Thursday, November 21, 2024 11/21/2024

An ethnically diverse genomic reference resource for the human heavy and light chain immunoglobulin loci

Award Number: R24AI138963
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY There is a fundamental gap in our understanding of how germline variation in the immunoglobulin (IG) heavy (IGH) and light chain (kappa, IGK; lambda, IGL) loci in the human population impacts the development of the functional antibody (Ab) response in health and disease. However, there is growing appreciation for the fact that IG polymorphism contributes to variability in the Ab repertoire, indicating that the integration of IG genetic data in basic and biomedical research can inform our understanding of how IG gene regulation, as well as Ab repertoire dynamics, function in various clinical contexts. A critical barrier to progress has been that existing genomic resources for the IG loci are incomplete and poorly represent diversity across human populations, particularly those from non-European ancestries. Evidence continues to accumulate in support of the notion that the IG regions are among the most structurally complex and polymorphic regions of the human genome, enriched for large structural variants (SVs) and single nucleotide variants (SNVs), resulting in extreme interindividual haplotype variation. These complexities have long made the IG loci difficult to study using standard high- throughput methods, with direct negative impacts on genetic disease association studies and, more recently, the analysis of adaptive immune receptor repertoire sequencing (AIRR-seq) data. As a result, knowledge of human IG germline diversity, particularly in populations underrepresented in genomics databases, and its contribution to disease lags far behind that of other well-studied immune loci. This highlights a direct need for publicly available, well-characterized IG haplotype references and accurate variant catalogues from diverse ethnic backgrounds to facilitate the design and integration of more accurate genotyping tools, analysis pipelines, and their interpretation. To meet these needs, we have developed this renewal proposal, which will build the most comprehensive IG genomic dataset to date, with transformative potential impact for the fields of B cell immunology and immunogenetics. The resource generated will: (i) shed light on the extent of IG diversity worldwide; (ii) establish a framework for linking genetic data to expressed antibody repertoire variation to inform our understanding of V(D)J recombination and seed models of antibody repertoire dynamics; and (iii) substantially augment key databases and research initiatives pushing the frontiers of genomics and immunology research. This renewal project will seamlessly build and expand upon the foundational IG genomics data generated in our initial proposal and continue to establish desperately needed genomic resources for the human IG loci, particularly in underrepresented populations and cohorts of immediate biomedical relevance, which will serve the immunology and larger genomics communities for years to come.


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 = $782,409 )
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	002	7	8/12/2024	NON-COMPETING CONTINUATION	$782,409
2024	2022	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	001	5	2/7/2024	COMPETING CONTINUATION	$37,524
2024	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	4	2/7/2024	NON-COMPETING CONTINUATION	-$37,524
														Subtotal = $782,409

Issue Date FY: 2023 ( Subtotal = $782,409 )
2023	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	6	8/17/2023	NON-COMPETING CONTINUATION	$782,409
														Subtotal = $782,409

Issue Date FY: 2022 ( Subtotal = $782,096 )
2022	2022	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	001	5	8/30/2022	COMPETING CONTINUATION	$782,096
2022	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	4	8/22/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $782,096

Issue Date FY: 2021 ( Subtotal = $381,785 )
2021	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	4	6/25/2021	NON-COMPETING CONTINUATION	$381,785
														Subtotal = $381,785

Issue Date FY: 2020 ( Subtotal = $386,405 )
2020	2020	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	3	6/25/2020	NON-COMPETING CONTINUATION	$386,405
														Subtotal = $386,405

Issue Date FY: 2019 ( Subtotal = $394,002 )
2019	2019	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	2	6/14/2019	NON-COMPETING CONTINUATION	$394,002
														Subtotal = $394,002

Issue Date FY: 2018 ( Subtotal = $415,871 )
2018	2018	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	1	7/23/2018	NEW	$415,871
														Subtotal = $415,871

Grand Total All Awards = $3,924,977

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An ethnically diverse genomic reference resource for the human heavy and light chain immunoglobulin loci

Award Number: R24AI138963

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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