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Article ; Online: Widespread contribution of transposable elements to the rewiring of mammalian 3D genomes.

Choudhary, Mayank N K / Quaid, Kara / Xing, Xiaoyun / Schmidt, Heather / Wang, Ting

2023 Volume 14, Issue 1, Page(s) 634

Abstract: Transposable elements (TEs) are major contributors of genetic material in mammalian genomes. These often include binding sites for architectural proteins, including the multifarious master protein, CTCF, which shapes the 3D genome by creating loops, ... ...

Abstract	Transposable elements (TEs) are major contributors of genetic material in mammalian genomes. These often include binding sites for architectural proteins, including the multifarious master protein, CTCF, which shapes the 3D genome by creating loops, domains, compartment borders, and RNA-DNA interactions. These play a role in the compact packaging of DNA and have the potential to facilitate regulatory function. In this study, we explore the widespread contribution of TEs to mammalian 3D genomes by quantifying the extent to which they give rise to loops and domain border differences across various cell types and species using several 3D genome mapping technologies. We show that specific families and subfamilies of TEs have contributed to lineage-specific 3D chromatin structures across mammalian species. In many cases, these loops may facilitate sustained interaction between distant cis-regulatory elements and target genes, and domains may segregate chromatin state to impact gene expression in a lineage-specific manner. An experimental validation of our analytical findings using CRISPR-Cas9 to delete a candidate TE resulted in disruption of species-specific 3D chromatin structure. Taken together, we comprehensively quantify and selectively validate our finding that TEs contribute to shaping 3D genome organization and may, in some cases, impact gene regulation during the course of mammalian evolution.
MeSH term(s)	Humans ; Animals ; DNA Transposable Elements/genetics ; Mammals/genetics ; Gene Expression Regulation ; Regulatory Sequences, Nucleic Acid ; Chromatin/genetics ; Evolution, Molecular
Chemical Substances	DNA Transposable Elements ; Chromatin
Language	English
Publishing date	2023-02-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-36364-9
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Counties with Lower Insurance Coverage and Housing Problems Are Associated with Both Slower Vaccine Rollout and Higher COVID-19 Incidence.

Donadio, Gregory / Choudhary, Mayank / Lindemer, Emily / Pawlowski, Colin / Soundararajan, Venky

Vaccines

2021 Volume 9, Issue 9

Abstract: Equitable vaccination distribution is a priority for outcompeting the transmission of COVID-19. Here, the impact of demographic, socioeconomic, and environmental factors on county-level vaccination rates and COVID-19 incidence changes is assessed. In ... ...

Abstract	Equitable vaccination distribution is a priority for outcompeting the transmission of COVID-19. Here, the impact of demographic, socioeconomic, and environmental factors on county-level vaccination rates and COVID-19 incidence changes is assessed. In particular, using data from 3142 US counties with over 328 million individuals, correlations were computed between cumulative vaccination rate and change in COVID-19 incidence from 1 December 2020 to 6 June 2021, with 44 different demographic, environmental, and socioeconomic factors. This correlation analysis was also performed using multivariate linear regression to adjust for age as a potential confounding variable. These correlation analyses demonstrated that counties with high levels of uninsured individuals have significantly lower COVID-19 vaccination rates (Spearman correlation: -0.460,
Language	English
Publishing date	2021-08-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines9090973
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Article ; Online: The epigenomic landscape of transposable elements across normal human development and anatomy.

Pehrsson, Erica C / Choudhary, Mayank N K / Sundaram, Vasavi / Wang, Ting

Nature communications

2019 Volume 10, Issue 1, Page(s) 5640

Abstract: Transposable elements (TEs) have deposited functional regulatory elements throughout the human genome. Although most are silenced, certain TEs have been co-opted by the host. However, a comprehensive, multidimensional picture of the contribution of TEs ... ...

