Described as the most complete "user's guide" yet to the human genome, deCODE genetics, of Reykjavik, Iceland, published a paper in Nature Genetics, released online June 10, 2002. Its title: "A high-resolution recombination map of the human genome." The article's senior author is medical geneticist Kari Stefansson, deCODE's CEO and president.
"This is a major achievement in human genetics," Stefansson told BioWorld Today, "and we are proud to make our results and data available to researchers around the world. The entire set of deCODE's genotype data, coded for anonymity to protect privacy, is available to investigators with a valid research plan. The primary data - sex-specific and sex-average - will be provided upon request to those who are willing to commit themselves to use it for Institutional Review Board-approved, ethically acceptable, research only." They may address Stefansson by e-mail at email@example.com.
"By making this information available," Stefansson continued, "we are, I believe, living up to our commitment both to the patients and the people of Iceland who gave us their DNA to do this map - and also to the scientific community as a whole. We have a genotyping unit in our company that can generate some 15 million genotypes a month, which is about twice the number of genotypes that the public human genome sequencers can generate in a whole year. It took us only two weeks of genotyping to generate this high-resolution map.
"But at the same time," he added, "we are showing the world what we can do with deCODE's genotyping capacity and informatics. Our company has the world's largest genotyping facility, with genealogical data covering the entire Icelandic population of 277,906 men, women and children, and proprietary software for analyzing genotypic data from large sample groups."
To construct their record high-resolution map, deCODE geneticists tapped 869 volunteers of the country's 277,906 total population. This three-tenths-of-a-percent sample consisted of parents and their offspring - with an average of four children per family - from 146 Icelandic families. These comprised 149 sibships, "providing information on 628 male/paternal and 629 female/maternal meioses, with 5,136 microsatellite markers," the Nature Genetics paper reported. (Meiosis is a germ-line, cell-division process leading to an ovum or spermatozoon.)
"This framework," Stefansson pointed out, "provided approximately five times the resolution of the current standard map. By following how these markers were passed from parents to their children, we were able to gain detailed and unprecedented insight into their inheritance pattern, and thus how recombinations occurred. With these data it was possible to pinpoint the genetic and physical sites of the satellite markers on the chromosomes. The location of some 2 millions SNPs - single nucleotide polymorphisms marking differences in the human genome - could then also be determined."
Contributing To, Or Protecting Against, Disease
"Sequencing the human genome," Stefansson allowed, "provided an enormously valuable tool for genomic research. However the sequence data themselves provide only the beginning. Our study is the obligatory next step: a high-resolution framework for analyzing how and where the genome changes between generations. This is critical for tracking genes and their mutations, for either contributing to or protecting against disease. We have located major genetic factors in more than 20 common diseases of man.
"We are using population genomics," Stefansson observed, "to create a new paradigm for healthcare. With its uniquely comprehensive population data, deCODE is turning research on the genetic causes of common diseases into a growing range of products and services - in gene discovery, pharmaceuticals, DNA-based diagnostics, pharmacogenomics, in silico discovery tools and medical-decision support systems.
"The paper in Nature Genetics," he said, "referenced 104 errors that we detected in the international consortium's human genome sequence assembly, made public last year. One significant finding that could be measured is the number of errors, and the nature of those mistakes, that are in the sequence. There are a lot of errors in the sequence now that make it less than a purpose that we are using the human sequence for, which is to help us to locate, identify and characterize disease genes. This is very significant; it doesn't come as a surprise to anyone."
Recombination Variation: Vive La Différence!
Stefansson's paper discerned in its genetic analysis a teaser involving recombination rates (gene shuffling in human sperm and ova that produces genetic variation) in families and individuals. "A fascinating facet of this phenomenon," he said, "was finding sex differences in recombination rates between men and women. We found the recombination frequency in the autosomes of females to be 1.65 times higher than in the autosomes of males. There are families with high recombination rates, and families with low recombination rates. Are there going to be different kinds of diseases that are common in the families, and male and female populations, with high-recombination rates versus low? It only underscores the fact that there is a certain difference between men and women. For this finding there are all kinds of teleological explanations that we could cook up. It, too, shouldn't have come as a surprise to anyone.
"If recombination events drive evolution," he suggested, "women may contribute more, in this regard, than do men. This demonstrates that there is more to recombination than just gene sequence. We are looking now at correlations between the familial recombination rate and diseases. If you study the same mother and several of her offspring, the rate varies from one child to the next, which might give us a handle on environmental factors that may influence that recombination rate. For us, generation of the high-resolution recombination map meant first and foremost construction of an instrument that we can use in our isolation of disease. This is the best way to generate high-quality targets, both for drug development and diagnostics."
In a press release, Nature Genetics echoed this sentiment. "The Icelandic map makes a significant contribution to tidying the 3-billion-letter code of the human genome into a finalized and complete sequence," it said. "The map produced by the researchers has fivefold greater resolution than previous genetic maps. It will be an invaluable resource to medical geneticists trying to locate genes that are mutated in human diseases."