R-3 Repository :: Browsing by Author "Aiden, Erez Lieberman"

Browsing by Author "Aiden, Erez Lieberman"

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A Chromosome-length Assembly of the Black Petaltail (Tanypteryx hageni) Dragonfly
(Oxford University Press, 2023) Tolman, Ethan R; Beatty, Christopher D; Bush, Jonas; Kohli, Manpreet; Moreno, Carlos M; Ware, Jessica L; Weber, K Scott; Khan, Ruqayya; Maheshwari, Chirag; Weisz, David; Dudchenko, Olga; Aiden, Erez Lieberman; Frandsen, Paul B; Center for Theoretical Biological Physics
We present a chromosome-length genome assembly and annotation of the Black Petaltail dragonfly (Tanypteryx hageni). This habitat specialist diverged from its sister species over 70 million years ago, and separated from the most closely related Odonata with a reference genome 150 million years ago. Using PacBio HiFi reads and Hi-C data for scaffolding we produce one of the most high-quality Odonata genomes to date. A scaffold N50 of 206.6 Mb and a single copy BUSCO score of 96.2% indicate high contiguity and completeness.
A pan-genome and chromosome-length reference genome of narrow-leafed lupin (Lupinus angustifolius) reveals genomic diversity and insights into key industry and biological traits
(Wiley, 2022) Garg, Gagan; Kamphuis, Lars G.; Bayer, Philipp E.; Kaur, Parwinder; Dudchenko, Olga; Taylor, Candy M.; Frick, Karen M.; Foley, Rhonda C.; Gao, Ling-Ling; Aiden, Erez Lieberman; Edwards, David; Singh, Karam B.; Center for Theoretical Biological Physics
Narrow-leafed lupin (NLL; Lupinus angustifolius) is a key rotational crop for sustainable farming systems, whose grain is high in protein content. It is a gluten-free, non-genetically modified, alternative protein source to soybean (Glycine max) and as such has gained interest as a human food ingredient. Here, we present a chromosome-length reference genome for the species and a pan-genome assembly comprising 55 NLL lines, including Australian and European cultivars, breeding lines and wild accessions. We present the core and variable genes for the species and report on the absence of essential mycorrhizal associated genes. The genome and pan-genomes of NLL and its close relative white lupin (Lupinus albus) are compared. Furthermore, we provide additional evidence supporting LaRAP2-7 as the key alkaloid regulatory gene for NLL and demonstrate the NLL genome is underrepresented in classical NLR disease resistance genes compared to other sequenced legume species. The NLL genomic resources generated here coupled with previously generated RNA sequencing datasets provide new opportunities to fast-track lupin crop improvement.
A rapid, low-cost, and highly sensitive SARS-CoV-2 diagnostic based on whole-genome sequencing
(Public Library of Science, 2023) Adastra, Per A.; Durand, Neva C.; Mitra, Namita; Pulido, Saul Godinez; Mahajan, Ragini; Blackburn, Alyssa; Colaric, Zane L.; Theisen, Joshua W. M.; Weisz, David; Dudchenko, Olga; Gnirke, Andreas; Rao, Suhas S. P.; Kaur, Parwinder; Aiden, Erez Lieberman; Aiden, Aviva Presser; Center for Theoretical Biological Physics
Early detection of SARS-CoV-2 infection is key to managing the current global pandemic, as evidence shows the virus is most contagious on or before symptom onset. Here, we introduce a low-cost, high-throughput method for diagnosing and studying SARS-CoV-2 infection. Dubbed Pathogen-Oriented Low-Cost Assembly & Re-Sequencing (POLAR), this method amplifies the entirety of the SARS-CoV-2 genome. This contrasts with typical RT-PCR-based diagnostic tests, which amplify only a few loci. To achieve this goal, we combine a SARS-CoV-2 enrichment method developed by the ARTIC Network (https://artic.network/) with short-read DNA sequencing and de novo genome assembly. Using this method, we can reliably (>95% accuracy) detect SARS-CoV-2 at a concentration of 84 genome equivalents per milliliter (GE/mL). The vast majority of diagnostic methods meeting our analytical criteria that are currently authorized for use by the United States Food and Drug Administration with the Coronavirus Disease 2019 (COVID-19) Emergency Use Authorization require higher concentrations of the virus to achieve this degree of sensitivity and specificity. In addition, we can reliably assemble the SARS-CoV-2 genome in the sample, often with no gaps and perfect accuracy given sufficient viral load. The genotypic data in these genome assemblies enable the more effective analysis of disease spread than is possible with an ordinary binary diagnostic. These data can also help identify vaccine and drug targets. Finally, we show that the diagnoses obtained using POLAR of positive and negative clinical nasal mid-turbinate swab samples 100% match those obtained in a clinical diagnostic lab using the Center for Disease Control’s 2019-Novel Coronavirus test. Using POLAR, a single person can manually process 192 samples over an 8-hour experiment at the cost of ~$36 per patient (as of December 7th, 2022), enabling a 24-hour turnaround with sequencing and data analysis time. We anticipate that further testing and refinement will allow greater sensitivity using this approach.
