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JOURNAL ARTICLE
Ryan Lorig-Roach, Melissa Meredith, Jean Monlong, Miten Jain, Hugh Olsen, Brandy McNulty, David Porubsky, Tessa Montague, Julian Lucas, Chris Condon, Jordan M Eizenga, Sissel Juul, Sean McKenzie, Sara E Simmonds, Jimin Park, Mobin Asri, Sergey Koren, Evan Eichler, Richard Axel, Bruce Martin, Paolo Carnevali, Karen Miga, Benedict Paten
Reference-free genome phasing is vital for understanding allele inheritance and the impact of single-molecule DNA variation on phenotypes. To achieve thorough phasing across homozygous or repetitive regions of the genome, long-read sequencing technologies are often used to perform phased de novo assembly. As a step toward reducing the cost and complexity of this type of analysis, we describe new methods for accurately phasing Oxford Nanopore Technologies (ONT) sequence data with the Shasta genome assembler and a modular tool for extending phasing to the chromosome scale called GFAse...
April 16, 2024: Genome Research
#2
JOURNAL ARTICLE
Emily Neuhaus, Hannah Rea, Elizabeth Jones, Hannah Benavidez, Conor Miles, Alana Whiting, Margaret Johansson, Curtis Eayrs, Evangeline C Kurtz-Nelson, Rachel Earl, Raphael A Bernier, Evan E Eichler
BACKGROUND: Neurodevelopmental conditions such as intellectual disability (ID) and autism spectrum disorder (ASD) can stem from a broad array of inherited and de novo genetic differences, with marked physiological and behavioral impacts. We currently know little about the psychiatric phenotypes of rare genetic variants associated with ASD, despite heightened risk of psychiatric concerns in ASD more broadly. Understanding behavioral features of these variants can identify shared versus specific phenotypes across gene groups, facilitate mechanistic models, and provide prognostic insights to inform clinical practice...
April 15, 2024: Journal of Neurodevelopmental Disorders
#3
JOURNAL ARTICLE
Glennis A Logsdon, Allison N Rozanski, Fedor Ryabov, Tamara Potapova, Valery A Shepelev, Claudia R Catacchio, David Porubsky, Yafei Mao, DongAhn Yoo, Mikko Rautiainen, Sergey Koren, Sergey Nurk, Julian K Lucas, Kendra Hoekzema, Katherine M Munson, Jennifer L Gerton, Adam M Phillippy, Mario Ventura, Ivan A Alexandrov, Evan E Eichler
Human centromeres have been traditionally very difficult to sequence and assemble owing to their repetitive nature and large size1 . As a result, patterns of human centromeric variation and models for their evolution and function remain incomplete, despite centromeres being among the most rapidly mutating regions2,3 . Here, using long-read sequencing, we completely sequenced and assembled all centromeres from a second human genome and compared it to the finished reference genome4,5 . We find that the two sets of centromeres show at least a 4...
April 3, 2024: Nature
#4
Elizabeth G Plender, Timofey Prodanov, PingHsun Hsieh, Evangelos Nizamis, William T Harvey, Arvis Sulovari, Katherine M Munson, Eli J Kaufman, Wanda K O'Neal, Paul N Valdmanis, Tobias Marschall, Jesse D Bloom, Evan E Eichler
The secreted mucins MUC5AC and MUC5B play critical defensive roles in airway pathogen entrapment and mucociliary clearance by encoding large glycoproteins with variable number tandem repeats (VNTRs). These polymorphic and degenerate protein coding VNTRs make the loci difficult to investigate with short reads. We characterize the structural diversity of MUC5AC and MUC5B by long-read sequencing and assembly of 206 human and 20 nonhuman primate (NHP) haplotypes. We find that human MUC5B is largely invariant (5761-5762aa); however, seven haplotypes have expanded VNTRs (6291-7019aa)...
March 20, 2024: bioRxiv
#5
Mir Henglin, Maryam Ghareghani, William Harvey, David Porubsky, Sergey Koren, Evan E Eichler, Peter Ebert, Tobias Marschall
Haplotype information is crucial for biomedical and population genetics research. However, current strategies to produce de-novo haplotype-resolved assemblies often require either difficult-to-acquire parental data or an intermediate haplotype-collapsed assembly. Here, we present Graphasing, a workflow which synthesizes the global phase signal of Strand-seq with assembly graph topology to produce chromosome-scale de-novo haplotypes for diploid genomes. Graphasing readily integrates with any assembly workflow that both outputs an assembly graph and has a haplotype assembly mode...
