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Mechanisms and evolutionary consequences of transposon strategies to counteract host silencing

Award Number: R01GM140163
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Mechanisms and evolutionary consequences of transposon strategies to counteract host silencing - PROJECT SUMMARY Harboring active transposable elements (TEs) imposes a substantial mutational burden on the host genome. To reduce this burden, most organisms have evolved sophisticated, and often multi-layered, mechanisms for identifying and inactivating TEs. In spite of these defenses, active TEs are found in the genomes of almost all eukaryotes. One explanation for the evolutionary persistence of TEs is that they are in an “arms race” with their host genome: TEs are constantly evolving novels ways to block or evade host silencing while the host genome is continuously evolving to re-establish TE suppression. While this theory is appealing, there is a gap in knowledge because the mechanisms by which TEs could block or evade host defenses are largely unknown. The long-term goal of this applicant’s laboratory is to understand the evolutionary dynamics of TE/host co- evolution. The overall objective of this project is to understand and functionally validate a novel TE strategy, discovered in the applicant’s laboratory, that involves TEs using their own piRNAs to target host silencing factors for suppression. Preliminary data produced in the applicant’s laboratory suggests that the Drosophila melanogaster telomeric transposon TART-A captured a portion of the host TE silencing factor nxf2, which allows TART-A to produce piRNAs targeting nxf2 for suppression. The rationale for the proposed research is that it will provide critical insight into the mechanisms of host-TE conflict and how TE counter-defense strategies can impact host gene expression and fitness. The objective of this project will be achieved by pursuing three specific aims: 1) Identify genes acquired by telomeric TEs across Drosophila; 2) Determine whether non-telomeric transposons also use a piRNA-mediated counter-silencing strategy; and 3) Disrupt TE counter-silencing using CRISPR in D. melanogaster. Telomeric TEs will be identified in 28 species of Drosophila and assayed to determine whether they have acquired host gene fragments. The applicant’s laboratory has identified 45 candidate genes in D. melanogaster that share homology with TE-derived piRNAs and are known to play a role in TE suppression. These genes will be tested to determine if they suppress the same TE with which they share homology. Candidate TE/gene pairs will be validated using CRISPR genome editing to erase their shared homology, which should result in upregulation of the gene in question. The proposed research is innovative because it represents a substantial departure from the status quo: instead of the host-centric view of previous studies, which examine how the genome responds to TE activity, this project will study the TE side of the equation by investigating how TEs respond to and counteract host defenses. One of the major goals of the field is to understand why host genes involved in TE silencing are rapidly evolving. The proposed research is significant because it will support this goal by characterizing and functionally validating a specific TE counter-defense strategy, which will provide empirical support for the arms race theory, while also increasing understanding of the co-evolutionary dynamics between host genomes and their TE associates.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $314,000 )
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	1/22/2024	NON-COMPETING CONTINUATION	$282,600
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	4	6/20/2024	NON-COMPETING CONTINUATION	$31,400
														Subtotal = $314,000

Issue Date FY: 2023 ( Subtotal = $382,039 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	3	12/14/2022	NON-COMPETING CONTINUATION	$282,600
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	3	1/18/2023	SUPPLEMENT FOR EXPANSION	$68,039
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	002	3	3/28/2023	NON-COMPETING CONTINUATION	$31,400
														Subtotal = $382,039

Issue Date FY: 2022 ( Subtotal = $450,078 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	12/20/2021	NON-COMPETING CONTINUATION	$282,600
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	2	1/11/2022	SUPPLEMENT FOR EXPANSION	$136,078
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	002	2	8/3/2022	NON-COMPETING CONTINUATION	$31,400
														Subtotal = $450,078

Issue Date FY: 2021 ( Subtotal = $381,039 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	1	6/18/2021	SUPPLEMENT FOR EXPANSION	$68,039
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	12/22/2020	NEW	$313,000
														Subtotal = $381,039

Grand Total All Awards = $1,527,156

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Mechanisms and evolutionary consequences of transposon strategies to counteract host silencing

Award Number: R01GM140163

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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