Centromere Sequence, Variation, and Function

着丝粒序列、变异和功能

基本信息

批准号：
10226097
负责人：
Glennis Amelia Logsdon
金额：
$ 6.86万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226097
关键词：
Address Affect Aneuploidy Area Basic Science Biological Assay Biological Process Biological Sciences Biology CRISPR/Cas technology Cell division Cells Centromere Chromosome Segregation Chromosomes Communities Computational algorithm Congenital Abnormality Copy Number Polymorphism DNA DNA Sequence Data Data Set Defect Down Syndrome Elements Ensure Epigenetic Process Event Evolution Future Gene Conversion Genetic Transcription Genetic Variation Genomics Goals Haploidy Histones Human Human Cell Line Human Genome Hydatidiform Mole Individual Kinetochores Knowledge Lead Length Malignant Neoplasms Methods Modeling Nature Nucleotides Pattern Play Pongidae Population Process RNA Recording of previous events Research Research Personnel Resources Role Satellite DNA Site Source Spontaneous abortion Structure Tandem Repeat Sequences Technology Testing Transcript Transcription Coactivator Transcription Repressor Untranslated RNA Variant Work base centromere protein A computerized tools contig genetic information genome integrity genomic locus human reference genome nanopore nonhuman primate novel research study scaffold targeted nucleases tool transcriptomics tumorigenesis

项目摘要

Project Summary/Abstract The accurate segregation of chromosomes ensures the faithful inheritance of genetic information. Defects in chromosome segregation can cause an imbalance in chromosome number, or aneuploidy, which is the leading cause of over 90% of human cancers and contributes to spontaneous abortion and birth defects (e.g. Down syndrome). The locus that ensures that chromosomes are equally segregated during cell division is the centromere. Centromeres are comprised of repetitive α-satellite that span several megabases on each chromosome. The repetitive nature of these regions has posed an enormous challenge to standard short-read sequencing and assembly methods, and as a result, all centromeres remain unassembled in the human genome. The lack of centromere sequence assemblies has greatly hindered our understanding of the role these sequences play in essential cell biological processes required to maintain genome integrity. This proposal aims to address this gap in knowledge by generating linear sequence assemblies of each human centromere using a combination of long-read sequencing technologies and novel computational assembly tools. The proposed work will also reconstruct the evolutionary history of centromeres by elucidating the genetic variation of centromeres in humans and apes. In addition, this work will uncover how genetic variation at centromeres impacts the transcriptional landscape by sequencing and annotating full-length centromeric transcripts in the human genome. Finally, this proposal will determine if genetic variation at centromeres impacts the ability of chromosomes to be accurately segregated during cell division using cell-based assays. Taken together, this research will uncover the linear organization of human centromeric regions and elucidate how genetic variation in these regions impacts the accuracy of chromosome segregation during cell division.

项目概要/摘要染色体的精确分离保证了遗传信息的忠实遗传。染色体分离可导致染色体数量不平衡或非整倍体，这是主要的原因 90%以上的人类癌症都是由它引起的，并会导致自然流产和出生缺陷（例如唐氏综合症）确保染色体在细胞分裂过程中均匀分离的位点是着丝粒由重复的 α 卫星组成，每个卫星跨越几个兆碱基。这些区域的重复性质对标准短读提出了巨大的挑战。测序和组装方法，因此，人类基因组中的所有着丝粒仍然未组装。着丝粒序列组装的缺乏极大地阻碍了我们对这些作用的理解该提案的目的是在维持基因组完整性所需的重要细胞生物过程中发挥作用。通过使用所提出的工作结合了长读长测序技术和新颖的计算组装工具。还将通过阐明着丝粒的遗传变异，重建着丝粒的进化史此外，这项工作将揭示着丝粒的遗传变异如何影响着丝粒。通过对人类基因组中的全长着丝粒转录物进行测序和注释来绘制转录景观。最后，该提案将确定着丝粒的遗传变异是否影响染色体的能力总而言之，这项研究将揭示如何在细胞分裂过程中使用基于细胞的检测准确分离。人类着丝粒区域的线性组织并阐明这些区域的遗传变异影响细胞分裂过程中染色体分离的准确性。