A Transferable Model for Chromosome Architecture
(National Academy of Sciences, 2016) Di Pierro, M.; Zhang, Boyu; Aiden, Erez Lieberman; Wolynes, P.G.; Onuchic, José Nelson
In vivo, the human genome folds into a characteristic ensemble of 3D structures. The mechanism driving the folding process remains unknown. We report a theoretical model for chromatin (Minimal Chromatin Model) that explains the folding of interphase chromosomes and generates chromosome conformations consistent with experimental data. The energy landscape of the model was derived by using the maximum entropy principle and relies on two experimentally derived inputs: a classification of loci into chromatin types and a catalog of the positions of chromatin loops. First, we trained our energy function using the Hi-C contact map of chromosome 10 from human GM12878 lymphoblastoid cells. Then, we used the model to perform molecular dynamics simulations producing an ensemble of 3D structures for all GM12878 autosomes. Finally, we used these 3D structures to generate contact maps. We found that simulated contact maps closely agree with experimental results for all GM12878 autosomes. The ensemble of structures resulting from these simulations exhibited unknotted chromosomes, phase separation of chromatin types, and a tendency for open chromatin to lie at the periphery of chromosome territories.
Chromatin alternates between A and B compartments at kilobase scale for subgenic organization
(Springer Nature, 2023) Harris, Hannah L.; Gu, Huiya; Olshansky, Moshe; Wang, Ailun; Farabella, Irene; Eliaz, Yossi; Kalluchi, Achyuth; Krishna, Akshay; Jacobs, Mozes; Cauer, Gesine; Pham, Melanie; Rao, Suhas S. P.; Dudchenko, Olga; Omer, Arina; Mohajeri, Kiana; Kim, Sungjae; Nichols, Michael H.; Davis, Eric S.; Gkountaroulis, Dimos; Udupa, Devika; Aiden, Aviva Presser; Corces, Victor G.; Phanstiel, Douglas H.; Noble, William Stafford; Nir, Guy; Di Pierro, Michele; Seo, Jeong-Sun; Talkowski, Michael E.; Aiden, Erez Lieberman; Rowley, M. Jordan; Center for Theoretical Biological Physics
Nuclear compartments are prominent features of 3D chromatin organization, but sequencing depth limitations have impeded investigation at ultra fine-scale. CTCF loops are generally studied at a finer scale, but the impact of looping on proximal interactions remains enigmatic. Here, we critically examine nuclear compartments and CTCF loop-proximal interactions using a combination of in situ Hi-C at unparalleled depth, algorithm development, and biophysical modeling. Producing a large Hi-C map with 33 billion contacts in conjunction with an algorithm for performing principal component analysis on sparse, super massive matrices (POSSUMM), we resolve compartments to 500 bp. Our results demonstrate that essentially all active promoters and distal enhancers localize in the A compartment, even when flanking sequences do not. Furthermore, we find that the TSS and TTS of paused genes are often segregated into separate compartments. We then identify diffuse interactions that radiate from CTCF loop anchors, which correlate with strong enhancer-promoter interactions and proximal transcription. We also find that these diffuse interactions depend on CTCF’s RNA binding domains. In this work, we demonstrate features of fine-scale chromatin organization consistent with a revised model in which compartments are more precise than commonly thought while CTCF loops are more protracted.
