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Mechanisms and Evolution of Host Tolerance to Transposable Elements

Award Number: R35GM138112
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: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Mechanisms and Evolution of Host Tolerance to Transposable Elements - PROJECT SUMMARY/ABSTRACT Transposable elements (TEs) are omnipresent genomic parasites, comprising >70% of the nuclear DNA in certain lineages. In addition to producing deleterious mutations, TEs can exert lethal, genotoxic effects on host cells by causing double-stranded breaks during insertion and excision. Host genomes have two mechanisms for avoiding the fitness costs of parasitic TEs: resistance and tolerance. Mechanisms of resistance reduce TE load by repressing transposition, while mechanisms of tolerance reduce the fitness consequences of existing TEs. While resistance to TEs is studied extensively, with small-RNAs in particular emerging as a taxonomically widespread strategy, tolerance is a new concept that I have recently proposed. Furthermore, through an innovative QTL mapping experiment, I provided critical proof-of-principle for tolerant genetic variants in Drosophila melanogaster. In the future, I propose to build on these recent discoveries to expand our understanding of tolerance mechanisms and evolution. First, we will study the mechanism and recent evolutionary history of bruno-dependent tolerance to P- element DNA transposons. Bruno is a developmental regulator of oogenesis, which we have recently demonstrated is a major determinant of female germline tolerance to unregulated P-element transposition. By combining genetic analysis of mutant alleles, as well tolerant bruno variants we have isolated from natural populations, we will reveal the underlying mechanism of bruno-dependent tolerance. Furthermore, by taking advantage of the unique opportunity provided by historic D. melanogaster collections, we will evaluate the contribution of bruno tolerant variants to the host adaptation to the P-element invasion in the mid 20th century. My second research direction is motivated by our discovery that natural variation in heterochromatin is an important determinant of how cells are impacted by unregulated transposition: larger doses of heterochromatin and reduced heterochromatin formation decrease cellular tolerance. These observations are reminiscent of Barbara McClintock's “genomic shock” model, in which tremors arising from DNA damage or cellular stress trigger the release normally quiescent repeats. I therefore propose to interrogate the relationship between heterochromatic variation and response to genotoxic stress at both the cellular and regulatory levels. My long-term goal is to reveal complex and intimate relationships between TEs and their hosts, which contribute to genome evolution and shape the evolution of gametogenesis. A better understanding of these interactions is of vital importance because: 1) they are the interface at which TEs and host cells coevolve, 2) TE activity is implicated in the onset, progression of many tumor types and age related neurodegenerative diseases, and 3) vast differences in TE content and distribution between host genomes remain largely unexplained.


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 = $322,468 )
2024	2024	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	000	5	5/6/2024	NON-COMPETING CONTINUATION	$322,468
														Subtotal = $322,468

Issue Date FY: 2023 ( Subtotal = $345,449 )
2023	2023	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	001	4	6/29/2023	SUPPLEMENT FOR EXPANSION	$22,981
2023	2023	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	000	4	4/26/2023	NON-COMPETING CONTINUATION	$322,468
														Subtotal = $345,449

Issue Date FY: 2022 ( Subtotal = $386,214 )
2022	2022	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	3	4/20/2022	NON-COMPETING CONTINUATION	$386,214
														Subtotal = $386,214

Issue Date FY: 2021 ( Subtotal = $384,722 )
2021	2021	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	2	4/22/2021	NON-COMPETING CONTINUATION	$384,722
														Subtotal = $384,722

Issue Date FY: 2020 ( Subtotal = $385,263 )
2020	2020	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	1	6/22/2020	NEW	$385,263
														Subtotal = $385,263

Grand Total All Awards = $1,824,116

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Mechanisms and Evolution of Host Tolerance to Transposable Elements

Award Number: R35GM138112

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: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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