Two mechanisms contribute to human DNA diversity: genetic recombination and de novo mutations, or new gene variants that are not inherited. With a new genetic map developed using whole-genome sequence data, scientists at Amgen’s genomics research subsidiary deCODE Genetics have uncovered patterns in the two processes, offering fresh insights for future medical research.
Drawing on sequence data from more than 155,000 Icelanders, the deCODE researchers examined the location, rate and connection between the two key drivers of human evolution. “What we show in this paper is how tightly linked recombinations and new mutations are,” Kari Stefansson, CEO of deCODE and the senior author of the study published in Science, told FierceBiotechResearch.
The genetic map has a resolution of 682 base (or nucleotide) pairs. That's likely as high a resolution as any gene map has been and almost “as much as theoretically possible,” Stefansson said.
Stefansson and colleagues pinpointed the exact locations where 4.5 million exchanges of genetic material between chromosomes from parents happen and found more than 200,000 new mutations. As it turns out, most chromosomal crossovers occur in so-called hot spots, which cover less than 2% of the genome.
The most important finding of the study, Stefansson said, is that mutations don’t appear to happen randomly, as scientists have long assumed. “In about a thousand bases flanking the sides of recombinations, a mutation rate is increased almost 50-fold,” Stefansson said. This suggests that crossovers do have a role in the formation of new mutations.
“The classic premise of evolution is that it is powered first by random genetic change. But we see here in great detail how this process is in fact systematically regulated—by the genome itself and by the fact that recombination and de novo mutation are linked,” Stefansson said in a statement.
Moreover, the team identified 35 loci affecting recombination rate and location. Women appear to contribute more to recombination and men to de novo mutation—a common cause of rare diseases of childhood. Recombination rate also increases with the age of the mother but doesn’t appear to be affected by the father’s age, the study showed.
While the current study is not about any specific mutation that contributes to a genetic disease, Stefansson said it sheds light on basic processes of evolution and generation of new diversity while also laying the groundwork for future research on human health.
Iceland-based deCode has largely kept a low profile since it went bankrupt and was bought up by Amgen in 2012 for a handsome $415 million. Soon after that, Amgen spun out part of deCODE’s services that provides genetic diagnostic services to physicians and patients into a separate firm called NextCODE, which itself was later scooped up WuXi AppTec to form what’s now known as WuXi NextCODE.
After those transactions, Amgen was left with deCODE’s library of hereditary information and its ability to analyze large-scale sequence data to help with its drug R&D efforts. Since then, deCODE has focused on genome research. Back in 2015, the company turned up four papers in Nature Genetics, laying out the technology that enabled researchers to collect whole-genome sequencing data as well as some potential therapeutic targets.
The latest research from deCODE could provide “opportunities to make further discoveries on variants that are associated with disease,” Stefansson said. “It is a study that yields background information that makes it easier for us to find drug targets.”
Stefansson also points to the possibility of using the findings to aid in cancer research. “Our study of new mutations and recombinations could be used as a model to try to understand the mutations and genomic rearrangements that happen in cancers,” he said.