Chromatin architecture transitions from zebrafish sperm through early embryogenesis
(Cold Spring Harbor Laboratory Press, 2021) Wike, Candice L.; Guo, Yixuan; Tan, Mengyao; Nakamura, Ryohei; Shaw, Dana Klatt; Díaz, Noelia; Whittaker-Tademy, Aneasha F.; Durand, Neva C.; Aiden, Erez Lieberman; Vaquerizas, Juan M.; Grunwald, David; Takeda, Hiroyuki; Cairns, Bradley R.; Center for Theoretical Biological Physics
Chromatin architecture mapping in 3D formats has increased our understanding of how regulatory sequences and gene expression are connected and regulated in a genome. The 3D chromatin genome shows extensive remodeling during embryonic development, and although the cleavage-stage embryos of most species lack structure before zygotic genome activation (pre-ZGA), zebrafish has been reported to have structure. Here, we aimed to determine the chromosomal architecture in paternal/sperm zebrafish gamete cells to discern whether it either resembles or informs early pre-ZGA zebrafish embryo chromatin architecture. First, we assessed the higher-order architecture through advanced low-cell in situ Hi-C. The structure of zebrafish sperm, packaged by histones, lacks topological associated domains and instead displays “hinge-like” domains of ∼150 kb that repeat every 1–2 Mbs, suggesting a condensed repeating structure resembling mitotic chromosomes. The pre-ZGA embryos lacked chromosomal structure, in contrast to prior work, and only developed structure post-ZGA. During post-ZGA, we find chromatin architecture beginning to form at small contact domains of a median length of ∼90 kb. These small contact domains are established at enhancers, including super-enhancers, and chemical inhibition of Ep300a (p300) and Crebbpa (CBP) activity, lowering histone H3K27ac, but not transcription inhibition, diminishes these contacts. Together, this study reveals hinge-like domains in histone-packaged zebrafish sperm chromatin and determines that the initial formation of high-order chromatin architecture in zebrafish embryos occurs after ZGA primarily at enhancers bearing high H3K27ac.
A Chromosome-Length Assembly of the Hawaiian Monk Seal (Neomonachus schauinslandi): A History of “Genetic Purging” and Genomic Stability
(MDPI, 2022) Mohr, David W.; Gaughran, Stephen J.; Paschall, Justin; Naguib, Ahmed; Pang, Andy Wing Chun; Dudchenko, Olga; Aiden, Erez Lieberman; Church, Deanna M.; Scott, Alan F.; Center for Theoretical Biological Physics
The Hawaiian monk seal (HMS) is the single extant species of tropical earless seals of the genus Neomonachus. The species survived a severe bottleneck in the late 19th century and experienced subsequent population declines until becoming the subject of a NOAA-led species recovery effort beginning in 1976 when the population was fewer than 1000 animals. Like other recovering species, the Hawaiian monk seal has been reported to have reduced genetic heterogeneity due to the bottleneck and subsequent inbreeding. Here, we report a chromosomal reference assembly for a male animal produced using a variety of methods. The final assembly consisted of 16 autosomes, an X, and portions of the Y chromosomes. We compared variants in this animal to other HMS and to a frequently sequenced human sample, confirming about 12% of the variation seen in man. To confirm that the reference animal was representative of the HMS, we compared his sequence to that of 10 other individuals and noted similarly low variation in all. Variation in the major histocompatibility (MHC) genes was nearly absent compared to the orthologous human loci. Demographic analysis predicts that Hawaiian monk seals have had a long history of small populations preceding the bottleneck, and their current low levels of heterozygosity may indicate specialization to a stable environment. When we compared our reference assembly to that of other species, we observed significant conservation of chromosomal architecture with other pinnipeds, especially other phocids. This reference should be a useful tool for future evolutionary studies as well as the long-term management of this species.
