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Study Finds Somatic CNVs Accumulate With Age

By Andrea Anderson

NEW YORK (GenomeWeb News) – Aging is associated with an uptick in somatic, structural changes in the human genome, a new study online in the American Journal of Human Genetics suggests.

An international group led by investigators in Sweden found an overall rise in both small and very large copy number changes in blood cell genomes with age, based on data for more than 300 identical twins and nearly as many single-born participants. In a few of the individuals sampled multiple times over several years, though, the researchers also saw variability in the frequency and nature of these rearrangements — with some of the CNV-containing cells weeded out of the blood over time and some persisting.

"It's more dynamic than we anticipated," HudsonAlpha Institute for Biotechnology researcher Devin Absher, a co-author on the new study, told GenomeWeb Daily News. "Although the general trend is that the number of CNVs goes up as we age."

From studies published over more than two decades, researchers knew that aging is linked to changes in nuclear and mitochondrial genomes that would be expected to produce mosaicism within somatic cells. Nevertheless, not much was known about the relationship between somatic CNV patterns in the genome and aging.

To look at this in more detail, Absher and his colleagues started out using Illumina arrays to assess CNV patterns in blood samples from 318 identical twins, including 162 twins who were 55 years old or younger and 156 twins who were at least 60 years old.

"By having two monozygotic twins, we get to compare two genomes that started out, theoretically, identical," Absher said. "We can distinguish, then, germline copy number events — that is, CNVs that were inherited and would be common to both twins — and those that were somatic … that arose after the twins separated."

From microarray analyses, coupled with additional microarray, quantitative PCR, and array comparative genomic hybridization data, the team found five CNVs affecting at least a million bases of DNA sequence.

Each of these large CNVs turned up in the older twin group, leading researchers to suspect that copy number changes accumulate in the genome with age — a notion that they verified by doing similar copy number analyses using blood samples from 296 single-born individuals.

"We were observing CNVs that were as large as a megabase, which typically aren't even viable or would produce very severe phenotypes if they were actually germline changes and affected all of the cells in an individual," Absher noted.

"Even in our single-born population, when we observe a CNV of that scale we can be pretty confident that that's not a germline CNV, but a somatic CNV," he added, "because these are all phenotypically normal people who do not have any severe syndromes that you would expect from a large chromosomal abnormality."

Amongst three individuals with CNVs spanning a million or more bases, the team saw rearrangements related to sites on chromosomes 4, 8, and 20 that were previously linked to a blood disease called myelodysplastic syndrome.

While none of the three participants carrying these CNVs had been diagnosed with MDS, Absher noted, the findings hint that malignancy-related mutations that occur at sub-clinical frequencies in a cell population may be more common than appreciated.

Smaller rearrangements appeared to be more common in the genome with advancing age too, though results from 43 individuals sampled more than once over several years suggest that both large and smaller CNVs in blood cell DNA are dynamic. That is, the rearrangements can appear, disappear, and shift in frequency, rather than simply accumulating steadily.

For example, researchers saw some instances in which the relative abundance of cells containing a given CNV rose or fell in an individual's blood cells after a number of years.

Moreover, the findings point to variability in CNV accumulation between individuals from the same age group, suggesting these changes could be a consequence of more than chronological age.

"There's certainly a wide range," Absher said. "Although the trend is for an accumulation over time, there are some individuals who have a very high CNV load and others who have very low CNV loads who are basically the same age."

Researchers don't have access to DNA from other tissue types from the study participants, though they suspect that CNVs accumulate in other parts of the body as well. Even so, Absher noted that the rate and nature of these rearrangements may depend, in part, on how rapidly cells in a given tissue divide.

"As blood cells are rapidly dividing, they might be more prone to this kind of thing than muscle cells or neurons, for instance," he explained.

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