Abstract

The overall objective of this proposal is to characterize the structure and function of human centromeres, which are the fundamental chromosome components that ensure proper chromosome segregation during cell division. Errors in chromosome segregation result in aneuploidy and birth defects, and neoplasias. Neocentromeres are a clinically ascertained human centromere variant that provide mitotic stability to chromosomal fragments that have separated from endogenous centromeres. They have formed on single or low copy genomic DNA and do not contain the tandemly repeated alpha satellite DNA found at all endogenous human centromeres. The formation of neocentromeres on complex low-copy genomic DNA permits the structural and functional dissection of human centromeres onto the underlying linear DNA sequences. The following three Specific Aims will investigate human centromeres by 1) identification of the DNA sequences found at a collection of 12 neocentromeres that have formed in chromosome 13q, 2) use of neocentromeres to investigate the chromatin domain structure and minimal DNA sequences required for human centromere function, 3) analysis of the DNA sequence and chromosomal context at multiple independent neocentromeres from the same chromosomal location to investigate the requirements for human centromere formation. Investigation of human centromere structure, function and formation will greatly facilitate the construction of artificial human chromosomes for use as autonomous gene expression vectors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061150-06
Application #
7031773
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Anderson, Richard A
Project Start
2000-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
6
Fiscal Year
2006
Total Cost
$287,726
Indirect Cost

  Institution

Name
Mount Sinai School of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029

  Publications

Hasson, Dan; Alonso, Alicia; Cheung, Fanny et al. (2011) Formation of novel CENP-A domains on tandem repetitive DNA and across chromosome breakpoints on human chromosome 8q21 neocentromeres. Chromosoma 120:621-32
Alonso, Alicia; Fritz, Bjorn; Hasson, Dan et al. (2007) Co-localization of CENP-C and CENP-H to discontinuous domains of CENP-A chromatin at human neocentromeres. Genome Biol 8:R148
Qin, N; Bartley, J; Wang, J-C et al. (2007) A neocentromere derived from a supernumerary marker deleted from the long arm of chromosome 6. Cytogenet Genome Res 119:154-7
Cardone, Maria Francesca; Alonso, Alicia; Pazienza, Michele et al. (2006) Independent centromere formation in a capricious, gene-free domain of chromosome 13q21 in Old World monkeys and pigs. Genome Biol 7:R91
Knegt, A C; Li, S; Engelen, J J M et al. (2003) Prenatal diagnosis of a karyotypically normal pregnancy in a mother with a supernumerary neocentric 13q21 -->13q22 chromosome and balancing reciprocal deletion. Prenat Diagn 23:215-20
Alonso, Alicia; Mahmood, Radma; Li, Shulan et al. (2003) Genomic microarray analysis reveals distinct locations for the CENP-A binding domains in three human chromosome 13q32 neocentromeres. Hum Mol Genet 12:2711-21
Assumpcao, Juliana Godoy; Berkofsky-Fessler, Windy; Viguetti Campos, Nilma et al. (2002) Identification of a neocentromere in a rearranged Y chromosome with no detectable DYZ3 centromeric sequence. Am J Med Genet 113:263-7
Li, Shulan; Malafiej, Paul; Levy, Brynn et al. (2002) Chromosome 13q neocentromeres: molecular cytogenetic characterization of three additional cases and clinical spectrum. Am J Med Genet 110:258-67
Warburton, P E (2001) Epigenetic analysis of kinetochore assembly on variant human centromeres. Trends Genet 17:243-7
Levy, B; Papenhausen, P; Tepperberg, J et al. (2000) Prenatal molecular cytogenetic diagnosis of partial tetrasomy 10p due to neocentromere formation in an inversion duplication analphoid marker chromosome. Cytogenet Cell Genet 91:165-70

Showing the most recent 10 out of 11 publications