Abstract	Transposable elements (TEs) have deposited functional regulatory elements throughout the human genome. Although most are silenced, certain TEs have been co-opted by the host. However, a comprehensive, multidimensional picture of the contribution of TEs to normal human gene regulation is still lacking. Here, we quantify the epigenomic status of TEs across human anatomy and development using data from the Roadmap Epigenomics Project. We find that TEs encompass a quarter of the human regulatory epigenome, and 47% of elements can be in an active regulatory state. We demonstrate that SINEs are enriched relative to other classes for active and transcribed marks, that TEs encompass a higher proportion of enhancer states in the hematopoietic lineage, and that DNA methylation of Alu elements decreases with age, corresponding with a loss of CpG islands. Finally, we identify TEs that may perform an evolutionarily conserved regulatory function, providing a systematic profile of TE activity in normal human tissue.
MeSH term(s)	Aging/genetics ; Alu Elements ; Animals ; Conserved Sequence/genetics ; DNA Transposable Elements/genetics ; Epigenesis, Genetic ; Epigenome ; Epigenomics ; Evolution, Molecular ; Growth and Development/genetics ; Humans ; Mice ; Molecular Sequence Annotation ; Organ Specificity/genetics
Chemical Substances	DNA Transposable Elements
Language	English
Publishing date	2019-12-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-13555-x
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Counties with lower insurance coverage are associated with both slower vaccine rollout and higher COVID-19 incidence across the United States

Lindemer, Emily / Choudhary, Mayank / Donadio, Gregory / Pawlowski, Colin / Soundararajan, Venky

medRxiv

Abstract: Efficient and equitable vaccination distribution is a priority for effectively outcompeting the transmission of COVID-19 globally. A recent study from the Centers for Disease Control and Prevention (CDC) identified that US counties with high social ... ...

Abstract	Efficient and equitable vaccination distribution is a priority for effectively outcompeting the transmission of COVID-19 globally. A recent study from the Centers for Disease Control and Prevention (CDC) identified that US counties with high social vulnerability according to metrics such as poverty, unemployment, low income, and no high school diploma, have significantly lower rates of vaccination compared to the national average1. Here, we build upon this analysis to consider associations between county-level vaccination rates and 68 different demographic, socioeconomic, and environmental factors for 1,510 American counties with over 228 million individuals for which vaccination data was also available. Our analysis reveals that counties with high levels of uninsured individuals have significantly lower COVID-19 vaccination rates (Spearman correlation: -0.264), despite the fact that the CDC has mandated that all COVID-19 vaccines are free and cannot be denied to anyone based upon health insurance coverage or immigration status. Furthermore, we find that the counties with high levels of uninsured individuals tend to have the highest COVID-19 incidence rates in March 2021 relative to December 2020 (Spearman correlation: 0.388). Among the 68 factors analyzed, insurance coverage is the only factor which is highly correlated with both vaccination rate and change in COVID-19 incidence during the vaccination period (\|Spearman correlation\| > 0.25). We also find that counties with higher percentages of Black and Hispanic individuals have significantly lower vaccination rates (Spearman correlations: -0.128, -0.136) and lesser declines of COVID-incidence rates (Spearman correlations: 0.334, 0.330) during the vaccination period. Surprisingly however, after controlling for race, we find that the association between lack of insurance coverage and vaccination rate as well as COVID-19 incidence rates is largely driven by counties with a majority white population. Among the counties with high proportions of white residents (top 10% decile), the association between insurance coverage and vaccination rate is significant (Spearman correlation: -0.210, p-value: 0.002), but among counties with low proportions of white residents (bottom 10% decile) this association is not significant (Spearman correlation: 0.072, p-value: 0.088). Taken together, this study highlights the fact that intricate socioeconomic factors are correlated not just to COVID-19 vaccination rates, but also to COVID-19 incidence fluctuations, underscoring the need to improve COVID-19 vaccination campaigns in marginalized communities. The strong positive correlation between low levels of health insurance coverage and low vaccination rates is particularly concerning, and calls for improved public health messaging to emphasize the fact that health insurance is not required to be eligible for any of the FDA-authorized COVID-19 vaccines in the United States.
Keywords	covid19
Language	English
Publishing date	2021-03-26
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2021.03.24.21254270
Database	COVID19

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Article ; Online: Co-opted transposons help perpetuate conserved higher-order chromosomal structures.

