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Discovery and functional analysis of novel candidate genes and variants underlying craniofacial diversification in Cyprinodon pupfishes

Award Number: R01DE027052
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary: Craniofacial abnormalities are the most common form of human birth defect, but their molecular basis remains poorly understood. Highly conserved craniofacial developmental pathways shared across diverse vertebrate species have been shaped by adaptive evolution to produce a tremendous diversity of adaptive craniofacial phenotypes. Fundamental investigation of the genetic basis of these phenotypes will lead to better diagnosis, prevention, and treatment of human birth defects. Indeed, complementary or new information on the genetic basis of many human pathologies can be obtained from naturally occurring organisms, particularly non-model vertebrates, that display analogous divergent phenotypes, known as ‘evolutionary mutant’ models. These natural systems are becoming increasingly tractable for genomic and transgenic approaches and provide an opportunity for ‘evolutionary’ forward genetics. Here I propose to build on my lab’s demonstrated success developing a new vertebrate system studying the genetic basis of highly divergent craniofacial morphology in Caribbean pupfishes. Pupfish exhibit novel craniofacial features not found in other non-model fish systems and are highly tractable for laboratory studies with life histories and eggs comparable to zebrafish. Ongoing gene flow and strong selection for divergent craniofacial features provide an ideal natural ‘experiment’ for fine-mapping candidate variants associated with these traits. Our initial success confirming three new craniofacial genes in Caribbean pupfishes and identifying 27 candidate craniofacial genes found in other vertebrates demonstrates the power and potential of our approach. I hypothesize that fixed mutations between these species control spatiotemporal expression of both known and novel craniofacial genes underlying the highly divergent craniofacial features observed in pupfishes. I propose to investigate the genetic basis of novel adaptive phenotypes in this non-model system using a combination of population genomics, de novo genome assemblies, phenomics, quantitative genetics, transcriptomics, in situ hybridization, gene overexpression and chemical inhibition, and CRISPR-Cas9 genome editing. By integrating candidate gene and variant discovery with functional genetics in a natural system exhibiting diverse craniofacial features the proposed research will demonstrate the feasibility and power of new non-model systems to gain novel insights into the developmental genetics of human diseases.


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 = $428,985 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Oral Diseases and Disorders Research	000	7	3/20/2024	COMPETING CONTINUATION	$428,985
														Subtotal = $428,985

Issue Date FY: 2022 ( Subtotal = $337,282 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Oral Diseases and Disorders Research	000	6	5/16/2022	NON-COMPETING CONTINUATION	$337,282
														Subtotal = $337,282

Issue Date FY: 2021 ( Subtotal = $341,951 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Oral Diseases and Disorders Research	000	5	5/19/2021	NON-COMPETING CONTINUATION	$341,951
														Subtotal = $341,951

Issue Date FY: 2020 ( Subtotal = $343,153 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Oral Diseases and Disorders Research	005	4	6/12/2020	NON-COMPETING CONTINUATION	$343,153
2020	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Oral Diseases and Disorders Research	003	2	3/14/2020	NON-COMPETING CONTINUATION	-$24,482
2020	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Oral Diseases and Disorders Research	004	3	3/14/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$262,039
2020	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Oral Diseases and Disorders Research	000	2	11/25/2019	NON-COMPETING CONTINUATION	-$334,158
2020	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Oral Diseases and Disorders Research	001	3	11/27/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$334,158
2020	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Oral Diseases and Disorders Research	002	1	3/14/2020	NEW	-$237,557
														Subtotal = $343,153

Issue Date FY: 2019 ( Subtotal = $358,640 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Oral Diseases and Disorders Research	000	2	5/15/2019	NON-COMPETING CONTINUATION	$358,640
														Subtotal = $358,640

Issue Date FY: 2018 ( Subtotal = $358,797 )
2018	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Oral Diseases and Disorders Research	000	1	7/31/2018	NEW	$358,797
														Subtotal = $358,797

Grand Total All Awards = $2,168,808

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Discovery and functional analysis of novel candidate genes and variants underlying craniofacial diversification in Cyprinodon pupfishes

Award Number: R01DE027052

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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