphisms. A genetic g factor accounts for 58.4% (SE = 4.8%) of the genetic variance in the cognitive traits, with trait-specific genetic factors accounting for the remaining 41.6%. We distill genetic loci broadly relevant for many cognitive traits ( g ) from loci associated with only individual cognitive traits. These results elucidate the etiological basis for a long-known yet poorly-understood phenomenon, revealing a fundamental dimension of genetic sharing across diverse cognitive traits.

3: Long non-coding RNA gene regulation and trait associations across human tissues
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Posted to bioRxiv 04 Oct 2019

Long non-coding RNA gene regulation and trait associations across human tissues
1,109 downloads genetics

Olivia M. de Goede, Nicole M. Ferraro, Daniel C. Nachun, Abhiram Rao, François Aguet, Alvaro N Barbeira, Stephane E Castel, Sarah Kim-Hellmuth, YoSon Park, Alexandra J Scott, Benjamin J. Strober, GTEx Consortium, Christopher D Brown, Xiaoquan Wen, Ira M Hall, Alexis Battle, Tuuli Lappalainen, Hae Kyung Im, Kristin G Ardlie, Thomas Quertermous, Karla Kirkegaard, Stephen B. Montgomery

Long non-coding RNA (lncRNA) genes are known to have diverse impacts on gene regulation. However, it is still a major challenge to distinguish functional lncRNAs from those that are byproducts of surrounding transcriptional activity. To systematically identify hallmarks of biological function, we used the GTEx v8 data to profile the expression, regulation, network relationships and trait associations of lncRNA genes across 49 tissues encompassing 87 distinct traits. In addition to revealing widespread differences in regulatory patterns between lncRNA and protein-coding genes, we identified novel disease-associated lncRNAs, such as C6orf3 for psoriasis and LINC01475/RP11-129J12.1 for ulcerative colitis. This work provides a comprehensive resource to interrogate lncRNA genes of interest and annotate cell type and human trait relevance.

4: Population genomics of the Viking world
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Posted to bioRxiv 17 Jul 2019

Population genomics of the Viking world
706 downloads genetics

Ashot Margaryan, Daniel Lawson, Martin Sikora, Fernando Racimo, Simon Rasmussen, Ida Moltke, Lara Cassidy, Emil Jørsboe, Andrés Ingason, Mikkel Pedersen, Thorfinn Korneliussen, Helene Wilhelmson, Magdalena Buś, Peter de Barros Damgaard, Rui Martiniano, Gabriel Renaud, Claude Bhérer, J. Víctor Moreno-Mayar, Anna Fotakis, Marie Allen, Martyna Molak, Enrico Cappellini, Gabriele Scorrano, Alexandra Buzhilova, Allison Fox, Anders Albrechtsen, Berit Schütz, Birgitte Skar, Caroline Arcini, Ceri Falys, Charlotte Hedenstierna Jonson, Dariusz Błaszczyk, Denis Pezhemsky, Gordon Turner-Walker, Hildur Gestsdóttir, Inge Lundstrøm, Ingrid Gustin, Ingrid Mainland, Inna Potekhina, Italo Muntoni, Jade Cheng, Jesper Stenderup, Jilong Ma, Julie Gibson, Jüri Peets, Jörgen Gustafsson, Katrine Iversen, Linzi Simpson, Lisa Strand, Louise Loe, Maeve Sikora, Marek Florek, Maria Vretemark, Mark Redknap, Monika Bajka, Tamara Pushkina, Morten Søvsø, Natalia Grigoreva, Tom Christensen, Ole Kastholm, Otto Uldum, Pasquale Favia, Per Holck, Raili Allmäe, Sabine Sten, Símun Arge, Sturla Ellingvåg, Vayacheslav Moiseyev, Wiesław Bogdanowicz, Yvonne Magnusson, Ludovic Orlando, Daniel Bradley, Marie Louise Jørkov, Jette Arneborg, Niels Lynnerup, Neil Price, M. Thomas Gilbert, Morten Allentoft, Jan Bill, Søren Sindbæk, Lotte Hedeager, Kristian Kristiansen, Rasmus Nielsen, Thomas Werge, Eske Willerslev

