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Structurally complex genome loci in human populations and human phenotypes

Award Number: R01HG006855
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/18/2012
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Structurally complex genome loci in human populations and human phenotypes - SUMMARY/ABSTRACT Structurally complex loci (SCLs) are hotspots of genome dynamism whose relationship to human phenotypic variation is unknown. SCLs have multiple segments of duplicated DNA sequence which can contain or flank genes, exons, or regulatory elements; these repeated sequences recombine with one another to generate new alleles by non-allelic homologous recombination and gene conversion, creating many functionally distinct alleles with different gene dosages and/or protein structures. Human genetics does not yet know the alleles that are present at most SCLs, nor their relationship to human phenotypic variation. Genetic variation at SCLs tends to arise from many alleles, to be hard to assemble, and to have complex relationships to nearby SNPs and SNP haplotypes. Yet SCLs provide a real opportunity to relate phenotypes to allelic series of functional alleles with interpretable effects on gene dosage or protein domain structure. In this work, we will develop ways to ascertain how SCLs at loci across the genome are comprised of allelic series and relate to a diverse set of human phenotypes. To do this, we will combine data from many forms of genome analysis – definitive long-read data (n ~102 and growing), whole-genome and whole-exome sequence data (104-105) and SNP array data (105-107) with companion phenotype data. In Aim 1, we will develop methods to reveal the full spectrum of variation at SCLs. We will (a) identify variable DNA features and the ways in which these features vary and co-distribute across thousands of people of diverse ancestries, and (b) find the underlying alleles and allele frequencies that explain this population-scale variation. In Aim 2, we will enable powerful genotype-phenotype analyses that leverage vast existing SNP data sets; we will do this by creating large panels of reference haplotypes of SCL alleles and surrounding SNPs, and advancing methods for imputing SCL alleles into SNP data. In Aim 3, we will advance approaches for genetic association analysis and fine-mapping at SCLs, and explore the functional consequences of SCLs on quantitative traits and disease risk. We aspire to make and enable many more discoveries about how allelic series at structurally complex loci shape human phenotypes.


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: 2026 ( Subtotal = $710,192 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	13	1/28/2026	NON-COMPETING CONTINUATION	$710,192
														Subtotal = $710,192

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	12	9/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $710,192 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	12	6/5/2024	NON-COMPETING CONTINUATION	$710,192
														Subtotal = $710,192

Issue Date FY: 2023 ( Subtotal = $724,685 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	11	6/1/2023	NON-COMPETING CONTINUATION	$724,685
														Subtotal = $724,685

Issue Date FY: 2022 ( Subtotal = $724,685 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	001	10	8/18/2022	NON-COMPETING CONTINUATION	$724,685
2022	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	9	1/31/2022	COMPETING CONTINUATION	$0
														Subtotal = $724,685

Issue Date FY: 2021 ( Subtotal = $722,548 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	001	9	8/12/2021	COMPETING CONTINUATION	$722,548
2021	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	8	2/5/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $722,548

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	8	9/23/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $655,416 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	8	5/22/2019	NON-COMPETING CONTINUATION	$655,416
														Subtotal = $655,416

Issue Date FY: 2018 ( Subtotal = $655,416 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	7	5/25/2018	NON-COMPETING CONTINUATION	$655,416
														Subtotal = $655,416

Issue Date FY: 2017 ( Subtotal = $655,416 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	002	6	5/27/2017	NON-COMPETING CONTINUATION	$655,416
2017	2016	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	001	5	1/5/2017	COMPETING CONTINUATION	$13,242
2017	2015	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	4	1/5/2017	NON-COMPETING CONTINUATION	-$13,242
														Subtotal = $655,416

Issue Date FY: 2016 ( Subtotal = $655,416 )
2016	2016	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	001	5	8/22/2016	COMPETING CONTINUATION	$655,416
2016	2015	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	4	8/19/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $655,416

Issue Date FY: 2015 ( Subtotal = $487,499 )
2015	2015	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	4	6/16/2015	NON-COMPETING CONTINUATION	$487,499
														Subtotal = $487,499

Issue Date FY: 2014 ( Subtotal = $490,000 )
2014	2014	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	3	5/22/2014	NON-COMPETING CONTINUATION	$490,000
														Subtotal = $490,000

Issue Date FY: 2013 ( Subtotal = $477,500 )
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	2	7/20/2013	NON-COMPETING CONTINUATION	$477,500
														Subtotal = $477,500

Issue Date FY: 2012 ( Subtotal = $500,000 )
2012	2012	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	1	8/17/2012	NEW	$500,000
														Subtotal = $500,000

Grand Total All Awards = $8,168,965

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Structurally complex genome loci in human populations and human phenotypes

Award Number: R01HG006855

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/18/2012

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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