February 16, 2024: bioRxiv
#6
Jonas A Gustafson, Sophia B Gibson, Nikhita Damaraju, Miranda Pg Zalusky, Kendra Hoekzema, David Twesigomwe, Lei Yang, Anthony A Snead, Phillip A Richmond, Wouter De Coster, Nathan D Olson, Andrea Guarracino, Qiuhui Li, Angela L Miller, Joy Goffena, Zachery Anderson, Sophie Hr Storz, Sydney A Ward, Maisha Sinha, Claudia Gonzaga-Jauregui, Wayne E Clarke, Anna O Basile, Andre Corvelo, Catherine E Reeves, Adrienne Helland, Rajeeva Lochan Musunuri, Mahler Revsine, Karynne E Patterson, Cate Paschal, Christina Zakarian, Sara Goodwin, Tanner D Jensen, Esther Robb, W Richard McCombie, Fritz J Sedlazeck, Justin M Zook, Stephen B Montgomery, Erik Garrison, Mikhail Kolmogorov, Michael C Schatz, Richard N McLaughlin, Harriet Dashnow, Michael C Zody, Matthew Loose, Miten Jain, Evan E Eichler, Danny E Miller
Less than half of individuals with a suspected Mendelian condition receive a precise molecular diagnosis after comprehensive clinical genetic testing. Improvements in data quality and costs have heightened interest in using long-read sequencing (LRS) to streamline clinical genomic testing, but the absence of control datasets for variant filtering and prioritization has made tertiary analysis of LRS data challenging. To address this, the 1000 Genomes Project ONT Sequencing Consortium aims to generate LRS data from at least 800 of the 1000 Genomes Project samples...
March 7, 2024: medRxiv
#7
F Kumara Mastrorosa, Allison N Rozanski, William T Harvey, Jordan Knuth, Gage Garcia, Katherine M Munson, Kendra Hoekzema, Glennis A Logsdon, Evan E Eichler
Down syndrome is the most common form of human intellectual disability caused by precocious segregation and nondisjunction of chromosome 21. Differences in centromere structure have been hypothesized to play a potential role in this process in addition to the well-established risk of advancing maternal age. Using long-read sequencing, we completely sequenced and assembled the centromeres from a parent-child trio where Trisomy 21 arose in the child as a result of a meiosis I error. The proband carries three distinct chromosome 21 centromere haplotypes that vary by 11-fold in length--both the largest (H1) and smallest (H2) originating from the mother...
February 26, 2024: bioRxiv
#8
JOURNAL ARTICLE
Yafei Mao, William T Harvey, David Porubsky, Katherine M Munson, Kendra Hoekzema, Alexandra P Lewis, Peter A Audano, Allison Rozanski, Xiangyu Yang, Shilong Zhang, DongAhn Yoo, David S Gordon, Tyler Fair, Xiaoxi Wei, Glennis A Logsdon, Marina Haukness, Philip C Dishuck, Hyeonsoo Jeong, Ricardo Del Rosario, Vanessa L Bauer, Will T Fattor, Gregory K Wilkerson, Yuxiang Mao, Yongyong Shi, Qiang Sun, Qing Lu, Benedict Paten, Trygve E Bakken, Alex A Pollen, Guoping Feng, Sara L Sawyer, Wesley C Warren, Lucia Carbone, Evan E Eichler
We sequenced and assembled using multiple long-read sequencing technologies the genomes of chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, owl monkey, and marmoset. We identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. We estimate that 819.47 Mbp or ∼27% of the genome has been affected by SVs across primate evolution. We identify 1,607 structurally divergent regions wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (e...
February 23, 2024: Cell
#9
JOURNAL ARTICLE
Charles E Schwartz, Arthur S Aylsworth, Judith Allanson, Agatino Battaglia, John C Carey, Cynthia J Curry, Kay E Davies, Evan E Eichler, John M Graham, Bryan Hall, Judith G Hall, Lewis B Holmes, H Eugene Hoyme, Alasdair Hunter, Jeffrey Innis, John Johnson, Kim M Keppler-Noreuil, Jules G Leroy, Cynthia Moore, David L Nelson, Giovanni Neri, John M Opitz, David Picketts, F Lucy Raymond, Stavit Allon Shalev, Roger E Stevenson, Connie T R M Stumpel, Grant Sutherland, David H Viskochil, David D Weaver, Elaine H Zackai
Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders...
