Errors in the copying and reading of genes can have very serious consequences. Fortunately human genetic material is available in duplicate as everyone inherits a complete genome from both their mother and father. However, the two genomes are different: researchers refer to the different variants of the gene sequence on the individual chromosomes as "haplotypes" and the complete analysis of the genome requires detailed knowledge of both haplotypes. Scientists at the Max Planck Institute for Molecular Genetics in Berlin have now comprehensively decoded both sets of chromosomes from a human genome separately for the first time. This step is essential for gaining a deeper understanding of human biology, the analysis of disease risks and, accordingly, the development of new and more individualised strategies for the prevention and treatment of diseases.
The genome fully decoded by Margret Hoehe's team is also the first completely sequenced genome of a German individual.
Everyone inherits a genome from their mother and father, meaning that each of their 22 chromosomes (autosomes), including the genes they contain, exist in duplicate. The only exceptions to this rule are the two sex chromosomes (23rd chromosome pair). The two chromosome sets differ from each other, and these different versions at equivalent genomic regions are called haplotypes. Scientists from the Max Planck Institute for Molecular Genetics in Berlin have now resolved a human genome almost completely into its molecular haplotypes, thus decoding the two individual genomes. In the current edition of the journal Genome Research, Margret Hoehe and her colleagues describe how they assigned over 99 percent of all base differences (SNPs), a total of over three million SNPs, to one of the two versions of each chromosome. This is the first German genome to have been completely decoded and the first to be analysed at this previously unattained level of detail.
Current sequencing technologies do not deliver both sets of chromosomes separately but instead provide a composite of both versions. Therefore, the scientists had to develop a new method to be able to identify the different sequences of genetic letters for both versions of the chromosomes separately. "In essence, we each have two genomes, inherited from each of our parents, and we need to look at these separately and at their interactions to fully understand the biology of genomes," says Margret Hoehe, leader of the research group. "We constantly refer to 'the' genome. However, it is essential for the development of personalised medicine that an individual's two sets of chromosomes are considered separately as they can differ regarding their genetic codes and, consequently also, their encoded functions."
This comprehensive systematic analysis of the haplotypes of a human genome, carried out in Berlin, represents an important scientific advancement. In their study, which was funded by the German National Genome Research Network, Hoehe and her team succeeded in separately decoding for both chromosome sets the sequence of almost all of the genes in the genome of a 51-year-old German male. Importantly, 90 percent of the genes exist in two different molecular forms. "The two chromosome sets in our personal genome differ at a total of about two million positions. Consequently, in order to portray our natural biological blueprint in its entirety, instead of reading the genome as a mixed product, as was previously the case, in future, each of the two haplotypes must be determined separately," says Hoehe.
The scientists also succeeded for the first time in recording a genome in its molecular individuality. Between 60 and 70 percent, i.e. the majority of the genes, only arise in their characteristic molecular forms in the individual whose genome has just been analysed. "Our findings show very clearly that the biology of genes and genomes has a strong individual component," explains Hoehe. This insight is particularly important for the development of personalised treatments for individual patients as "for truly effective personalised medicine we must know both of a person's haplotypes because both influence his or her state of health or disease," says Hoehe. A good example of this is the BRCA1 gene, which causes a predisposition for breast cancer in its mutated form. The genome of the 51-year-old subject examined in this study carries two mutations in this breast cancer gene -- fortunately in the same gene copy. The copy on the other chromosome is unaltered. As a consequence, despite these two mutations, the genome has a healthy version of the gene. "The knowledge whether mutations affect both haplotypes is essential to be able to assess a patient's future risk of developing a disease," says Hoehe. Overall, the scientists identified 159 mutated genes in their test subject with a disease-predisposing potential, which can impair the function of proteins. In 86 of these genes, the mutations were found in the same copy of the gene.
The findings of the Max Planck scientists raise new and fundamental questions for future consideration: How do the two different molecular forms of a gene behave towards each other? Do they work together or against each other? Which of the two gene forms is dominant and why? A gene can only make a person sick if one form of it overrides the other or if both copies are affected. "Therefore, the distinction of haplotypes is essential to enable us to understand in future how diseases arise and how they can be treated," says Hoehe.
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