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Evolutionary dynamics of antibody affinity maturation

Award Number: F31AI150163
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 05/01/2022

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Evolutionary dynamics of antibody affinity maturation - Project summary To defend against rapidly evolving pathogens, jawed vertebrates have specialized cells—lymphocytes—that evolve during an individual's lifetime to mount adaptive immune responses. Massive somatic diversity is maintained in loci that encode receptors on lymphocytes that can detect foreign antigen. B cells—lymphocytes that make antibodies—bind antigen with the B cell receptor (BCR), and diversify in microanatomical structures called germinal centers (GCs) where they proliferate while mutating the BCR. This process of afﬁnity matura- tion is classically understood to impose selection for increased antigen binding afﬁnity: surviving cells mature to become high-afﬁnity memory B cells or plasma cells that secrete antibodies (the soluble form of the BCR). There is great potential for productive dialog between experiment, theory, and computation to learn new immunology and new evolutionary dynamics from these systems. Indeed, recent studies reveal a literature conﬂicted regarding GC evolution as adaptive toward high afﬁnity. The hypothesis of this application is that GC evolutionary dynamics balance adaptation towards antigen speciﬁcity with neutral diversiﬁcation that fortiﬁes against antigenic drift. The research strategy is to develop quantitative models of GC evolution in a tight feedback loop with model organism experimental design of increasing complexity. Using mouse models, control can be exerted over B cell repertoire diversity, receptor afﬁnity, and antigen targeting. Evolution in GCs can be tracked using both receptor sequencing and lineage tracing technology. Aim 1 will analyze GC BCR evolution in a mouse model with a monoclonal BCR and a model antigen exposure, such that all GC reactions constitute replicated evolution from the same ancestral state. Aim 2 will develop theoretical and computational tools to infer ﬁtness, convergence, and contingency from the (quasi-)replicated evolutionary dynamics that characterize both our experimental models and natural repertoires. Aim 3 will design and analyze two mouse models of increasing repertoire complexity, and investigate recall responses to modiﬁed antigens. The training plan is designed to synthesize expertise in theoretical and computational evolutionary biology with immunology, and advance both hard and soft skills necessary for a future as a independent investigator. Co-sponsors Dr. Frederick Matsen and Dr. Kelley Harris combine expertise in mathematical and computa- tional biology and immunology, and population genetics. B cell immunologist Dr. Gabriel Victora will be a close collaborator; his lab will lead experimental development of the mouse models. I will also collaborate with theoretical physicist Dr. Armita Nourmohammad, who has expertise in rapid evolutionary dynamics. My thesis committee adds Dr. Phil Green and Dr. Joe Felsenstein as computational and theoretical resources. This interdisciplinary research team is matched to the proposed aims as a synthesis of distinct ﬁelds.


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: 2023 ( Subtotal = -$31,017 )
2023	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	4	5/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$11,994
2023	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	3	5/15/2023	NON-COMPETING CONTINUATION	-$1,526
2023	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	4	10/14/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$17,497
														Subtotal = -$31,017

Issue Date FY: 2022 ( Subtotal = $44,191 )
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	3	5/27/2022	NON-COMPETING CONTINUATION	-$36,887
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	4	5/27/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$37,603
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	3	12/16/2021	NON-COMPETING CONTINUATION	$43,475
														Subtotal = $44,191

Issue Date FY: 2021 ( Subtotal = $43,475 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	12/11/2020	NON-COMPETING CONTINUATION	$42,959
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	2	2/11/2021	NON-COMPETING CONTINUATION	$516
														Subtotal = $43,475

Issue Date FY: 2020 ( Subtotal = $42,959 )
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	1	12/19/2019	NEW	$0
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	12/19/2019	NEW	$42,455
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	1	3/5/2020	NEW	$504
														Subtotal = $42,959

Grand Total All Awards = $99,608

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Evolutionary dynamics of antibody affinity maturation

Award Number: F31AI150163

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 05/01/2022

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