February 8, 2024: American Journal of Medical Genetics. Part A
#10
JOURNAL ARTICLE
Michael E Goldberg, Michelle D Noyes, Evan E Eichler, Aaron R Quinlan, Kelley Harris
Short tandem repeats (STRs) are hotspots of genomic variability in the human germline because of their high mutation rates, which have long been attributed largely to polymerase slippage during DNA replication. This model suggests that STR mutation rates should scale linearly with a father's age, as progenitor cells continually divide after puberty. In contrast, it suggests that STR mutation rates should not scale with a mother's age at her child's conception, since oocytes spend a mother's reproductive years arrested in meiosis II and undergo a fixed number of cell divisions that are independent of the age at ovulation...
January 31, 2024: Genetics
#11
Sébastien Küry, Janelle E Stanton, Geeske van Woerden, Tzung-Chien Hsieh, Cory Rosenfelt, Marie Pier Scott-Boyer, Victoria Most, Tianyun Wang, Jonas Johannes Papendorf, Charlotte de Konink, Wallid Deb, Virginie Vignard, Maja Studencka-Turski, Thomas Besnard, Anna Marta Hajdukowicz, Franziska Thiel, Sophie Möller, Laëtitia Florenceau, Silvestre Cuinat, Sylvain Marsac, Ingrid Wentzensen, Annabelle Tuttle, Cara Forster, Johanna Striesow, Richard Golnik, Damara Ortiz, Laura Jenkins, Jill A Rosenfeld, Alban Ziegler, Clara Houdayer, Dominique Bonneau, Erin Torti, Amber Begtrup, Kristin G Monaghan, Sureni V Mullegama, C M L Nienke Volker-Touw, Koen L I van Gassen, Renske Oegema, Mirjam de Pagter, Katharina Steindl, Anita Rauch, Ivan Ivanovski, Kimberly McDonald, Emily Boothe, Andrew Dauber, Janice Baker, Noelle Andrea V Fabie, Raphael A Bernier, Tychele N Turner, Siddharth Srivastava, Kira A Dies, Lindsay Swanson, Carrie Costin, Rebekah K Jobling, John Pappas, Rachel Rabin, Dmitriy Niyazov, Anne Chun-Hui Tsai, Karen Kovak, David B Beck, McV Malicdan, David R Adams, Lynne Wolfe, Rebecca D Ganetzky, Colleen Muraresku, Davit Babikyan, Zdeněk Sedláček, Miroslava Hančárová, Andrew T Timberlake, Hind Al Saif, Berkley Nestler, Kayla King, M J Hajianpour, Gregory Costain, D'Arcy Prendergast, Chumei Li, David Geneviève, Antonio Vitobello, Arthur Sorlin, Christophe Philippe, Tamar Harel, Ori Toker, Ataf Sabir, Derek Lim, Mark Hamilton, Lisa Bryson, Elaine Cleary, Sacha Weber, Trevor L Hoffman, Anna Maria Cueto-González, Eduardo Fidel Tizzano, David Gómez-Andrés, Marta Codina-Solà, Athina Ververi, Efterpi Pavlidou, Alexandros Lambropoulos, Kyriakos Garganis, Marlène Rio, Jonathan Levy, Sarah Jurgensmeyer, Anne M McRae, Mathieu Kent Lessard, Maria Daniela D'Agostino, Isabelle De Bie, Meret Wegler, Rami Abou Jamra, Susanne B Kamphausen, Viktoria Bothe, Larissa M Busch, Uwe Völker, Elke Hammer, Kristian Wende, Benjamin Cogné, Bertrand Isidor, Jens Meiler, Amélie Bosc-Rosati, Julien Marcoux, Marie-Pierre Bousquet, Jeremie Poschmann, Frédéric Laumonnier, Peter W Hildebrand, Evan E Eichler, Kirsty McWalter, Peter M Krawitz, Arnaud Droit, Ype Elgersma, Andreas M Grabrucker, Francois V Bolduc, Stéphane Bézieau, Frédéric Ebstein, Elke Krüger
Neurodevelopmental proteasomopathies represent a distinctive category of neurodevelopmental disorders (NDD) characterized by genetic variations within the 26S proteasome, a protein complex governing eukaryotic cellular protein homeostasis. In our comprehensive study, we identified 23 unique variants in PSMC5 , which encodes the AAA-ATPase proteasome subunit PSMC5/Rpt6, causing syndromic NDD in 38 unrelated individuals. Overexpression of PSMC5 variants altered human hippocampal neuron morphology, while PSMC5 knockdown led to impaired reversal learning in flies and loss of excitatory synapses in rat hippocampal neurons...