The Viking maritime expansion from Scandinavia (Denmark, Norway, and Sweden) marks one of the swiftest and most far-flung cultural transformations in global history. During this time (c. 750 to 1050 CE), the Vikings reached most of western Eurasia, Greenland, and North America, and left a cultural legacy that persists till today. To understand the genetic structure and influence of the Viking expansion, we sequenced the genomes of 442 ancient humans from across Europe and Greenland ranging from the Bronze Age (c. 2400 BC) to the early Modern period (c. 1600 CE), with particular emphasis on the Viking Age. We find that the period preceding the Viking Age was accompanied by foreign gene flow into Scandinavia from the south and east: spreading from Denmark and eastern Sweden to the rest of Scandinavia. Despite the close linguistic similarities of modern Scandinavian languages, we observe genetic structure within Scandinavia, suggesting that regional population differences were already present 1,000 years ago. We find evidence for a majority of Danish Viking presence in England, Swedish Viking presence in the Baltic, and Norwegian Viking presence in Ireland, Iceland, and Greenland. Additionally, we see substantial foreign European ancestry entering Scandinavia during the Viking Age. We also find that several of the members of the only archaeologically well-attested Viking expedition were close family members. By comparing Viking Scandinavian genomes with present-day Scandinavian genomes, we find that pigmentation-associated loci have undergone strong population differentiation during the last millennia. Finally, we are able to trace the allele frequency dynamics of positively selected loci with unprecedented detail, including the lactase persistence allele and various alleles associated with the immune response. We conclude that the Viking diaspora was characterized by substantial foreign engagement: distinct Viking populations influenced the genomic makeup of different regions of Europe, while Scandinavia also experienced increased contact with the rest of the continent.

5: Y-chromosome haplogroups from Hun, Avar and conquering Hungarian period nomadic people of the Carpathian Basin
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Posted to bioRxiv 03 Apr 2019

Y-chromosome haplogroups from Hun, Avar and conquering Hungarian period nomadic people of the Carpathian Basin
596 downloads genetics

Endre Neparaczki, Zoltán Maróti, Tibor Kalmár, Kitti Maár, István Nagy, Dóra Latinovics, Ágnes Kustár, György Pálfi, Erika Molnár, Antónia Marcsik, Csilla Balogh, Gábor Lőrinczy, Szilárd Sándor Gál, Péter Tomka, Bernadett Kovacsóczy, László Kovács, István Raskó, Tibor Török

Hun, Avar and conquering Hungarian nomadic groups arrived into the Carpathian Basin from the Eurasian Steppes and significantly influenced its political and ethnical landscape. In order to shed light on the genetic affinity of above groups we have determined Y chromosomal haplogroups and autosomal loci, from 49 individuals, supposed to represent military leaders. Haplogroups from the Hun-age are consistent with Xiongnu ancestry of European Huns. Most of the Avar-age individuals carry east Eurasian Y haplogroups typical for modern north-eastern Siberian and Buryat populations and their autosomal loci indicate mostly unmixed Asian characteristics. In contrast the conquering Hungarians seem to be a recently assembled population incorporating pure European, Asian and admixed components. Their heterogeneous paternal and maternal lineages indicate similar phylogeographic origin of males and females, derived from Central-Inner Asian and European Pontic Steppe sources. Composition of conquering Hungarian paternal lineages is very similar to that of Baskhirs, supporting historical sources that report identity of the two groups.

6: The genetic landscape of Ethiopia: diversity, intermixing and the association with culture
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Posted to bioRxiv 05 Sep 2019

The genetic landscape of Ethiopia: diversity, intermixing and the association with culture
582 downloads genetics

Saioa Lopez, Ayele Tarekegn, Gavin Band, Lucy van Dorp, Tamiru Oljira, Ephrem Mekonnen, Endashaw Bekele, Roger Blench, Mark G. Thomas, Garrett Hellenthal

The rich linguistic, ethnic and cultural diversity of Ethiopia provides an unprecedented opportunity to understand the level to which cultural factors correlate with -- and shape -- genetic structure in human populations. Using primarily novel genetic variation data covering 1,268 Ethiopians representing 68 different ethnic groups, together with information on individuals' birthplaces, linguistic/religious practices and 31 cultural practices, we disentangle the effects of geographic distance, elevation, and social factors upon shaping the genetic structure of Ethiopians today. We provide examples of how social behaviours have directly -- and strongly -- increased genetic differences among present-day peoples. We also show the fluidity of intermixing across linguistic and religious groups. We identify correlations between cultural and genetic patterns that likely indicate a degree of social selection involving recent intermixing among individuals that have certain practices in common. In addition to providing insights into the genetic structure and history of Ethiopia, including how they correlate with current linguistic classifications, these results identify the most important cultural and geographic proxies for genetic differentiation and provide a resource for designing sampling protocols for future genetic studies involving Ethiopians.

