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The coevolutionary dynamics of pleiotropic genetic architecture

Award Number: R35GM138007
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: 05/11/2025

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The coevolutionary dynamics of pleiotropic genetic architecture - PROJECT SUMMARY/ABSTRACT The coevolution of hosts and parasites is mediated by genetic mutations that allow one side to gain an advantage over the other. As the host immune system bears the primary burden of responding to evolving parasites, it is expected to adapt or diversify in response to natural selection. However, recent population genetics analyses from a variety of animal taxa only partially bear out this hypothesis, revealing a paucity of adaptive evolution among innate immune gene repertoires relative to expectations. My recent work suggests that an appreciable proportion of genes associated with innate immune responses in taxa as broad as humans, insects and plants are pleiotropic, meaning that they also play unrelated roles in other organismal traits like development and the response to abiotic stress. This observation raises the possibility of temporal and evolutionary tension between the use of a gene product for developmental and immunological functions. Current coevolutionary theory largely fails to account for sources of genetic constraint on host defenses, impeding the translation of existing coevolutionary models into predictions for evolutionary dynamics at the molecular or system level. Moving forward, a major focus of research in my lab will be to explore the role of pleiotropic genetic architecture on the evolvability of host immune systems in response to parasite pressure. To tackle this long-term objective, my lab will employ several complementary approaches. Using transcriptome data, we will define the extent and dynamics of pleiotropy among developmental, stress, and immunological pathway genes in a variety of insect model species. We will perform genome-wide evolutionary genetics analyses in these insect species to quantify signatures of selection on pleiotropic and non-pleiotropic developmental, immunological, and stress response gene sets relative to null expectations. We will build mathematical models of immune pathway protein networks possessing different properties – modularity, redundancy, complexity, pleiotropy – and allow them to co-evolve with parasites, quantifying changes in fitness landscapes to better understand network structures that constrain or promote host adaptation. In parallel, we will run coevolution experiments using the flour beetle Tribolium castaneum and its natural parasites. We will manipulate the strength of pleiotropic antagonism among immunity and other processes in these experiments by limiting host-microbe interactions to a particular developmental stage or altering abiotic stress conditions, and then compare the evolutionary trajectories and genetic bases of host-microbe interaction outcomes. Together, these research avenues will provide insight into an array of fundamental questions about the extent of genetic pleiotropy among essential physiological processes, the influence of pleiotropy on coevolutionary dynamics, and the role of immune system architecture in host adaptation to parasite pressure. Gaining greater insight into the evolutionary forces that shape biological systems has important implications for predicting human pathogen evolution, understanding the origins of diseases like autoimmunity and sepsis, and designing therapeutic treatments that minimize side effects.


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: 2025 ( Subtotal = $435,637 )
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	6	5/11/2025	COMPETING CONTINUATION	$435,637
2025	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	002	5	8/27/2025	NON-COMPETING CONTINUATION	$0
2025	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	5	4/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $435,637

Issue Date FY: 2024 ( Subtotal = $396,004 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	5	7/23/2024	NON-COMPETING CONTINUATION	$39,600
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	5	3/21/2024	NON-COMPETING CONTINUATION	$356,404
														Subtotal = $396,004

Issue Date FY: 2023 ( Subtotal = $396,004 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	4	4/26/2023	NON-COMPETING CONTINUATION	$396,004
														Subtotal = $396,004

Issue Date FY: 2022 ( Subtotal = $396,004 )
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	3	4/4/2022	NON-COMPETING CONTINUATION	$356,403
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	3	7/14/2022	NON-COMPETING CONTINUATION	$39,601
														Subtotal = $396,004

Issue Date FY: 2021 ( Subtotal = $395,796 )
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	2	4/22/2021	NON-COMPETING CONTINUATION	$395,796
														Subtotal = $395,796

Issue Date FY: 2020 ( Subtotal = $386,636 )
2020	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	1	6/22/2020	NEW	$386,636
														Subtotal = $386,636

Grand Total All Awards = $2,406,081

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The coevolutionary dynamics of pleiotropic genetic architecture

Award Number: R35GM138007

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: 05/11/2025

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