Chromosome-length genome assembly and linkage map of a critically endangered Australian bird: the helmeted honeyeater
(Oxford University Press, 2022) Robledo-Ruiz, Diana A.; Gan, Han Ming; Kaur, Parwinder; Dudchenko, Olga; Weisz, David; Khan, Ruqayya; Aiden, Erez Lieberman; Osipova, Ekaterina; Hiller, Michael; Morales, Hernán E.; Magrath, Michael J.L.; Clarke, Rohan H.; Sunnucks, Paul; Pavlova, Alexandra; Center for Theoretical Biological Physics
The helmeted honeyeater (Lichenostomus melanops cassidix) is a Critically Endangered bird endemic to Victoria, Australia. To aid its conservation, the population is the subject of genetic rescue. To understand, monitor, and modulate the effects of genetic rescue on the helmeted honeyeater genome, a chromosome-length genome and a high-density linkage map are required.We used a combination of Illumina, Oxford Nanopore, and Hi-C sequencing technologies to assemble a chromosome-length genome of the helmeted honeyeater, comprising 906 scaffolds, with length of 1.1 Gb and scaffold N50 of 63.8 Mb. Annotation comprised 57,181 gene models. Using a pedigree of 257 birds and 53,111 single-nucleotide polymorphisms, we obtained high-density linkage and recombination maps for 25 autosomes and Z chromosome. The total sex-averaged linkage map was 1,347 cM long, with the male map being 6.7% longer than the female map. Recombination maps revealed sexually dimorphic recombination rates (overall higher in males), with average recombination rate of 1.8 cM/Mb. Comparative analyses revealed high synteny of the helmeted honeyeater genome with that of 3 passerine species (e.g., 32 Hi-C scaffolds mapped to 30 zebra finch autosomes and Z chromosome). The genome assembly and linkage map suggest that the helmeted honeyeater exhibits a fission of chromosome 1A into 2 chromosomes relative to zebra finch. PSMC analysis showed a ∼15-fold decline in effective population size to ∼60,000 from mid- to late Pleistocene.The annotated chromosome-length genome and high-density linkage map provide rich resources for evolutionary studies and will be fundamental in guiding conservation efforts for the helmeted honeyeater.
Chromosome-length genome assembly and structural variations of the primal Basenji dog (Canis lupus familiaris) genome
(Springer Nature, 2021) Edwards, Richard J.; Field, Matt A.; Ferguson, James M.; Dudchenko, Olga; Keilwagen, Jens; Rosen, Benjamin D.; Johnson, Gary S.; Rice, Edward S.; Hillier, La Deanna; Hammond, Jillian M.; Towarnicki, Samuel G.; Omer, Arina; Khan, Ruqayya; Skvortsova, Ksenia; Bogdanovic, Ozren; Zammit, Robert A.; Aiden, Erez Lieberman; Warren, Wesley C.; Ballard, J. William O.; Center for Theoretical and Biological Physics
Basenjis are considered an ancient dog breed of central African origins that still live and hunt with tribesmen in the African Congo. Nicknamed the barkless dog, Basenjis possess unique phylogeny, geographical origins and traits, making their genome structure of great interest. The increasing number of available canid reference genomes allows us to examine the impact the choice of reference genome makes with regard to reference genome quality and breed relatedness.
Chromosome-length genome assembly of Teladorsagia circumcincta – a globally important helminth parasite in livestock
(Springer Nature, 2023) Hassan, Shamshad Ul; Chua, Eng Guan; Paz, Erwin A.; Tay, Chin Yen; Greeff, Johan C.; Palmer, Dieter G.; Dudchenko, Olga; Aiden, Erez Lieberman; Martin, Graeme B.; Kaur, Parwinder; Center for Theoretical Biological Physics
Gastrointestinal (GIT) helminthiasis is a global problem that affects livestock health, especially in small ruminants. One of the major helminth parasites of sheep and goats, Teladorsagia circumcincta, infects the abomasum and causes production losses, reductions in weight gain, diarrhoea and, in some cases, death in young animals. Control strategies have relied heavily on the use of anthelmintic medication but, unfortunately, T. circumcincta has developed resistance, as have many helminths. Vaccination offers a sustainable and practical solution, but there is no commercially available vaccine to prevent Teladorsagiosis. The discovery of new strategies for controlling T. circumcincta, such as novel vaccine targets and drug candidates, would be greatly accelerated by the availability of better quality, chromosome-length, genome assembly because it would allow the identification of key genetic determinants of the pathophysiology of infection and host-parasite interaction. The available draft genome assembly of T. circumcincta (GCA_002352805.1) is highly fragmented and thus impedes large-scale investigations of population and functional genomics.