7: Optimization of AsCas12a for combinatorial genetic screens in human cells
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Posted to bioRxiv 28 Aug 2019

Optimization of AsCas12a for combinatorial genetic screens in human cells
573 downloads genetics

Kendall R Sanson, Peter C DeWeirdt, Annabel K Sangree, Ruth E Hanna, Mudra Hegde, Teng Teng, Samantha M Borys, Christine Strand, J. Keith Joung, Benjamin P. Kleinstiver, Xuewen Pan, Alan Huang, John G. Doench

Cas12a enzymes have attractive properties for scalable delivery of multiplexed perturbations, yet widespread usage has lagged behind Cas9-based strategies. Here we describe the optimization of Cas12a from Acidaminococcus (AsCas12a) for use in pooled genetic screens in human cells. By assaying the activity of thousands of guides, we confirm on-target design rules and extend them to an enhanced activity variant, enAsCas12a. We also develop the first comprehensive set of off-target rules for Cas12a, and demonstrate that we can predict and exclude promiscuous guides. Finally, to enable efficient higher-order multiplexing via lentiviral delivery, we screen thousands of direct repeat variants and identify 38 that outperform the wildtype sequence. We validate this optimized AsCas12a toolkit by targeting 12 synthetic lethal gene pairs with up to 400 guide pairs each, and demonstrate effective triple knockout via flow cytometry. These results establish AsCas12a as a robust system for combinatorial applications of CRISPR technology.

8: ATP7B Variant c.1934T>G p.Met645Arg Causes Wilson Disease by Promoting Exon 6 Skipping
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Posted to bioRxiv 05 Jul 2019

ATP7B Variant c.1934T>G p.Met645Arg Causes Wilson Disease by Promoting Exon 6 Skipping
570 downloads genetics

Daniele Merico, Carl Spickett, Matthew O’Hara, Boyko Kakaradov, Amit G Deshwar, Phil Fradkin, Shreshth Gandhi, Jiexin Gao, Solomon Grant, Ken Kron, Frank W. Schmitges, Zvi Shalev, Mark Sun, Marta Verby, Matthew Cahill, James J Dowling, Johan Fransson, Erno Wienholds, Brendan J Frey

Wilson Disease is a recessive genetic disorder caused by pathogenic loss-of-function variants in the ATP7B gene. It is characterized by disrupted copper homeostasis resulting in liver disease and/or neurological abnormalities. The variant NM_000053.3:c.1934T>G (Met645Arg) has been reported as compound heterozygous and is highly prevalent among Wilson Disease patients of Spanish descent. Accordingly, it is classified as pathogenic by leading molecular diagnostic centers. However, functional studies suggest that the amino acid change does not alter protein function, leading one ClinVar submitter to question its pathogenicity. Here we used a minigene system and gene-edited HepG2 cells to demonstrate that c.1934T>G causes approximately 70% skipping of exon 6. Exon 6 skipping results in frameshift and stop gain, which is expected to cause loss of ATP7B function. The elucidation of the mechanistic effect for this variant resolves any doubt about its pathogenicity and enables the development of genetic medicines for restoring correct splicing.

9: Localization of a feline autosomal dominant dwarfism locus: a novel model of chondrodysplasia
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Posted to bioRxiv 08 Jul 2019

Localization of a feline autosomal dominant dwarfism locus: a novel model of chondrodysplasia
564 downloads genetics

L.A. Lyons, D.B. Fox, K.L. Chesney, L.G. Britt, R.M. Buckley, J.R. Coates, B. Gandolfi, R.A. Grahn, M.J. Hamilton, J.R. Middleton, S.T. Sellers, N.A. Villani, S. Pfleuger, the 99 Lives Consortium

Despite the contribution of a few major genes for disproportionate dwarfism in humans, many dwarf patients are yet genetically undiagnosed. In domestic cats, disproportionate dwarfism has led to the development of a defined breed, the Munchkin or Minuet. This study examined the genetic aspects of feline dwarfism to consider cats as a new biomedical model. DNA from dwarf cats was genetically analyzed using parentage, linkage, and genome-wide association studies as well as whole genome sequencing. Each genetic approach localized the dwarfism phenotype to a region on cat chromosome B1. No coding variants suspected as causal for the feline dwarfism were identified but a critical region of ~5.7 Mb from B1:170,278,183-175,975,857 was defined, which implicates a novel gene controlling disproportionate dwarfism. A yet unidentified but novel gene variant, likely structural or regulatory, produces disproportionate dwarfism in cats, which may define undiagnosed human patients.

