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Adaptive Protein Evolution of the Drosophila Germline Stem Cell Gene Bag of Marbles

Award Number: R01GM095793
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: 08/01/2011
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Adaptive Protein Evolution of the Drosophila Germline Stem Cell Gene Bag of Marbles - PROJECT SUMMARY Animals contain a small number of germline stem cells (GSCs) that are essential for making sperm or eggs. The decision for a dividing stem cell to renew itself or to differentiate, and the regulation of early GSC divisions are some of the most critical processes in development. Studies in the fruit fly, Drosophila melanogaster, have identified many of the key genes involved in the cellular signaling for GSC maintenance and differentiation. We have shown that the gene bag of marbles (bam), the key “switch” for GSC differentiation, is adaptively evolving with a dramatic excess of amino acid substitutions in D. melanogaster, D. simulans, D. yakuba but not in six other related species. During our current funding period we have generated new bam null mutations in sequenced genomes of D. melanogaster, D. simulans, D. yakuba, D. teissieri, and D. ananassae to test for conservation of function. These have allowed us to demonstrate that surprisingly unlike in D. melanogaster, bam is not required for female GSC differentiation in D. teissieri nor is it required for male GSC differentiation in D. teissieri and D. ananassae. We have shown that infection with different strains of the intracellular endosymbiont Wolbachia pipientis vary in their degree of rescue of the fertility defects characteristic of the bam hypomorph. This proposal focuses on identifying the functional and evolutionary consequences of observed sequence diversification at bam and discriminating between the hypothesis that bam’s role in GSC function has been selected for new functions, vs the hypothesis that interactions between bam and W. pipientis has been the evolutionary force driving changes at bam. This includes generating and analyzing novel bam hypomorphs in D. melanogaster and D. simulans, and testing interactions of these new hypomorphs with intra and interspecific Wolbachia strains. We will carry out RNA-seq studies of the bam rescue by W. pipientis. We are developing a computational model to generate experimentally testable predictions of sequence diversification under several mechanisms of interaction between W. pipientis and GSC genes. Finally, we will functionally evaluate evolutionary diversification of the bam protein sequence between D. melanogaster and D. simulans, and the loss of the requirement for bam for female and male gametogenesis and fertility in D. teissieri compared to its close relative D. yakuba. What we learn will contribute significantly to our understanding of how GSCs are regulated during development in diverse species, how such critical developmental functions can evolve, and how their mis-regulation due to mutation and interaction with germline parasites can lead to infertility, germline cancers, and reproductive isolation.


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 = $329,247 )
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	12	5/8/2024	NON-COMPETING CONTINUATION	$329,247
														Subtotal = $329,247

Issue Date FY: 2023 ( Subtotal = $339,529 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	11	5/18/2023	NON-COMPETING CONTINUATION	$339,529
														Subtotal = $339,529

Issue Date FY: 2022 ( Subtotal = $337,569 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	002	10	5/6/2022	NON-COMPETING CONTINUATION	$337,569
2022	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	9	4/15/2022	COMPETING CONTINUATION	$2,368
2022	2020	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	8	4/15/2022	NON-COMPETING CONTINUATION	-$2,368
														Subtotal = $337,569

Issue Date FY: 2021 ( Subtotal = $337,569 )
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	9	7/30/2021	COMPETING CONTINUATION	$337,569
2021	2020	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	8	7/22/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $337,569

Issue Date FY: 2020 ( Subtotal = $322,164 )
2020	2020	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	8	4/30/2020	NON-COMPETING CONTINUATION	$322,164
														Subtotal = $322,164

Issue Date FY: 2019 ( Subtotal = $322,683 )
2019	2019	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	7	5/9/2019	NON-COMPETING CONTINUATION	$322,683
														Subtotal = $322,683

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	6	5/14/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $323,144 )
2017	2017	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	002	6	6/16/2017	NON-COMPETING CONTINUATION	$323,144
2017	2016	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	5	1/28/2017	COMPETING CONTINUATION	$19,858
2017	2014	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	4	1/28/2017	NON-COMPETING CONTINUATION	-$19,858
														Subtotal = $323,144

Issue Date FY: 2016 ( Subtotal = $323,555 )
2016	2016	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	002	5	9/16/2016	COMPETING CONTINUATION	$323,555
2016	2014	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	4	7/26/2016	NON-COMPETING CONTINUATION	$0
2016	2014	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	4	9/13/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $323,555

Issue Date FY: 2014 ( Subtotal = $309,794 )
2014	2014	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	4	7/31/2014	NON-COMPETING CONTINUATION	$309,794
														Subtotal = $309,794

Issue Date FY: 2013 ( Subtotal = $299,090 )
2013	2013	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	3	7/29/2013	NON-COMPETING CONTINUATION	$299,090
														Subtotal = $299,090

Issue Date FY: 2012 ( Subtotal = $310,066 )
2012	2012	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	2	7/17/2012	NON-COMPETING CONTINUATION	$310,066
														Subtotal = $310,066

Issue Date FY: 2011 ( Subtotal = $310,180 )
2011	2011	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	1	7/25/2011	NEW	$310,180
														Subtotal = $310,180

Grand Total All Awards = $3,864,590

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Adaptive Protein Evolution of the Drosophila Germline Stem Cell Gene Bag of Marbles

Award Number: R01GM095793

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: 08/01/2011

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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