Latest Genetic Map Finds Recombination Is Not So Random

By Deborah Borfitz 

March 6, 2019 | The latest genetic map published by Reykjavík, Iceland-based deCODE Genetics may well be the last, according to CEO and founder Kári Stefánsson. The high-resolution map of human recombination—which uses whole-genome sequence (WGS) data on nearly 130,000 people—is about as good as it can theoretically get. It should prove useful in the company’s decades-long search for genetic variants linked to disease and help Amgen, which acquired deCODE late in 2012, identify drug targets and develop genetic models used to inform choices about clinical trials.

High resolution is important because it reveals sequence features that favor recombination and, since WGS was used, correlations between de novo mutations and recombination, explains Stefánsson. Genetic diversity is generated in one of these two ways, although this is not a gender-neutral proposition, he notes. The sequence-level genetic map also demonstrates a 50-fold increase in mutation rates in regions near recombination sites, but again with some demographic caveats.

A key discovery is that recombination is under “exquisite genetic control,” Stefánsson says. “We found a very large number of variants, much greater than we thought, which have an impact on recombination”—including where and how quickly they happen. The protein-coding gene PRDM9 has been viewed as “the most important” driver on the recombination landscape, he adds, but many other genes also have a lot of impact. “It’s much less random than people might think.”

No less than 35 loci (fixed position on a chromosome) have been associated with the recombination rate or location of crossovers, Stefánsson says. Genes linked to the synaptonemal complex, the protein structure between chromosomes, also turn out to be determinants of crossovers. “The whole story is fairly logical.”

Age and Gender Matter

An important distinction between the genders is that “recombination comes more from the mother and de novo mutations come more from the father,” says Stefánsson, adding that the latter account for a large proportion of rare diseases in children.

During his medical training, older mothers were “inappropriately criticized” for posing more of a danger to their unborn child, Stefánsson continues. “The fact of the matter is the only thing that increases with the age of the mother is extremely rare chromosomal disorders such as Down Syndrome.” The father’s age is the greater hazard, he adds. “A child conceived by a 40-year-old father is two to three times more likely to develop schizophrenia than a child born to 20-year-old father. A dramatic increase in all cancers is seen with advancing age of the father but not the mother.” Scientists at deCODE Genetics have also found that older mothers confer benefits on their offspring in terms of educational achievement, lower likelihood of developing alcoholism and other addictive disorders, and less risk of cardiovascular disease.

The new genetic map further shows that in women relative to genetic averages, higher mutation rates can be observed up to 40 kilobases from crossovers, particularly for complex crossovers that increase with maternal age. 

Building on Success

deCODE Genetics set up shop back in 1996, giving it the head start advantage, and its research model is starting to be replicated around the world, Stefánsson says. The company built the popular online database called Íslendingabók containing all available genealogical information on Icelanders, which is integrated with the company’s research with genetic information and detailed medical data contributed by 175,000 citizens who have participated in related research projects. It also published two earlier genetic maps, he says, the first in 2002 creating a “user guide” to the human genome by properly sequencing SNPs to 99% accuracy that enabled final assembly of the first reference human genome.

Unlike maps based on genetic linkage that speak to averages, Stefánsson says, the ones produced by deCODE offer a view of recombination among unique individuals and has no competition. Iceland has a remarkably homogenous population representing a relatively small number of ancestral lines, meaning mutations that rarely occur in most places are relatively common here.

Next up, says Stefánsson, will be a paper looking at new mutations in identical twins to learn how they come into being.

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