10: Expanding Parkinson's disease genetics: novel risk loci, genomic context, causal insights and heritable risk.
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Posted to bioRxiv 09 Aug 2018

Expanding Parkinson's disease genetics: novel risk loci, genomic context, causal insights and heritable risk.
534 downloads genetics

Mike A Nalls, Cornelis Blauwendraat, Costanza L. Vallerga, Karl Heilbron, Sara Bandres-Ciga, Diana Chang, Manuela Tan, Demis A Kia, Alastair J. Noyce, Angli Xue, Jose Bras, Emily Young, Rainer von Coelln, Javier Simón-Sánchez, Claudia Schulte, Manu Sharma, Lynne Krohn, Lasse Pihlstrom, Ari Siitonen, Hirotaka Iwaki, Hampton Leonard, Faraz Faghri, J. Raphael Gibbs, Dena G. Hernandez, Sonja W Scholz, Juan A Botia, Maria Martinez, Jean-Christophe Corvol, Suzanne Lesage, Joseph Jankovic, Lisa M. Shulman, The 23andMe Research Team, System Genomics of Parkinson’s Disease (SGPD) Consortium, Margaret Sutherland, Pentti Tienari, Kari Majamaa, Mathias Toft, Ole A Andreassen, Tushar Bangale, Alexis Brice, Jian Yang, Ziv Gan-Or, Thomas Gasser, Peter Heutink, Joshua M Shulman, Nicolas Wood, David A. Hinds, John A. Hardy, Huw R Morris, Jacob Gratten, Peter M. Visscher, Robert R Graham, Andrew B. Singleton, for the International Parkinson’s Disease Genomics Consortium

We performed the largest genome-wide association study of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls. We identified 90 independent genome-wide significant signals across 78 loci, including 38 independent risk signals in 37 novel loci. These variants explained 26-36% of the heritable risk of PD. Tests of causality within a Mendelian randomization framework identified putatively causal genes for 70 risk signals. Tissue expression enrichment analysis suggested that signatures of PD loci were heavily brain-enriched, consistent with specific neuronal cell types being implicated from single cell expression data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. In sum, these data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified.

11: Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism
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Posted to bioRxiv 30 Nov 2018

Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism
512 downloads genetics

F. Kyle Satterstrom, Jack A. Kosmicki, Jiebiao Wang, Michael S. Breen, Silvia De Rubeis, Joon-Yong An, Minshi Peng, Ryan Collins, Jakob Grove, Lambertus Klei, Christine Stevens, Jennifer Reichert, Maureen S. Mulhern, Mykyta Artomov, Sherif Gerges, Brooke Sheppard, Xinyi Xu, Aparna Bhaduri, Utku Norman, Harrison Brand, Grace Schwartz, Rachel Nguyen, Elizabeth E. Guerrero, Caroline Dias, Branko Aleksic, Richard Anney, Mafalda Barbosa, Somer Bishop, Alfredo Brusco, Jonas Bybjerg-Grauholm, Angel Carracedo, Marcus C.Y. Chan, Andreas G. Chiocchetti, Brian H. Y. Chung, Hilary Coon, Michael L. Cuccaro, Aurora Currò, Bernardo Dalla Bernardina, Ryan Doan, Enrico Domenici, Shan Dong, Chiara Fallerini, Montserrat Fernández-Prieto, Giovanni Battista Ferrero, Christine M. Freitag, Menachem Fromer, J. Jay Gargus, Daniel Geschwind, Elisa Giorgio, Javier González-Peñas, Stephen Guter, Danielle Halpern, Emily Hansen-Kiss, Xin He, Gail E. Herman, Irva Hertz-Picciotto, David M Hougaard, Christina M Hultman, Iuliana Ionita-Laza, Suma Jacob, Jesslyn Jamison, Astanand Jugessur, Miia Kaartinen, Gun Peggy Knudsen, Alexander Kolevzon, Itaru Kushima, So Lun Lee, Terho Lehtimäki, Elaine T Lim, Carla Lintas, W. Ian Lipkin, Diego Lopergolo, Fátima Lopes, Yunin Ludena, Patricia Maciel, Per Magnus, Behrang Mahjani, Nell Maltman, Dara S Manoach, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Eduarda Montenegro M. de Souza, Danielle Moreira, Eric M Morrow, Ole Mors, Preben Bo Mortensen, Matthew Mosconi, Pierandrea Muglia, Benjamin Neale, Merete Nordentoft, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Margaret Pericak-Vance, Antonio Persico, Isaac Pessah, Kaija Puura, Abraham Reichenberg, Alessandra Renieri, Evelise Riberi, Elise B Robinson, Kaitlin E. Samocha, Sven Sandin, Susan L Santangelo, Gerry Schellenberg, Stephen W Scherer, Sabine Schlitt, Rebecca Schmidt, Lauren Schmitt, Isabela Maya W. Silva, Tarjinder Singh, Paige M. Siper, Moyra Smith, Gabriela Soares, Camilla Stoltenberg, Pål Suren, Ezra Susser, John Sweeney, Peter Szatmari, Lara Tang, Flora Tassone, Karoline Teufel, Elisabetta Trabetti, Maria del Pilar Trelles, Christopher Walsh, Lauren A. Weiss, Thomas Werge, Donna Werling, Emilie M. Wigdor, Emma Wilkinson, Jeremy A Willsey, Tim Yu, Mullin H.C. Yu, Ryan Yuen, Elaine Zachi, iPSYCH consortium, Catalina Betancur, Edwin H. Cook, Louise Gallagher, Michael Gill, James S Sutcliffe, Audrey Thurm, Michael E. Zwick, Anders D. Børglum, Matthew W State, A. Ercument Cicek, Michael E. Talkowski, David J. Cutler, Bernie Devlin, Stephan Sanders, Kathryn Roeder, Mark J. Daly, Joseph D. Buxbaum

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 Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the 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 human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

12: Complement component 4 genes contribute sex-specific vulnerability in diverse illnesses
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Posted to bioRxiv 09 Sep 2019

Complement component 4 genes contribute sex-specific vulnerability in diverse illnesses
431 downloads genetics

Nolan Kamitaki, Aswin Sekar, Robert E Handsaker, Heather de Rivera, Katherine Tooley, David L. Morris, Kimberly E. Taylor, Christopher W Whelan, Philip Tombleson, Loes M Olde Loohuis, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Michael Boehnke, Robert P. Kimberly, Kenneth M. Kaufman, John B. Harley, Carl D. Langefeld, Christine E. Seidman, Michele T Pato, Carlos N Pato, Roel A. Ophoff, Robert R Graham, Lindsey A. Criswell, Timothy J. Vyse, Steven A McCarroll

Many common illnesses differentially affect men and women for unknown reasons. The autoimmune diseases lupus and Sjögren's syndrome affect nine times more women than men1,2, whereas schizophrenia affects men more frequently and severely3-5. All three illnesses have their strongest common-genetic associations in the Major Histocompatibility Complex (MHC) locus, an association that in lupus and Sjögren's syndrome has long been thought to arise from HLA alleles6-13. Here we show that the complement component 4 ( C4 ) genes in the MHC locus, recently found to increase risk for schizophrenia14, generate 7-fold variation in risk for lupus (95% CI: 5.88-8.61; p < 10-117 in total) and 16-fold variation in risk for Sjögren's syndrome (95% CI: 8.59-30.89; p < 10-23 in total), with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia, greatly reduced risk for lupus and Sjögren's syndrome. In all three illnesses, C4 alleles acted more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for lupus and 31-fold variation in risk for Sjögren's syndrome in men (vs. 6-fold and 15-fold among women respectively) and affected schizophrenia risk about twice as strongly in men as in women. At a protein level, both C4 and its effector (C3) were present at greater levels in men than women in cerebrospinal fluid ( p < 10-5 for both C4 and C3) and plasma among adults ages 20-5015-17, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help explain the larger effects of C4 alleles in men, women's greater risk of SLE and Sjögren's, and men's greater vulnerability in schizophrenia. These results nominate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

13: A genome-wide genetic pleiotropy approach identified shared loci between multiple system atrophy and inflammatory bowel disease
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Posted to bioRxiv 31 Aug 2019

A genome-wide genetic pleiotropy approach identified shared loci between multiple system atrophy and inflammatory bowel disease
423 downloads genetics