A Chromosome-Length Reference Genome for the Endangered Pacific Pocket Mouse Reveals Recent Inbreeding in a Historically Large Population
(Oxford University Press, 2022) Wilder, Aryn P; Dudchenko, Olga; Curry, Caitlin; Korody, Marisa; Turbek, Sheela P; Daly, Mark; Misuraca, Ann; Wang, Gaojianyong; Khan, Ruqayya; Weisz, David; Fronczek, Julie; Aiden, Erez Lieberman; Houck, Marlys L; Shier, Debra M; Ryder, Oliver A; Steiner, Cynthia C; Center for Theoretical Biological Physics
High-quality reference genomes are fundamental tools for understanding population history, and can provide estimates of genetic and demographic parameters relevant to the conservation of biodiversity. The federally endangered Pacific pocket mouse (PPM), which persists in three small, isolated populations in southern California, is a promising model for studying how demographic history shapes genetic diversity, and how diversity in turn may influence extinction risk. To facilitate these studies in PPM, we combined PacBio HiFi long reads with Omni-C and Hi-C data to generate a de novo genome assembly, and annotated the genome using RNAseq. The assembly comprised 28 chromosome-length scaffolds (N50 = 72.6 MB) and the complete mitochondrial genome, and included a long heterochromatic region on chromosome 18 not represented in the previously available short-read assembly. Heterozygosity was highly variable across the genome of the reference individual, with 18% of windows falling in runs of homozygosity (ROH) >1 MB, and nearly 9% in tracts spanning >5 MB. Yet outside of ROH, heterozygosity was relatively high (0.0027), and historical Ne estimates were large. These patterns of genetic variation suggest recent inbreeding in a formerly large population. Currently the most contiguous assembly for a heteromyid rodent, this reference genome provides insight into the past and recent demographic history of the population, and will be a critical tool for management and future studies of outbreeding depression, inbreeding depression, and genetic load.
Chromosome-level genome of Schistosoma haematobium underpins genome-wide explorations of molecular variation
(Public Library of Science, 2022) Stroehlein, Andreas J.; Korhonen, Pasi K.; Lee, V. Vern; Ralph, Stuart A.; Mentink-Kane, Margaret; You, Hong; McManus, Donald P.; Tchuenté, Louis-Albert Tchuem; Stothard, J. Russell; Kaur, Parwinder; Dudchenko, Olga; Aiden, Erez Lieberman; Yang, Bicheng; Yang, Huanming; Emery, Aidan M.; Webster, Bonnie L.; Brindley, Paul J.; Rollinson, David; Chang, Bill C.H.; Gasser, Robin B.; Young, Neil D.; Center for Theoretical Biological Physics
Urogenital schistosomiasis is caused by the blood fluke Schistosoma haematobium and is one of the most neglected tropical diseases worldwide, afflicting > 100 million people. It is characterised by granulomata, fibrosis and calcification in urogenital tissues, and can lead to increased susceptibility to HIV/AIDS and squamous cell carcinoma of the bladder. To complement available treatment programs and break the transmission of disease, sound knowledge and understanding of the biology and ecology of S. haematobium is required. Hybridisation/introgression events and molecular variation among members of the S. haematobium-group might effect important biological and/or disease traits as well as the morbidity of disease and the effectiveness of control programs including mass drug administration. Here we report the first chromosome-contiguous genome for a well-defined laboratory line of this blood fluke. An exploration of this genome using transcriptomic data for all key developmental stages allowed us to refine gene models (including non-coding elements) and annotations, discover ‘new’ genes and transcription profiles for these stages, likely linked to development and/or pathogenesis. Molecular variation within S. haematobium among some geographical locations in Africa revealed unique genomic ‘signatures’ that matched species other than S. haematobium, indicating the occurrence of introgression events. The present reference genome (designated Shae.V3) and the findings from this study solidly underpin future functional genomic and molecular investigations of S. haematobium and accelerate systematic, large-scale population genomics investigations, with a focus on improved and sustained control of urogenital schistosomiasis.