Choudhary, Mayank Nk / Friedman, Ryan Z / Wang, Julia T / Jang, Hyo Sik / Zhuo, Xiaoyu / Wang, Ting

Genome biology

2020 Volume 21, Issue 1, Page(s) 16

Abstract: Background: Transposable elements (TEs) make up half of mammalian genomes and shape genome regulation by harboring binding sites for regulatory factors. These include binding sites for architectural proteins, such as CTCF, RAD21, and SMC3, that are ... ...

Abstract	Background: Transposable elements (TEs) make up half of mammalian genomes and shape genome regulation by harboring binding sites for regulatory factors. These include binding sites for architectural proteins, such as CTCF, RAD21, and SMC3, that are involved in tethering chromatin loops and marking domain boundaries. The 3D organization of the mammalian genome is intimately linked to its function and is remarkably conserved. However, the mechanisms by which these structural intricacies emerge and evolve have not been thoroughly probed. Results: Here, we show that TEs contribute extensively to both the formation of species-specific loops in humans and mice through deposition of novel anchoring motifs, as well as to the maintenance of conserved loops across both species through CTCF binding site turnover. The latter function demonstrates the ability of TEs to contribute to genome plasticity and reinforce conserved genome architecture as redundant loop anchors. Deleting such candidate TEs in human cells leads to the collapse of conserved loop and domain structures. These TEs are also marked by reduced DNA methylation and bear mutational signatures of hypomethylation through evolutionary time. Conclusions: TEs have long been considered a source of genetic innovation. By examining their contribution to genome topology, we show that TEs can contribute to regulatory plasticity by inducing redundancy and potentiating genetic drift locally while conserving genome architecture globally, revealing a paradigm for defining regulatory conservation in the noncoding genome beyond classic sequence-level conservation.
MeSH term(s)	Animals ; Binding Sites ; CCCTC-Binding Factor/metabolism ; Cell Line ; Chromatin/chemistry ; Chromosomes, Mammalian/chemistry ; Humans ; Interspersed Repetitive Sequences ; Mice
Chemical Substances	CCCTC-Binding Factor ; Chromatin
Language	English
Publishing date	2020-01-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2040529-7
ISSN	1474-760X ; 1474-760X
ISSN (online)	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-019-1916-8
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Article: Publisher Correction: Co-opted transposons help perpetuate conserved higher-order chromosomal structures

Choudhary, Mayank N. K / Friedman, Ryan Z / Wang, Julia T / Jang, Hyo Sik / Zhuo, Xiaoyu / Wang, Ting

Genome biology. 2020 Dec., v. 21, no. 1

2020

Abstract: Following publication of the original paper [1], an error was reported in the processing of Fig. 2. The correct Fig. 2 is supplied below and the original article [1] has been corrected. The publishers apologize for the error. ...

Abstract	Following publication of the original paper [1], an error was reported in the processing of Fig. 2. The correct Fig. 2 is supplied below and the original article [1] has been corrected. The publishers apologize for the error.
Language	English
Dates of publication	2020-12
Size	p. 28.
Publishing place	BioMed Central
Document type	Article
Note	Published Erratum
ZDB-ID	2040529-7
ISSN	1474-760X ; 1465-6906
ISSN (online)	1474-760X
ISSN	1465-6906
DOI	10.1186/s13059-020-1944-4
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Publisher Correction: Co-opted transposons help perpetuate conserved higher-order chromosomal structures.

Choudhary, Mayank N K / Friedman, Ryan Z / Wang, Julia T / Jang, Hyo Sik / Zhuo, Xiaoyu / Wang, Ting

Genome biology

2020 Volume 21, Issue 1, Page(s) 28

Abstract	Following publication of the original paper [1], an error was reported in the processing of Fig. 2. The correct Fig. 2 is supplied below and the original article [1] has been corrected. The publishers apologize for the error.
Language	English
Publishing date	2020-02-07
Publishing country	England
Document type	Published Erratum
ZDB-ID	2040529-7
ISSN	1474-760X ; 1465-6906
ISSN (online)	1474-760X
ISSN	1465-6906
DOI	10.1186/s13059-020-1944-4
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Article ; Online: Author Correction: Exploring the coronavirus pandemic with the WashU Virus Genome Browser.