Alexey A. Shadrin, Sören Mucha, David Ellinghaus, Mary B. Makarious, Cornelis Blauwendraat, Ashwin A Sreelatha, Antonio Heras-Garvin, Jinhui Ding, Monia Hammer, Alexandra Foubert-Samier, Wassilios G Meissner, Oliver Rascol, Anne Pavy-Le Traon, Oleksandr A Frei, Kevin S. O'Connell, Shahram Bahrami, Stefan Schreiber, Wolfgang Lieb, Martina Müller-Nuraysid, Andreas Arnold, Georg Homuth, Carsten O Schmidt, Markus Nöthen, Per Hoffmann, Christian Gieger, European Multiple System Atrophy Study Group, J. Raphael Gibbs, Andre Franke, John Hardy, Gregor Wenning, Nadia Stefanova, Thomas Gasser, Andrew Singleton, Henry Houlden, Sonja W Scholz, Ole A Andreassen, Manu Sharma

We aimed to identify shared genetic background between multiple system atrophy (MSA) and autoimmune diseases by using the conjFDR approach. Our study showed significant genetic overlap between MSA and inflammatory bowel disease and identified DENND1B, C7, and RSP04 loci, which are linked to significant changes in methylation or expression levels of adjacent genes. We obtained evidence of enriched heritability involving immune/digestive categories. Finally, an MSA mouse model showed dysregulation of the C7 gene in the degenerating midbrain compared to wildtype mice. The results identify novel molecular mechanisms and implicate immune and gut dysfunction in MSA pathophysiology.

14: Activity-by-Contact model of enhancer specificity from thousands of CRISPR perturbations
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Posted to bioRxiv 26 Jan 2019

Activity-by-Contact model of enhancer specificity from thousands of CRISPR perturbations
423 downloads genetics

Charles P Fulco, Joseph Nasser, Thouis R Jones, Glen Munson, Drew T Bergman, Vidya Subramanian, Sharon R Grossman, Rockwell Anyoha, Tejal A Patwardhan, Tung H Nguyen, Michael Kane, Benjamin Doughty, Elizabeth M. Perez, Neva C. Durand, Elena K Stamenova, Erez Lieberman Aiden, Eric S Lander, Jesse M Engreitz

Mammalian genomes harbor millions of noncoding elements called enhancers that quantitatively regulate gene expression, but it remains unclear which enhancers regulate which genes. Here we describe an experimental approach, based on CRISPR interference, RNA FISH, and flow cytometry (CRISPRi-FlowFISH), to perturb enhancers in the genome, and apply it to test >3,000 potential regulatory enhancer-gene connections across multiple genomic loci. A simple equation based on a mechanistic model for enhancer function performed remarkably well at predicting the complex patterns of regulatory connections we observe in our CRISPR dataset. This Activity-by-Contact (ABC) model involves multiplying measures of enhancer activity and enhancer-promoter 3D contacts, and can predict enhancer-gene connections in a given cell type based on chromatin state maps. Together, CRISPRi-FlowFISH and the ABC model provide a systematic approach to map and predict which enhancers regulate which genes, and will help to interpret the functions of the thousands of disease risk variants in the noncoding genome.

15: Bayesian analysis of GWAS summary data reveals differential signatures of natural selection across human complex traits and functional genomic categories
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Posted to bioRxiv 01 Sep 2019

Bayesian analysis of GWAS summary data reveals differential signatures of natural selection across human complex traits and functional genomic categories
420 downloads genetics

Jian Zeng, Angli Xue, Longda Jiang, Luke R Lloyd-Jones, Yang Wu, Huanwei Wang, Zhili Zheng, Loic Yengo, Kathryn E. Kemper, Michael E Goddard, Naomi R. Wray, Peter M. Visscher, Jian Yang

Understanding how natural selection has shaped the genetic architecture of complex traits and diseases is of importance in medical and evolutionary genetics. Bayesian methods have been developed using individual-level data to estimate multiple features of genetic architecture, including signatures of natural selection. Here, we present an enhanced method (SBayesS) that only requires GWAS summary statistics and incorporates functional genomic annotations. We analysed GWAS data with large sample sizes for 155 complex traits and detected pervasive signatures of negative selection with diverse estimates of SNP-based heritability and polygenicity. Projecting these estimates onto a map of genetic architecture obtained from evolutionary simulations revealed relatively strong natural selection on genetic variants associated with cardiorespiratory and cognitive traits and relatively small number of mutational targets for diseases. Averaging across traits, the joint distribution of SNP effect size and MAF varied across functional genomic regions (likely to be a consequence of natural selection), with enrichment in both the number of associated variants and the magnitude of effect sizes in regions such as transcriptional start sites, coding regions and 5'- and 3'-UTRs.