Cohesin depleted cells rebuild functional nuclear compartments after endomitosis
(Springer Nature, 2020) Cremer, Marion; Brandstetter, Katharina; Maiser, Andreas; Rao, Suhas S.P.; Schmid, Volker J.; Guirao-Ortiz, Miguel; Mitra, Namita; Mamberti, Stefania; Klein, Kyle N.; Gilbert, David M.; Leonhardt, Heinrich; Cardoso, M. Cristina; Aiden, Erez Lieberman; Harz, Hartmann; Cremer, Thomas
Cohesin plays an essential role in chromatin loop extrusion, but its impact on a compartmentalized nuclear architecture, linked to nuclear functions, is less well understood. Using live-cell and super-resolved 3D microscopy, here we find that cohesin depletion in a human colon cancer derived cell line results in endomitosis and a single multilobulated nucleus with chromosome territories pervaded by interchromatin channels. Chromosome territories contain chromatin domain clusters with a zonal organization of repressed chromatin domains in the interior and transcriptionally competent domains located at the periphery. These clusters form microscopically defined, active and inactive compartments, which likely correspond to A/B compartments, which are detected with ensemble Hi-C. Splicing speckles are observed nearby within the lining channel system. We further observe that the multilobulated nuclei, despite continuous absence of cohesin, pass through S-phase with typical spatio-temporal patterns of replication domains. Evidence for structural changes of these domains compared to controls suggests that cohesin is required for their full integrity.
CTCF looping is established during gastrulation in medaka embryos
(Cold Spring Harbor Laboratory Press, 2021) Nakamura, Ryohei; Motai, Yuichi; Kumagai, Masahiko; Wike, Candice L.; Nishiyama, Haruyo; Nakatani, Yoichiro; Durand, Neva C.; Kondo, Kaori; Kondo, Takashi; Tsukahara, Tatsuya; Shimada, Atsuko; Cairns, Bradley R.; Aiden, Erez Lieberman; Morishita, Shinichi; Takeda, Hiroyuki; Center for Theoretical Biological Physics
Chromatin looping plays an important role in genome regulation. However, because ChIP-seq and loop-resolution Hi-C (DNA-DNA proximity ligation) are extremely challenging in mammalian early embryos, the developmental stage at which cohesin-mediated loops form remains unknown. Here, we study early development in medaka (the Japanese killifish, Oryzias latipes) at 12 time points before, during, and after gastrulation (the onset of cell differentiation) and characterize transcription, protein binding, and genome architecture. We find that gastrulation is associated with drastic changes in genome architecture, including the formation of the first loops between sites bound by the insulator protein CTCF and a large increase in the size of contact domains. In contrast, the binding of the CTCF is fixed throughout embryogenesis. Loops form long after genome-wide transcriptional activation, and long after domain formation seen in mouse embryos. These results suggest that, although loops may play a role in differentiation, they are not required for zygotic transcription. When we repeated our experiments in zebrafish, loops did not emerge until gastrulation, that is, well after zygotic genome activation. We observe that loop positions are highly conserved in synteny blocks of medaka and zebrafish, indicating that the 3D genome architecture has been maintained for >110–200 million years of evolution.