Flynn, Jennifer A / Purushotham, Deepak / Choudhary, Mayank N K / Zhuo, Xiaoyu / Fan, Changxu / Matt, Gavriel / Li, Daofeng / Wang, Ting

Nature genetics

2020 Volume 52, Issue 10, Page(s) 1132

Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

Abstract	An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Keywords	covid19
Language	English
Publishing date	2020-09-16
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-020-00714-w
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Article ; Online: Exploring the coronavirus pandemic with the WashU Virus Genome Browser.

Flynn, Jennifer A / Purushotham, Deepak / Choudhary, Mayank N K / Zhuo, Xiaoyu / Fan, Changxu / Matt, Gavriel / Li, Daofeng / Wang, Ting

Nature genetics

2020 Volume 52, Issue 10, Page(s) 986–991

MeSH term(s)	Betacoronavirus/genetics ; COVID-19 ; Coronavirus Infections/virology ; Databases, Genetic ; Genome, Viral/genetics ; Humans ; Internet ; Pandemics ; Pneumonia, Viral/virology ; SARS-CoV-2
Keywords	covid19
Language	English
Publishing date	2020-09-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-020-0697-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Higher COVID-19 vaccination rates are linked to decreased county-level COVID-19 incidence across USA

Puranik, Arjun / Venkatakrishnan, AJ / Pawlowski, Colin / Raghunathan, Bharathwaj / Ramudu, Eshwan / Lenehan, Patrick / Agarwal, Vineet / Jayaram, Savita / Choudhary, Mayank / Soundararajan, Venky

medRxiv

Abstract: Real world evidence studies of mass vaccination across health systems have reaffirmed the safety and efficacy of the FDA-authorized mRNA vaccines for COVID-19. However, the impact of vaccination on community transmission remains to be characterized. Here, ...

Abstract	Real world evidence studies of mass vaccination across health systems have reaffirmed the safety and efficacy of the FDA-authorized mRNA vaccines for COVID-19. However, the impact of vaccination on community transmission remains to be characterized. Here, we compare the cumulative county-level vaccination rates with the corresponding COVID-19 incidence rates among 87 million individuals from 580 counties in the United States, including 12 million individuals who have received at least one vaccine dose. We find that cumulative county-level vaccination rate through March 1, 2021 is significantly associated with a concomitant decline in COVID-19 incidence (Spearman correlation ⍴ = -0.22, p-value = 8.3e-8), with stronger negative correlations in the Midwestern counties (⍴ = -0.37, p-value = 1.3e-7) and Southern counties (⍴ = -0.33, p-value = 4.5e-5) studied. Additionally, all examined US regions demonstrate significant negative correlations between cumulative COVID-19 incidence rate prior to the vaccine rollout and the decline in the COVID-19 incidence rate between December 1, 2020 and March 1, 2021, with the US western region being particularly striking (⍴ = -0.66, p-value = 5.3e-37). However, the cumulative vaccination rate and cumulative incidence rate are noted to be statistically independent variables, emphasizing the need to continue the ongoing vaccination roll out at scale. Given confounders such as different coronavirus restrictions and mask mandates, varying population densities, and distinct levels of diagnostic testing and vaccine availabilities across US counties, we are advancing a public health resource to amplify transparency in vaccine efficacy monitoring (https://public.nferx.com/covid-monitor-lab/vaccinationcheck). Application of this resource highlights outliers like Dimmit county (Texas), where infection rates have increased significantly despite higher vaccination rates, ostensibly owing to amplified travel as a vaccination hub; as well as Henry county (Ohio) which encountered shipping delays leading to postponement of the vaccine clinics. This study underscores the importance of tying the ongoing vaccine rollout to a real-time monitor of spatio-temporal vaccine efficacy to help turn the tide of the COVID-19 pandemic.
Keywords	covid19
Language	English
Publishing date	2021-03-08
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2021.03.05.21252946
Database	COVID19

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