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Sequencing of Blood and Brain Samples from Supercentenarian Unveils Background of Somatic Mutations

NEW YORK (GenomeWeb) – By delving into the genome of a supercentenarian, a team of researchers led by Erik Sistermans from the VU University Medical Center in Amsterdam found some 450 somatic mutations that arose during the woman's lifetime, as they reported in Genome Research today.

While previous studies have examined mutations that arise under certain disease conditions like leukemia, Sistermans and his colleagues noted that it wasn't known how many mutations can appear in the genomes of healthy cells.

He and his team deeply sequenced both blood and brain cells from a woman who died at age 115. As blood cells divide more frequently and thus are more prone to develop mutations than the comparatively static brain cells, the researchers found a number of mutations in the blood cells that weren't present in the brains cells.

"We conclude that there is a vast somatic mutation background, even in a healthy blood compartment," the researchers wrote.

Additionally, the blood cells' genomes had much shorter telomeres than the brain cells, which the researchers hypothesized might be why the supercentenarian's peripheral blood was derived from only two hematopoetic stem cells.

To determine how many mutations can arise over a lifetime, Sistermans and his colleagues sequenced blood and brain DNA samples from the 115-year-old woman to a more than 60x mean read depth using the SOLiD sequencing platform.

Most of the mutations the researchers identified appeared to be harmless passenger mutations. They found more than 600 candidate SNVs and 30 candidate indels in the blood that weren't present in the brain in addition to more than 100 candidate SNVs and three candidate indels in the brain that weren't in the blood cells.

After validating their findings, the researchers estimated there were about 450 somatic mutations in the non-repetitive genome, corresponding to approximately three mutations cropping up for every cell division.

These mutations, they noted, were neither present in the breast cancer that the woman had at age 100 nor in the gastric tumor she had at the time of her death.

Additionally, none of the 376 somatic mutations that mapped to coding regions were predicted by either the SIFT or PolyPhen algorithms to have a deleterious effect on protein function, and none of them were included in the COSMIC catalog of somatic cancer mutations or in the Human Gene Mutation Database.

Some of the mutations, Sistermans and his colleagues said, appear to have arisen through the deamination of methylated cytosines to thymines at CpG sites. They compared the methylation status of CpG sites in a H1 hESC stem cell line and a GM12878 lymphoblastoid cell line, particularly focusing on the 62 somatic mutation sites identified in the supercentenarian that mapped to CpG regions.

Through their comparison, the researchers found that about half of the GM12878 lymphoblastoid cell line CpG islands were methylated, while more than 85 percent of CpG islands in the H1 hESC stem cell line were methylated. Additionally, 61 of the 62 somatic mutation sites from the supercentenarian that mapped to CpG regions were methylated in the H1 hESC stem cell line; only 28 of 62 sites were methylated in the GM12878 line.

From this, the researchers concluded that somatic mutations are more likely to occur at methylated CpG sites, and that these mutations likely occurred in a cell with a methylation signature that is more similar to a stem cell than to a differentiated lymphoblastoid cell, such as a hematopoetic stem cell.

Other mutations, the researchers added, occurred in regions that were not evolutionarily conserved, AT-rich, or gene-poor regions.

Meanwhile, Sistermans and his colleagues noticed that the distribution of the variant allele frequencies indicated the majority — about 65 percent — of the peripheral blood cells they examined from the supercentenarian were from just two hematopoetic stem cells.

As the researchers had noted that the blood cells they sequenced had extremely short telomeres — on average, 17 times shorter than the telomeres in the brain cells — they suggested that over the course of the supercentenarian's life, her hematopoietic stem cells developed critically short telomeres and those cells disappeared from the hematopoietic stem cell pool.

"Because these blood cells had extremely short telomeres, we speculate that most hematopoietic stem cells may have died from 'stem cell exhaustion,' reaching the upper limit of stem cell divisions," first author Henne Holstege said in a statement.