De novo prediction of human chromosome structures: Epigenetic marking patterns encode genome architecture
(National Academy of Sciences, 2017) Di Pierro, Michele; Cheng, Ryan R.; Aiden, Erez Lieberman; Wolynes, Peter G.; Onuchic, José N.; Center for Theoretical Biological Physics
Inside the cell nucleus, genomes fold into organized structures that are characteristic of cell type. Here, we show that this chromatin architecture can be predicted de novo using epigenetic data derived from chromatin immunoprecipitation-sequencing (ChIP-Seq). We exploit the idea that chromosomes encode a 1D sequence of chromatin structural types. Interactions between these chromatin types determine the 3D structural ensemble of chromosomes through a process similar to phase separation. First, a neural network is used to infer the relation between the epigenetic marks present at a locus, as assayed by ChIP-Seq, and the genomic compartment in which those loci reside, as measured by DNA-DNA proximity ligation (Hi-C). Next, types inferred from this neural network are used as an input to an energy landscape model for chromatin organization [Minimal Chromatin Model (MiChroM)] to generate an ensemble of 3D chromosome conformations at a resolution of 50 kilobases (kb). After training the model, dubbed Maximum Entropy Genomic Annotation from Biomarkers Associated to Structural Ensembles (MEGABASE), on odd-numbered chromosomes, we predict the sequences of chromatin types and the subsequent 3D conformational ensembles for the even chromosomes. We validate these structural ensembles by using ChIP-Seq tracks alone to predict Hi-C maps, as well as distances measured using 3D fluorescence in situ hybridization (FISH) experiments. Both sets of experiments support the hypothesis of phase separation being the driving process behind compartmentalization. These findings strongly suggest that epigenetic marking patterns encode sufficient information to determine the global architecture of chromosomes and that de novo structure prediction for whole genomes may be increasingly possible.
Depletion of lamins B1 and B2 promotes chromatin mobility and induces differential gene expression by a mesoscale-motion-dependent mechanism
(Springer Nature, 2024) Pujadas Liwag, Emily M.; Wei, Xiaolong; Acosta, Nicolas; Carter, Lucas M.; Yang, Jiekun; Almassalha, Luay M.; Jain, Surbhi; Daneshkhah, Ali; Rao, Suhas S. P.; Seker-Polat, Fidan; MacQuarrie, Kyle L.; Ibarra, Joe; Agrawal, Vasundhara; Aiden, Erez Lieberman; Kanemaki, Masato T.; Backman, Vadim; Adli, Mazhar; Center for Theoretical Biological Physics
B-type lamins are critical nuclear envelope proteins that interact with the three-dimensional genomic architecture. However, identifying the direct roles of B-lamins on dynamic genome organization has been challenging as their joint depletion severely impacts cell viability. To overcome this, we engineered mammalian cells to rapidly and completely degrade endogenous B-type lamins using Auxin-inducible degron technology.
Emx2 underlies the development and evolution of marsupial gliding membranes
(Springer Nature, 2024) Moreno, Jorge A.; Dudchenko, Olga; Feigin, Charles Y.; Mereby, Sarah A.; Chen, Zhuoxin; Ramos, Raul; Almet, Axel A.; Sen, Harsha; Brack, Benjamin J.; Johnson, Matthew R.; Li, Sha; Wang, Wei; Gaska, Jenna M.; Ploss, Alexander; Weisz, David; Omer, Arina D.; Yao, Weijie; Colaric, Zane; Kaur, Parwinder; Leger, Judy St; Nie, Qing; Mena, Alexandria; Flanagan, Joseph P.; Keller, Greta; Sanger, Thomas; Ostrow, Bruce; Plikus, Maksim V.; Kvon, Evgeny Z.; Aiden, Erez Lieberman; Mallarino, Ricardo; Center for Theoretical Biological Physics
Phenotypic variation among species is a product of evolutionary changes to developmental programs1,2. However, how these changes generate novel morphological traits remains largely unclear. Here we studied the genomic and developmental basis of the mammalian gliding membrane, or patagium—an adaptative trait that has repeatedly evolved in different lineages, including in closely related marsupial species. Through comparative genomic analysis of 15 marsupial genomes, both from gliding and non-gliding species, we find that the Emx2 locus experienced lineage-specific patterns of accelerated cis-regulatory evolution in gliding species. By combining epigenomics, transcriptomics and in-pouch marsupial transgenics, we show that Emx2 is a critical upstream regulator of patagium development. Moreover, we identify different cis-regulatory elements that may be responsible for driving increased Emx2 expression levels in gliding species. Lastly, using mouse functional experiments, we find evidence that Emx2 expression patterns in gliders may have been modified from a pre-existing program found in all mammals. Together, our results suggest that patagia repeatedly originated through a process of convergent genomic evolution, whereby regulation of Emx2 was altered by distinct cis-regulatory elements in independently evolved species. Thus, different regulatory elements targeting the same key developmental gene may constitute an effective strategy by which natural selection has harnessed regulatory evolution in marsupial genomes to generate phenotypic novelty.
