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Causes and human health consequences of the evolution of retroelements and host restriction factors

Award Number: R00GM112941
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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DESCRIPTION (provided by applicant): Primates and their endogenous retroelements have coevolved for so long that almost half the human genome is derived from retroelements sequences. However, the replication of retroelements has the potential to inflict substantial harm by jumping into essential genes or activating the immune system to drive autoimmunity. To combat these deleterious effects on their genome, hosts have evolved a battery of restriction factors to block the replication of retroelements. Despite their importance to host fitness, I have found that many of these retroelements restriction factors have evolved rapidly during primate evolution, suggesting they have been recurrently selected for functional innovation. I hypothesize that primates and their endogenous retroelements are engaged in an `evolutionary arms race', or a recurrent cycle of evasion and restriction - retroelement adaptation to evade host restriction followed by host adaptation to restrict the newly evasive retroelement. In addition, my preliminary findings suggest that some restriction factors like APOBEC3A may also have been co- opted to restrict infectious viruses in addition to endogenous retroelements. In Aim 1, I propose to characterize the causes and consequences of the rapid evolution of the APOBEC3A and APOBEC3B restriction factors, including how these factors may be evolving to chase L1 retroelements and how co-option of APOBEC3A to restrict infectious viruses has affected its ability to restrict endogenous retroelements. In Aim 2, I propose to test the hypothesis that L1TD1 (a rapidly evolving, stem cell-specific gene that was domesticated from a portion of L1) functions as a retroelements restriction factor. In Aim 3, I propose to use evolutionary analyses, as well as engineer an in vitro evolution system to test whether variation can indeed increase retroelement replication and exert selective pressure on the host. While my past training has enabled me to generate these intriguing hypotheses, my immediate goals are to gain the additional training in virology, molecular evolution, and retroelement biology that are absolutely necessary for me to experimentally test these ideas. I have assembled an accomplished and highly skilled group of mentors/collaborators to provide me with this additional training. During the two year mentored phase, I will train with Dr. Michael Emerman to learn virology. My mentor, Dr. Harmit Malik will provide additional training in the computational analysis of repetitive elements, and Dr. John Moran will provide collaboration and training on my development of new reagents and techniques to study retroelements. This future training combined with my graduate and postdoctoral experience will enable me to pursue a multifaceted approach to understanding the biology and evolution of retroelements and their hosts. These experiments will also establish novel mechanisms by which this evolution may drive human disease.


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: 2022 ( Subtotal = $0 )
2022	2020	PACIFIC NW RESEARCH INSTITUTE	720 BROADWAY	SEATTLE	WA	98122	KING	USA	Biomedical Research and Research Training	000	5	8/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $249,000 )
2020	2020	PACIFIC NORTHWEST RESEARCH INSTITUTE	720 BROADWAY	SEATTLE	WA	98122	KING	USA	Biomedical Research and Research Training	000	5	2/27/2020	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2019 ( Subtotal = $249,000 )
2019	2019	PACIFIC NORTHWEST RESEARCH INSTITUTE	720 BROADWAY	SEATTLE	WA	98122	KING	USA	Biomedical Research and Research Training	000	4	2/22/2019	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2018 ( Subtotal = $250,894 )
2018	2018	PACIFIC NORTHWEST RESEARCH INSTITUTE	720 BROADWAY	SEATTLE	WA	98122	KING	USA	Biomedical Research and Research Training	001	3	2/23/2018	EXTENSION WITH OR WITHOUT FUNDS	$1,894
2018	2018	PACIFIC NORTHWEST RESEARCH INSTITUTE	720 BROADWAY	SEATTLE	WA	98122	KING	USA	Biomedical Research and Research Training	000	3	2/22/2018	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $250,894

Grand Total All Awards = $748,894

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Causes and human health consequences of the evolution of retroelements and host restriction factors

Award Number: R00GM112941

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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