Credit: NIGMS
A new study suggests the timing of DNA replication—including where the origin points are and in what order DNA segments are copied—varies from person to person.
The research also revealed the first genetic variants that orchestrate replication timing.
And researchers found evidence suggesting that differences in replication timing may explain why some people are more prone than others to developing myeloproliferative neoplasms (MPNs).
“Everyone’s cells have a plan for copying the genome,” said study author Steven McCarroll, PhD, of Harvard Medical School in Boston. “The idea that we don’t all have the same plan is surprising and interesting.”
Dr McCarroll and his colleagues described this research in Cell.
Replication timing and MPNs
The researchers noted that DNA replication is one of the most fundamental cellular processes, and any variation among people is likely to affect genetic inheritance, including individual disease risk as well as human evolution.
Replication timing is known to affect mutation rates. DNA segments that are copied too late or too early tend to have more errors.
The new study indicates that people with different timing programs therefore have different patterns of mutation risk across their genomes. For example, differences in replication timing could explain predisposition to MPNs.
Researchers previously showed that acquired mutations in JAK2 lead to MPNs. They also noticed that people with JAK2 mutations tend to have a distinctive set of inherited genetic variants nearby, but they weren’t sure how the inherited variants and the new mutations were connected.
Dr McCarroll’s team found that the inherited variants are associated with an “unusually early” replication origin point and proposed that JAK2 is more likely to develop mutations in people with that very early origin point.
“Replication timing may be a way that inherited variation contributes to the risk of later mutations and diseases that we usually think of as arising by chance,” Dr McCarroll said.
A new method of study
Dr McCarroll and his colleagues were able to make these discoveries, in large part, because they invented a new way to obtain DNA replication timing data. They turned to the 1000 Genomes Project, which maintains an online database of sequencing data collected from hundreds of people around the world.
Because much of the DNA in the 1000 Genomes Project had been extracted from actively dividing cells, the team hypothesized that information about replication timing lurked within, and they were right.
They counted the number of copies of individual genes in each genome. Because early replication origins had created more segment copies at the time the sample was taken than late replication origins had, the researchers were able to create a personalized replication timing map for each person.
“People had seen these patterns before but just dismissed them as artifacts of sequencing technology,” Dr McCarroll said. After conducting numerous tests to rule out that possibility, “we found that they reflect real biology.”
The researchers then compared each person’s copy number information with his or her genetic sequence data to see if they could match specific genetic variants to replication timing differences. From 161 samples, the team identified 16 variants. The variants were short, and most were common.
“I think this is the first time we can pinpoint genetic influences on replication timing in any organism,” said study author Amnon Koren, PhD, also of Harvard Medical School.
The variants were located near replication origin points, leading the researchers to wonder if they affect replication timing by altering where a person’s origin points are. The team also suspects the variants work by altering chromatin structure, exposing local sequences to replication machinery.
The group intends to find out. They also want to search for additional variants that control replication timing.
“These 16 variants are almost certainly just the tip of the iceberg,” Dr Koren said.
He and his colleagues believe that, as more variants come to light in future studies, researchers should be better able to manipulate replication timing in the lab and learn more about how it works and its biological significance.
“All you need to do to study replication timing is grow cells and sequence their DNA, which everyone is doing these days,” Dr Koren said. “[This new method] is much easier, faster, and cheaper, and I think it will transform the field because we can now do experiments in large scale.”
“We found that there is biological information in genome sequence data,” Dr McCarroll added. “But this was still an accidental biological experiment. Now imagine the results when we and others actually design experiments to study this phenomenon.”