16: A large-scale resource for tissue-specific CRISPR mutagenesis in Drosophila
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Posted to bioRxiv 13 May 2019

A large-scale resource for tissue-specific CRISPR mutagenesis in Drosophila
416 downloads genetics

Fillip Port, Claudia Strein, Mona Stricker, Benedikt Rauscher, Florian Heigwer, Jun Zhou, Celine Beyersdörffer, Jana Frei, Amy Hess, Katharina Kern, Roberta Malamud, Bojana Pavlovic, Kristin Rädecke, Lukas Schmitt, Lukas Voos, Erica Valentini, Michael Boutros

Genetic screens are powerful tools for the functional annotation of genomes. In the context of multicellular organisms, interrogation of gene function is greatly facilitated by methods that allow spatial and temporal control of gene abrogation. Here, we describe a large-scale transgenic short guide (sg) RNA library for efficient CRISPR-based disruption of specific target genes in a constitutive or conditional manner. The library consists currently of more than 2600 plasmids and 1400 fly lines with a focus on targeting kinases, phosphatases and transcription factors, each expressing two sgRNAs under control of the Gal4/UAS system. We show that conditional CRISPR mutagenesis is robust across many target genes and can be efficiently employed in various somatic tissues, as well as the germline. In order to prevent artefacts commonly associated with excessive amounts of Cas9 protein, we have developed a series of novel UAS-Cas9 transgenes, which allow fine tuning of Cas9 expression to achieve high gene editing activity without detectable toxicity. Functional assays, as well as direct sequencing of genomic sgRNA target sites, indicates that the vast majority of transgenic sgRNA lines mediate efficient gene disruption. Furthermore, we conducted the so far largest fully transgenic CRISPR screen in any metazoan organism, which further supported the high efficiency and accuracy of our library and revealed many so far uncharacterized genes essential for development.

17: Variable prediction accuracy of polygenic scores within an ancestry group
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Posted to bioRxiv 07 May 2019

Variable prediction accuracy of polygenic scores within an ancestry group
392 downloads genetics

Hakhamanesh Mostafavi, Arbel Harpak, Dalton Conley, Jonathan K Pritchard, Molly Przeworski

Fields as diverse as human genetics and sociology are increasingly using polygenic scores based on genome-wide association studies (GWAS) for phenotypic prediction. However, recent work has shown that polygenic scores have limited portability across groups of different genetic ancestries, restricting the contexts in which they can be used reliably and potentially creating serious inequities in future clinical applications. Using the UK Biobank data, we demonstrate that even within a single ancestry group, the prediction accuracy of polygenic scores depends on characteristics such as the age or sex composition of the individuals in which the GWAS and the prediction were conducted, and on the GWAS study design. Our findings highlight both the complexities of interpreting polygenic scores and underappreciated obstacles to their broad use.

18: Paleolithic DNA from the Caucasus reveals core of West Eurasian ancestry
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Posted to bioRxiv 21 Sep 2018

Paleolithic DNA from the Caucasus reveals core of West Eurasian ancestry
389 downloads genetics

Iosif Lazaridis, Anna Belfer-Cohen, Swapan Mallick, Nick Patterson, Olivia Cheronet, Nadin Rohland, Guy Bar-Oz, Ofer Bar-Yosef, Nino Jakeli, Eliso Kvavadze, David Lordkipanidze, Zinovi Matzkevich, Tengiz Meshveliani, Brendan J Culleton, Douglas J. Kennett, Ron Pinhasi, David Reich

