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New Human Genome Map Sheds Light on Mechanisms of Genetic Diversity

NEW YORK (GenomeWeb) – Researchers at Decode Genetics, a subsidiary of Amgen, have constructed a genetic map of the human genome from whole-genome sequencing and microarray data that sheds light on how genetic diversity is maintained.

Both recombination and de novo mutations fuel genetic diversity and contribute to human evolution, and the map enabled the researchers to examine how often and where these events occur in the genome.

With data on more than 150,000 people from Iceland, the researchers uncovered more than 4.5 million crossover recombinations and about 200,000 de novo mutations. As Decode CEO Kari Stefansson and his colleagues reported in Science today, they applied this to generate a map and to examine factors that influence recombination and mutation rates.

"The classic premise of evolution is that it is powered first by random genetic change," Stefansson said in a statement. "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."

Using data from Icelandic parent-child pairs who had undergone SNP chip-based genotyping, the researchers identified 1.48 million crossovers in 56,321 paternal meioses and 3.06 million crossovers in 70,086 maternal meioses. With this, the researchers homed in on crossover locations, which they refined by folding in whole-genome sequencing data.

The average resolution of their resulting genetic map is 682 base pairs, they reported.

The distribution of crossover events within the genome is non-random, the researchers noted. For instance, 68.4 percent of paternal crossovers and 52.5 percent of maternal crossovers occur in Pratto DSB regions — spots where double-strand breaks tend to occur during meiosis in human testes— even though those regions only make up about 3 percent of the human genome.

The researchers also estimated the contribution of crossovers to mutagenesis. In nearly parent-child 3,000 trios that underwent whole-genome sequencing, they found 200,435 de novo mutations. They calculated the mutation rate near crossover events to be about 50 times higher than the genomic average, noting that it drops with increasing distance.

The mutations, though, varied by parent. While C to T mutations cropped up near both paternal and maternal crossovers, such mutations near paternal crossovers tended to take place in a CpG context but those near maternal crossovers did not. This could be due to differences in sex-specific timing of meiosis in germline development, the researchers said.

Similarly, they noted that epigenetic factors influence crossovers and that crossovers are less frequent in transcribed regions, including regions marked by the H3K36me3 and H4K20me1 histone markers, and more common among enhancer regions, such as those with H3k27ac and H3K4me1 histone marks.

In combination with the increased de novo mutation rate observed near crossovers, the researchers theorized, evolution has guided crossover events toward regulatory regions and away from coding regions. That way, they said, it would reduce the number of harmful de novo mutations affecting coding regions while encouraging increased regulatory variation.

The researchers, meanwhile, conducted a series of genome-wide association studies to uncover genetic loci that influence recombination rate and related phenotypes. They linked, for instance, 20 loci with recombination rate. Three of those loci were coding variants affecting MEIOB, H2BFM, and HFM1, which encode a meiosis-specific protein, a member of the histone H2B family, and a DNA helicase, respectively.

The researchers said their findings highlight that recombination is mutagenic, though regulated. "What we see here is that the genome is an engine for generating diversity within certain bounds," Stefansson added. "This is clearly beneficial to the success of our species but at great cost to some individuals with rare diseases."