Exploring chromosomal structural heterogeneity across multiple cell lines
(eLife, 2020) Cheng, Ryan R.; Contessoto, Vinícius G.; Aiden, Erez Lieberman; Wolynes, Peter G.; Di Pierro, Michele; Onuchic, José Nelson; Center for Theoretical Biological Physics
Using computer simulations, we generate cell-specific 3D chromosomal structures and compare them to recently published chromatin structures obtained through microscopy. We demonstrate using machine learning and polymer physics simulations that epigenetic information can be used to predict the structural ensembles of multiple human cell lines. Theory predicts that chromosome structures are fluid and can only be described by an ensemble, which is consistent with the observation that chromosomes exhibit no unique fold. Nevertheless, our analysis of both structures from simulation and microscopy reveals that short segments of chromatin make two-state transitions between closed conformations and open dumbbell conformations. Finally, we study the conformational changes associated with the switching of genomic compartments observed in human cell lines. The formation of genomic compartments resembles hydrophobic collapse in protein folding, with the aggregation of denser and predominantly inactive chromatin driving the positioning of active chromatin toward the surface of individual chromosomal territories.
Genome-wide diversity in the California condor tracks its prehistoric abundance and decline
(Elsevier, 2021) Robinson, Jacqueline A.; Bowie, Rauri C. K.; Dudchenko, Olga; Aiden, Erez Lieberman; Hendrickson, Sher L.; Steiner, Cynthia C.; Ryder, Oliver A.; Mindell, David P.; Wall, Jeffrey D.; Center for Theoretical and Biological Physics
Due to their small population sizes, threatened and endangered species frequently suffer from a lack of genetic diversity, potentially leading to inbreeding depression and reduced adaptability.1 During the latter half of the twentieth century, North America’s largest soaring bird,2 the California condor (Gymnogyps californianus; Critically Endangered3), briefly went extinct in the wild. Though condors once ranged throughout North America, by 1982 only 22 individuals remained. Following decades of captive breeding and release efforts, there are now >300 free-flying wild condors and ∼200 in captivity. The condor’s recent near-extinction from lead poisoning, poaching, and loss of habitat is well documented,4 but much about its history remains obscure. To fill this gap and aid future management of the species, we produced a high-quality chromosome-length genome assembly for the California condor and analyzed its genome-wide diversity. For comparison, we also examined the genomes of two close relatives: the Andean condor (Vultur gryphus; Vulnerable3) and the turkey vulture (Cathartes aura; Least Concern3). The genomes of all three species show evidence of historic population declines. Interestingly, the California condor genome retains a high degree of variation, which our analyses reveal is a legacy of its historically high abundance. Correlations between genome-wide diversity and recombination rate further suggest a history of purifying selection against linked deleterious alleles, boding well for future restoration. We show how both long-term evolutionary forces and recent inbreeding have shaped the genome of the California condor, and provide crucial genomic resources to enable future research and conservation.
Genomic signatures of barley breeding for environmental adaptation to the new continents
(Wiley, 2023) Hu, Haifei; Wang, Penghao; Angessa, Tefera Tolera; Zhang, Xiao-Qi; Chalmers, Kenneth J.; Zhou, Gaofeng; Hill, Camilla Beate; Jia, Yong; Simpson, Craig; Fuller, John; Saxena, Alka; Al Shamaileh, Hadi; Iqbal, Munir; Chapman, Brett; Kaur, Parwinder; Dudchenko, Olga; Aiden, Erez Lieberman; Keeble-Gagnere, Gabriel; Westcott, Sharon; Leah, David; Tibbits, Josquin F.; Waugh, Robbie; Langridge, Peter; Varshney, Rajeev; He, Tianhua; Li, Chengdao; Center for Theoretical Biological Physics

Browsing by Author "Aiden, Erez Lieberman"

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