Alpha satellite DNA biology: finding function in the recesses of the genome.

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2018-09

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Abstract

Repetitive DNA, formerly referred to by the misnomer "junk DNA," comprises a majority of the human genome. One class of this DNA, alpha satellite, comprises up to 10% of the genome. Alpha satellite is enriched at all human centromere regions and is competent for de novo centromere assembly. Because of the highly repetitive nature of alpha satellite, it has been difficult to achieve genome assemblies at centromeres using traditional next-generation sequencing approaches, and thus, centromeres represent gaps in the current human genome assembly. Moreover, alpha satellite DNA is transcribed into repetitive noncoding RNA and contributes to a large portion of the transcriptome. Recent efforts to characterize these transcripts and their function have uncovered pivotal roles for satellite RNA in genome stability, including silencing "selfish" DNA elements and recruiting centromere and kinetochore proteins. This review will describe the genomic and epigenetic features of alpha satellite DNA, discuss recent findings of noncoding transcripts produced from distinct alpha satellite arrays, and address current progress in the functional understanding of this oft-neglected repetitive sequence. We will discuss unique challenges of studying human satellite DNAs and RNAs and point toward new technologies that will continue to advance our understanding of this largely untapped portion of the genome.

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10.1007/s10577-018-9582-3

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McNulty, Shannon M, and Beth A Sullivan (2018). Alpha satellite DNA biology: finding function in the recesses of the genome. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology, 26(3). pp. 115–138. 10.1007/s10577-018-9582-3 Retrieved from https://hdl.handle.net/10161/21535.

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Sullivan

Beth Ann Sullivan

James B. Duke Distinguished Professor

Research in the Sullivan Lab is focused on chromosome organization, with a specific emphasis on the genomics and epigenetics of the chromosomal locus called the centromere. The centromere is a specialized chromosomal site involved in chromosome architecture and movement, and when defective, is linked to cancer, birth defects, and infertility. The lab has described a unique type of chromatin (CEN chromatin) that forms exclusively at the centromere by replacement of core histone H3 by the centromeric histone variant CENP-A. Their studies also explore the composition of CEN chromatin and its relationship to the underlying highly repetitive alpha satellite DNA at the centromere. The Sullivan lab also discovered that genomic variation within alpha satellite DNA affects where the centromere is built and how well it functions. The Sullivan lab was part of the Telomere-to-Telomere T2T Consortium that used ultra long read sequencing and optical mapping to completely assemble each human chromosome, including through millions of basepairs of alpha satellite DNA at each centromere. Dr. Sullivan's group also builds human artificial chromosomes (HACs), using them as tools to test components required for a viable, transmissible chromosome and to study centromeric transcription and chromosome stability. The lab also studies formation and fate of chromosome abnormalities associated with birth defects, reproductive abnormalities, and cancer. Specifically, they study chromosomal abnormalities with two centromeres, called dicentric chromosomes. Originally described by Nobelist Barbara McClintock in the 1930s, dicentrics in most organisms are considered inherently unstable chromosomes because they trigger genome instability. However, dicentric chromosomes in humans are very stable and are often transmitted through multiple generations of a family. Using several approaches to experimentally reproduce dicentric chromosomes in human cells, the lab explores mechanisms of dicentric formation and their long-term fate.


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