January 26, 2024: medRxiv
#12
REVIEW
David Porubsky, Evan E Eichler
This perspective focuses on advances in genome technology over the last 25 years and their impact on germline variant discovery within the field of human genetics. The field has witnessed tremendous technological advances from microarrays to short-read sequencing and now long-read sequencing. Each technology has provided genome-wide access to different classes of human genetic variation. We are now on the verge of comprehensive variant detection of all forms of variation for the first time with a single assay...
January 23, 2024: Cell
#13
JOURNAL ARTICLE
William T Harvey, Peter Ebert, Jana Ebler, Peter A Audano, Katherine M Munson, Kendra Hoekzema, David Porubsky, Christine R Beck, Tobias Marschall, Kiran Garimella, Evan E Eichler
Advances in long-read sequencing (LRS) technologies continue to make whole-genome sequencing more complete, affordable, and accurate. LRS provides significant advantages over short-read sequencing approaches, including phased de novo genome assembly, access to previously excluded genomic regions, and discovery of more complex structural variants (SVs) associated with disease. Limitations remain with respect to cost, scalability, and platform-dependent read accuracy and the tradeoffs between sequence coverage and sensitivity of variant discovery are important experimental considerations for the application of LRS...
December 27, 2023: Genome Research
#14
Michael E Goldberg, Michelle D Noyes, Evan E Eichler, Aaron R Quinlan, Kelley Harris
Short tandem repeats (STRs) are hotspots of genomic variability in the human germline because of their high mutation rates, which have long been attributed largely to polymerase slippage during DNA replication. This model suggests that STR mutation rates should scale linearly with a father's age, as progenitor cells continually divide after puberty. In contrast, it suggests that STR mutation rates should not scale with a mother's age at her child's conception, since oocytes spend a mother's reproductive years arrested in meiosis II and undergo a fixed number of cell divisions that are independent of the age at ovulation...
December 23, 2023: bioRxiv
#15
JOURNAL ARTICLE
R Alan Harris, Muthuswamy Raveendran, Wes Warren, Hillier W LaDeana, Chad Tomlinson, Tina Graves-Lindsay, Richard E Green, Jenna K Schmidt, Julia C Colwell, Allison T Makulec, Shelley A Cole, Ian H Cheeseman, Corinna N Ross, Saverio Capuano, Evan E Eichler, Jon E Levine, Jeffrey Rogers
The common marmoset ( Callithrix jacchus ) is one of the most widely used nonhuman primate models of human disease. Owing to limitations in sequencing technology, early genome assemblies of this species using short-read sequencing suffered from gaps. In addition, the genetic diversity of the species has not yet been adequately explored. Using long-read genome sequencing and expert annotation, we generated a high-quality genome resource creating a 2.898 Gb marmoset genome in which most of the euchromatin portion is assembled contiguously (contig N50 = 25...
December 7, 2023: Genes
#16
Kateryna D Makova, Brandon D Pickett, Robert S Harris, Gabrielle A Hartley, Monika Cechova, Karol Pal, Sergey Nurk, DongAhn Yoo, Qiuhui Li, Prajna Hebbar, Barbara C McGrath, Francesca Antonacci, Margaux Aubel, Arjun Biddanda, Matthew Borchers, Erich Bomberg, Gerard G Bouffard, Shelise Y Brooks, Lucia Carbone, Laura Carrel, Andrew Carroll, Pi-Chuan Chang, Chen-Shan Chin, Daniel E Cook, Sarah J C Craig, Luciana de Gennaro, Mark Diekhans, Amalia Dutra, Gage H Garcia, Patrick G S Grady, Richard E Green, Diana Haddad, Pille Hallast, William T Harvey, Glenn Hickey, David A Hillis, Savannah J Hoyt, Hyeonsoo Jeong, Kaivan Kamali, Sergei L Kosakovsky Pond, Troy M LaPolice, Charles Lee, Alexandra P Lewis, Yong-Hwee E Loh, Patrick Masterson, Rajiv C McCoy, Paul Medvedev, Karen H Miga, Katherine M Munson, Evgenia Pak, Benedict Paten, Brendan J Pinto, Tamara Potapova, Arang Rhie, Joana L Rocha, Fedor Ryabov, Oliver A Ryder, Samuel Sacco, Kishwar Shafin, Valery A Shepelev, Viviane Slon, Steven J Solar, Jessica M Storer, Peter H Sudmant, Sweetalana, Alex Sweeten, Michael G Tassia, Françoise Thibaud-Nissen, Mario Ventura, Melissa A Wilson, Alice C Young, Huiqing Zeng, Xinru Zhang, Zachary A Szpiech, Christian D Huber, Jennifer L Gerton, Soojin V Yi, Michael C Schatz, Ivan A Alexandrov, Sergey Koren, Rachel J O'Neill, Evan Eichler, Adam M Phillippy
Apes possess two sex chromosomes-the male-specific Y and the X shared by males and females. The Y chromosome is crucial for male reproduction, with deletions linked to infertility. The X chromosome carries genes vital for reproduction and cognition. Variation in mating patterns and brain function among great apes suggests corresponding differences in their sex chromosome structure and evolution. However, due to their highly repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study...
