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A new system for modeling supernumerary chromosome dynamics and formation during meiosis.

Award Number: R00HD099276
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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A new system for modeling supernumerary chromosome dynamics and formation during meiosis. - PROJECT SUMMARY The normal growth, development, and reproduction of an organism relies on a defined set of essential chromosomes. At conception, the gain or loss of whole chromosomes is generally lethal and is thought to be the leading cause of spontaneous abortions in humans. Though the presence of a whole chromosome can be lethal, the gain of only part of a chromosome can be viable. Small supernumerary marker chromosomes (sSMCs) are structurally abnormal chromosomes that are present in ~1/2300 births and have been linked to infertility, fetal loss, and intellectual and developmental disabilities. Despite their clear impact on human health, very little is understood about important aspects of sSMC biology. Patient studies and human cell lines have been instrumental in determining the composition and frequency of existing sSMCs, but these systems are unable to model sSMC dynamics and formation during complex developmental processes. To close this knowledge gap, I will use the supernumerary B chromosomes recently found in D. melanogaster as a tractable model system to gain fundamental insight into supernumerary chromosome biology during female meiosis. Similar to some sSMCs described in humans, the B chromosomes can disrupt meiotic chromosome segregation, are subject to sex-specific differences in transmission frequency to progeny, and were formed from an essential chromosome. I will determine how B chromosomes disrupt the segregation of essential chromosomes during female meiosis using a genetic approach to monitor chromosome missegregation relative to a wide-ranging number of B chromosomes. I will then complement this genetic analysis with the visualization of live female meioses to gain a comprehensive view of meiotic supernumerary chromosome dynamics. To elucidate how B chromosomes are preferentially transmitted during female meiosis, I will identify differences in the centromeres of the B chromosomes and the essential chromosomes with high resolution by measuring the centromeric domains on chromatin fibers and conducting long-read sequencing and assembly of centromeric regions. Finally, I will determine the mechanism of supernumerary chromosome formation by strategically marking one of the essential chromosomes so that I can easily identify the formation of a new supernumerary chromosome. Based on the unique arrangement of markers this new supernumerary chromosome carries, I will deduce the mechanism by which it formed. Together, this work will allow me to gain research training in several areas that are essential for the continued investigation of supernumerary chromosome dynamics and formation, providing a foundation for my future research as an independent investigator examining how supernumerary chromosomes promote infertility, reduce gamete quality, and form de novo during meiosis.


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: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	000	5	1/16/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	000	5	9/10/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $228,192 )
2023	2023	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	003	5	1/20/2023	NON-COMPETING CONTINUATION	$205,374
2023	2023	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	004	5	2/7/2023	NON-COMPETING CONTINUATION	$22,819
2023	2022	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	002	4	12/15/2022	NON-COMPETING CONTINUATION	$79,473
2023	2021	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	001	3	11/15/2022	EXTENSION WITH OR WITHOUT FUNDS	$35,246
2023	2021	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	000	3	10/20/2022	EXTENSION WITH OR WITHOUT FUNDS	-$114,720
														Subtotal = $228,192

Issue Date FY: 2022 ( Subtotal = $237,107 )
2022	2022	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	002	4	4/22/2022	NON-COMPETING CONTINUATION	$23,712
2022	2022	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	001	4	3/3/2022	NON-COMPETING CONTINUATION	$98,675
2022	2021	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	000	3	2/16/2022	EXTENSION WITH OR WITHOUT FUNDS	$114,720
														Subtotal = $237,107

Issue Date FY: 2021 ( Subtotal = $249,000 )
2021	2021	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	000	3	1/11/2021	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $714,299

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A new system for modeling supernumerary chromosome dynamics and formation during meiosis.

Award Number: R00HD099276

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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