The most detailed template yet of the different ways in which women and men, individuals and populations, are driving one of the main motors of evolution

Scientists from deCODE genetics today publish in Nature the highest resolution recombination map of the human genome yet developed. Recombination is the reshuffling of the genome that occurs in the formation of eggs and sperm: we inherit one version of each chromosome from each of our parents, and create novel blends of the two that we pass on to our offspring. This process is fundamental to generating human diversity, providing novel configurations of the genome that enable the species to adapt to ever-changing environments. The map is published and made freely available to the scientific community at www.nature.com, and at www.decode.com/addendum, where updates will be provided.

In 2002, deCODE created a 6000-marker framework recombination map that enabled the correct assembly of the first sequence of the human genome. The map published today, which is put into the public domain as deCODE and other institutions begin to sequence and analyze large numbers of whole genomes, was constructed using 300,000 single-letter markers, or SNPs. It incorporates data from more than 15,000 parent-offspring pairs participating in deCODE’s gene discovery work in Iceland to show in high resolution where recombinations tend to take place. Among the findings are that some 15% of male and female recombination hotspots are unique to each sex. Moreover, women tend to contribute more to generating new combinations of genes, while men are doing more to create new versions of the genes themselves. So too, new variations in the PRDM9 gene have been identified that correlate with differences between individuals in how evenly recombinations are spread across the genome, and with different distributions of recombinations between people of African and European origin.

“This map is to me a thing of beauty. We are looking in quite high definition at the ingenious processes driving the generation of human diversity. From our previous work we have seen in basic terms that recombination is different between women and men, and between individuals and families. There are genetic factors that increase recombination in one sex while decreasing it in the other; women recombine at 1.6 times the rate of men; and women who recombine more tend to have more children. So we knew that nature is putting a premium on the generation of diversity. Here we see in detail the variations involved in generating variation, from women and men playing complementary roles in generating new versions and new configurations of genes, to differences in versions of PRDM9 between Africans and Europeans,” said Kari Stefansson, deCODE CEO and senior author on the paper.

The construction of this map was made possible by the unique breadth and comprehensiveness of deCODE’s population genetics resources in Iceland, and by new methods developed by deCODE statisticians for determining the parental origins of genetic markers. Because this new map is built by looking directly at real recombination events in large numbers of real families, it provides the first detailed picture of recombination differences between the sexes and individuals. By contrast, other recent recombination maps have been constructed using data on linkage disequilibrium – the frequency with which strings of genetic markers tend to be inherited together – in large numbers of unrelated people. The virtue of the latter maps is that they provide an historical catalogue of recombination as our species has evolved; the new deCODE map provides the complementary view of what this process looks like in a real population at a specific point in time.

deCODE scientists have discovered a single SNP that confers increased risk if inherited from the father, but is protective if inherited from the mother

Scientists at deCODE genetics, Inc. publish in the journal Nature the discovery of a version of a common single-letter variant in the sequence of the human genome (SNP) with a major impact on susceptibility to type 2 diabetes (T2D). The impact of the T2D variant is not only large, but unusual: if an individual inherits it from their father, the variant increases risk of T2D by more than 30% compared to those who inherit the non T2D-linked version; if inherited maternally, the variant  lowers risk by more than 10% compared to the non T2D-linked version. Nearly one quarter of those studied have the highest risk combination of the versions of this SNP, putting them at a roughly 50% greater lifetime risk of T2D than the quarter with the protective combination. This is the second largest effect of any genetic variant for T2D apart from SNPs in TCF7L2, discovered by deCODE in 2006.

“We could make this discovery beacause we are in the unique position of being able to distinguish what is inherited from the mother from what is inherited from the father. This we can do because of the large amount of data we have assembled on the Icelandic population. These data empower us in many ways. For example, using our ability to impute sequence data, we can multiply by 100 times the amount of information generated by sequencing one individual. We can use these tools to discover and integrate rarer variants into our tests and scans, identify drug targets for licensing, and put our know-how at the disposal of our service customers. We believe that this is an important advantage for conducting large-scale whole sequence studies over the next couple of years,” said Kari Stefansson, CEO of deCODE.

Because the risk is inherited and varies in this way, the SNP, located on chromsome 11, had never been linked to T2D even though it had been genotyped in large, traditional genome-wide association studies (GWAS). These do not distinguish between paternally and maternally inherited SNPs. But deCODE can track the parental origin of virtually any SNP in the genome of the tens of thousands of Icelandic participants in the company’s gene discovery work. In this study, deCODE used its population-wide genealogy database and proprietary statistical tools to determine the parent of origin of a number of SNPs in some 40,000 Icelandic participants in the company’s gene discovery programs. Some of these SNPs had previously been associated with different diseases and are located near “imprinted” genes – genes in which only the maternally or paternally inherited copy is “switched-on” to encode a protein. Five of these, one each in breast and skin cancer and three in T2D, showed that the parental origin of the variants affects the risk they confer.

The paper, “Parental origin of sequence variants associated with complex diseases,” is published online at www.nature.com, and will appear in the December 17 print edition.

In its work on the inherited components of dozens of common diseases, deCODE has discovered gene variants that significantly affect individual susceptibility or protection against disease. In the common forms of these conditions – such as obesity, type 2 diabetes and cardiovascular diseases – deCODE has previously shown that genetic variants confer increased or decreased risk by up-regulating or down-regulating the activity of major biological pathways.

In today’s paper, the deCODE team and collaborators from Merck demonstrate one of the principal ways in which the activity of biological pathways is functionally perturbed in a quintessentially complex condition: obesity.

Kari Stefansson, CEO of deCODE, put the study into context: “One of the observations we have made in our work on the isolation of disease genes is that the genetic risk of common diseases is often conferred by variations in the sequence of the genome that affect expression of genes. Hence, one of the ways to approach the study of common diseases is through the analysis of gene expression. This paper provides a substantial contribution towards the understanding of gene expression in man and one example of how it can be used to expand our knowledge of one disease, namely obesity.”