December 1, 2023: bioRxiv
#17
JOURNAL ARTICLE
Mariam Okhovat, Jake VanCampen, Kimberly A Nevonen, Lana Harshman, Weiyu Li, Cora E Layman, Samantha Ward, Jarod Herrera, Jackson Wells, Rory R Sheng, Yafei Mao, Blaise Ndjamen, Ana C Lima, Katinka A Vigh-Conrad, Alexandra M Stendahl, Ran Yang, Lev Fedorov, Ian R Matthews, Sarah A Easow, Dylan K Chan, Taha A Jan, Evan E Eichler, Sandra Rugonyi, Donald F Conrad, Nadav Ahituv, Lucia Carbone
Topological associating domains (TADs) are self-interacting genomic units crucial for shaping gene regulation patterns. Despite their importance, the extent of their evolutionary conservation and its functional implications remain largely unknown. In this study, we generate Hi-C and ChIP-seq data and compare TAD organization across four primate and four rodent species and characterize the genetic and epigenetic properties of TAD boundaries in correspondence to their evolutionary conservation. We find 14% of all human TAD boundaries to be shared among all eight species (ultraconserved), while 15% are human-specific...
December 7, 2023: Nature Communications
#18
JOURNAL ARTICLE
Marc A J Morgan, Saeid Mohammad Parast, Marta Iwanaszko, Yuki Aoi, DongAhn Yoo, Zachary J Dumar, Benjamin C Howard, Kathryn A Helmin, Qianli Liu, William R Thakur, Jacob M Zeidner, Benjamin D Singer, Evan E Eichler, Ali Shilatifard
The biological role of the repetitive DNA sequences in the human genome remains an outstanding question. Recent long-read human genome assemblies have allowed us to identify a function for one of these repetitive regions. We have uncovered a tandem array of conserved primate-specific retrogenes encoding the protein Elongin A3 (ELOA3), a homolog of the RNA polymerase II (RNAPII) elongation factor Elongin A (ELOA). Our genomic analysis shows that the ELOA3 gene cluster is conserved among primates and the number of ELOA3 gene repeats is variable in the human population and across primate species...
November 24, 2023: Science Advances
#19
JOURNAL ARTICLE
Annalisa Paparella, Alberto L'Abbate, Donato Palmisano, Gerardina Chirico, David Porubsky, Claudia R Catacchio, Mario Ventura, Evan E Eichler, Flavia A M Maggiolini, Francesca Antonacci
The impact of segmental duplications on human evolution and disease is only just starting to unfold, thanks to advancements in sequencing technologies that allow for their discovery and precise genotyping. The 15q11-q13 locus is a hotspot of recurrent copy number variation associated with Prader-Willi/Angelman syndromes, developmental delay, autism, and epilepsy and is mediated by complex segmental duplications, many of which arose recently during evolution. To gain insight into the instability of this region, we characterized its architecture in human and nonhuman primates, reconstructing the evolutionary history of five different inversions that rearranged the region in different species primarily by accumulation of segmental duplications...
October 31, 2023: International Journal of Molecular Sciences
#20
REVIEW
Karen H Miga, Evan E Eichler
Advances in long-read sequencing and assembly now mean that individual labs can generate phased genomes that are more accurate and more contiguous than the original human reference genome. With declining costs and increasing democratization of technology, we suggest that complete genome assemblies, where both parental haplotypes are phased telomere to telomere, will become standard in human genetics. Soon, even in clinical settings where rigorous sample-handling standards must be met, affected individuals could have reference-grade genomes fully sequenced and assembled in just a few hours given advances in technology, computational processing, and annotation...
November 2, 2023: American Journal of Human Genetics
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