Regions of Unstable Non-Coding DNA Pose Potential Health Risk

Genomics researchers have found that variation within the highly repetitive, non-coding DNA of human centromere satellite DNA regions has a pronounced impact on genome stability and basic chromosomal function that have ramifications regarding the health of the individual.

Satellite DNA, the main component of functional centromeres and of heterochromatin consists of very large arrays of tandem repeating, non-coding DNA. The name "satellite DNA" refers to how repetitions of a short DNA sequence tend to produce a different frequency of the nucleotides adenine, cytosine, guanine, and thymine, and thus have a different density from bulk DNA - such that they form a second or "satellite" band when genomic DNA is separated on a density gradient.


A defined number of 171 base pair monomers are organized into chromosome-specific higher order repeats (HORs) that are repeated thousands of times. At least half of all human chromosomes have two or more distinct HOR alpha satellite arrays within their centromere regions. These regions can affect the stability of the genome and the proper function of the chromosomes, leading to an increased risk of cancer, birth defects, and infertility.

Investigators at Duke University (Durham, NC, USA) previously showed that the two alpha satellite arrays of Homo sapiens chromosome 17 (HSA17), D17Z1 and D17Z1-B, behaved as centromeric epialleles, that is, the centromere, defined by chromatin containing the centromeric histone variant CENPA and recruitment of other centromere proteins, could form at either D17Z1 or D17Z1-B. Some individuals in the human population are functional heterozygotes in that D17Z1 is the active centromere on one homolog and D17Z1-B is active on the other.

In the current study, the investigators aimed at understanding the molecular basis for how centromere location was determined on HSA17. Specifically, they focused on D17Z1 genomic variation as a driver of epiallele formation.

They reported in the August 10, 2016, online edition of the journal Genome Research that D17Z1 arrays that were predominantly composed of HOR size and sequence variants were functionally less competent. These arrays either recruited decreased amounts of the centromere-specific histone variant CENPA and the HSA17 was mitotically unstable, or alternatively, the centromere was assembled at D17Z1-B and the HSA17 was stable.

This study demonstrated that genomic variation within highly repetitive, non-coding DNA of human centromere regions had a pronounced impact on genome stability and basic chromosomal function.

"Variation is not only important for how genes and proteins function, but it can also occur in the noncoding, repetitive portions of the genome," said senior author Dr. Elizabeth Sullivan, associate professor of molecular biology and microbiology at Duke University. "What we found in this study is probably the tip of the iceberg. There could be all sorts of functional consequences to having variation within the complex, repetitive portion of the genome that we do not know about yet."

"It is immensely fascinating to think that there are so many people walking around who are essentially centromere mosaics," said Dr. Sullivan. "One of their centromeres, on one of their chromosomes, has the potential to be dangerously unstable, and it could affect their ability to reproduce, or predispose them to cancer."

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