The earliest ancient DNA data of modern humans from Europe dates to ~40 thousand years ago, but that from the Caucasus and the Near East to only ~14 thousand years ago, from populations who lived long after the Last Glacial Maximum (LGM) ~26.5-19 thousand years ago. To address this imbalance and to better understand the relationship of Europeans and Near Easterners, we report genome-wide data from two ~26 thousand year old individuals from Dzudzuana Cave in Georgia in the Caucasus from around the beginning of the LGM. Surprisingly, the Dzudzuana population was more closely related to early agriculturalists from western Anatolia ~8 thousand years ago than to the hunter-gatherers of the Caucasus from the same region of western Georgia of ~13-10 thousand years ago. Most of the Dzudzuana population's ancestry was deeply related to the post-glacial western European hunter-gatherers of the 'Villabruna cluster', but it also had ancestry from a lineage that had separated from the great majority of non-African populations before they separated from each other, proving that such 'Basal Eurasians' were present in West Eurasia twice as early as previously recorded. We document major population turnover in the Near East after the time of Dzudzuana, showing that the highly differentiated Holocene populations of the region were formed by 'Ancient North Eurasian' admixture into the Caucasus and Iran and North African admixture into the Natufians of the Levant. We finally show that the Dzudzuana population contributed the majority of the ancestry of post-Ice Age people in the Near East, North Africa, and even parts of Europe, thereby becoming the largest single contributor of ancestry of all present-day West Eurasians.

19: Massive gene presence/absence variation in the mussel genome as an adaptive strategy: first evidence of a pan-genome in Metazoa
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Posted to bioRxiv 25 Sep 2019

Massive gene presence/absence variation in the mussel genome as an adaptive strategy: first evidence of a pan-genome in Metazoa
381 downloads genetics

Marco Gerdol, Rebeca Moreira, Fernando Cruz, Jessica Gomez-Garrido, Anna Vlasova, Umberto Rosani, Paola Venier, Miguel A. Naranjo-Ortiz, Maria Murgarella, Pablo Balseiro, Andre Corvelo, Leonor Frias, Marta Gut, Toni Gabaldon, Alberto Pallavicini, Carlos Canchaya, Beatriz Novoa, Tyler S Alioto, David Posada, Antonio Figueras

Mussels are ecologically and economically relevant edible marine bivalves, highly invasive and resilient to biotic and abiotic stressors causing recurrent massive mortalities in other species. Here we show that the Mediterranean mussel Mytilus galloprovincialis has a complex pan-genomic architecture, which includes a core set of 45,000 genes shared by all individuals plus a surprisingly high number of dispensable genes (~15,000). The latter are subject to presence/absence variation (PAV), i.e., they may be entirely missing in a given individual and, when present, they are frequently found as a single copy. The enrichment of dispensable genes in survival functions suggests an adaptive value for PAV, which might be the key to explain the extraordinary capabilities of adaptation and invasiveness of this species. Our study underpins a unique metazoan pan-genome architecture only previously described in prokaryotes and in a few non-metazoan eukaryotes, but that might also characterize other marine invertebrates.

20: Genome-wide genetic data on ~500,000 UK Biobank participants
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Posted to bioRxiv 20 Jul 2017

Genome-wide genetic data on ~500,000 UK Biobank participants
378 downloads genetics

Clare Bycroft, Colin Freeman, Desislava Petkova, Gavin Band, Lloyd T Elliott, Kevin Sharp, Allan Motyer, Damjan Vukcevic, Olivier Delaneau, Jared O’Connell, Adrian Cortes, Samantha Welsh, Gil McVean, Stephen Leslie, Peter Donnelly, Jonathan Marchini

The UK Biobank project is a large prospective cohort study of ~500,000 individuals from across the United Kingdom, aged between 40-69 at recruitment. A rich variety of phenotypic and health-related information is available on each participant, making the resource unprecedented in its size and scope. Here we describe the genome-wide genotype data (~805,000 markers) collected on all individuals in the cohort and its quality control procedures. Genotype data on this scale offers novel opportunities for assessing quality issues, although the wide range of ancestries of the individuals in the cohort also creates particular challenges. We also conducted a set of analyses that reveal properties of the genetic data (such as population structure and relatedness) that can be important for downstream analyses. In addition, we phased and imputed genotypes into the dataset, using computationally efficient methods combined with the Haplotype Reference Consortium (HRC) and UK10K haplotype resource. This increases the number of testable variants by over 100-fold to ~96 million variants. We also imputed classical allelic variation at 11 human leukocyte antigen (HLA) genes, and as a quality control check of this imputation, we replicate signals of known associations between HLA alleles and many common diseases. We describe tools that allow efficient genome-wide association studies (GWAS) of multiple traits and fast phenome-wide association studies (PheWAS), which work together with a new compressed file format that has been used to distribute the dataset. As a further check of the genotyped and imputed datasets, we performed a test-case genome-wide association scan on a well-studied human trait, standing height.

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