The deciphering of the human genome was considered the breakthrough of 2001. Since then, researchers have been looking for the small differences from person to person - and they turn out to be bigger than expected.
99.9 percent identical – that was the result of a research project, the dimensions of which were often compared to the moon landing. On February 15, 2001, the geneticists of the world - split into a publicly and privately funded group - presented the first raw version of the human genome. A revised version appeared three and a half years later.
And the almost three billion deciphered building blocks should be 99.9 percent the same for all people - for the individual as such there would be a tenth of a percent. But even if the genetic master key of mankind is of extraordinary importance for basic research, application-oriented scientists such as physicians and pharmacists are primarily interested in the small but subtle differences - this could be the explanation why certain people are more likely than others to develop diabetes, Cancer or Alzheimer's dementia and why some people respond differently to a drug than the general public.
Therefore, as soon as the human genome project was completed, geneticists jumped at what are known as SNPs (ssingle ucleotide polymorphisms), in laboratory jargon also called "snips". These are positions in the genome sequence that are occupied by at least one percent of individuals with a different DNA building block than the rest of the population. In 2005, the HapMap project was able to track down around ten million of these one-letter variations, which are often inherited in small groups as so-called haplotypes.
With this haplotype mapping, is the geneticist's job done? Not quite. Because the individual subtleties consist not only of SNPs, but also – to introduce a new abbreviation – of CNVs. These are copy umber variations, i.e. variations in the number of copies. What's behind it?
Freely adapted from Gregor Mendel, we have two copies of each gene, one from the father and one from the mother. But a closer look reveals that some genes occur more than once in the genome, while others are missing individual pieces. Of course, these variations, which geneticists know as duplications (doubling), deletions (loss) or inversions (reversal), have a decisive influence on the activity of the affected genes: the more often the genetic factor is represented in the genome, the more gene products can be produced.
An international working group led by Matthew Hurles from the British Wellcome Trust Sanger Institute in Cambridge and Stephen Scherer from the Canadian University of Toronto has now devoted itself to CNVs in the human genome. The scientists focused on areas that are at least a thousand base pairs long.
Their analysis was based on the HapMap project, which recorded the SNPs of 270 individuals from four separate populations: Chinese, Japanese, Nigerian, and American-American. And once again the researchers found what they were looking for: they were able to track down a total of 1447 CNVs in almost 3000 genes – in other words in more than ten percent of all human hereditary factors. These versions add up to a length of 360 million base pairs. In other words, the individual variations affect twelve percent of the human genome. In the DNA, the book of life, not only individual letters, but several sentences, sections or even entire pages can be swapped, duplicated or left out.
So does that mean that humanity shares less than 90 percent of its genetic make-up? No, because the differences don't all appear at the same time. The researchers estimate that any two people are, on average, 99.5 percent genetically alike. However, geneticists had previously underestimated the high number of copies of individual genes because it slips through the cracks in gene sequencing. "It was just swept under the rug," says geneticist Michael Wigler of Cold Spring Harbor Laboratory.
Each of us is unique
(Matthew Hurles) Now what do these variations mean? It was already known that some gene duplications play a role in various diseases: They can trigger diseases such as Alzheimer's dementia or Parkinson's disease, but they can also protect against them: For example, the duplication of the CCL3L1 gene ensures greater resistance to the AIDS pathogen HIV. However, obviously high variabilities do not have to be related to diseases, but rather seem to be "normal". "Until now, we had believed that such large changes must inevitably be involved in a disease," explains Stephen Scherer."But now we see that we can all have these deviations."
Interestingly, the researchers found most CNVs in areas that are young in terms of evolutionary biology, such as in genes for the immune system or brain maturation. Long-established things like cell division or embryonic development, on the other hand, mostly remained unaffected by variations. But the consequences of these differences from person to person remain a mystery in most cases.
The researchers suspect that the almost 1500 CNVs could only be the tip of the iceberg. The number of individual variations in the DNA keyboard is likely to be much higher - because, as Matthew Hurles sums up the surprising result: "Each of us is unique."