chapter_1 - Mutations and variation in the human genome....

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2003 marked the 50 th anniversary of the double helix model by Watson and Crick and the publication of the human genome sequence. The Human Genome Project started off in the nineties and resulted in an unprecedented international collaboration of different sequencing centres. In 1998 a privately held company, Celera Genomics, launched an independent initiative. Two different strategies were used to sequence the genome. The HGP developed the ‘hierarchical shotgun sequencing’ methodology. In this approach, the genome is digested into large DNA fragments (typically 100-250kb: P1 artificial chromosomes (PAC) and bacterial artificial chromosomes (BAC)) that are subcloned into smaller fragments that are amenable for sequencing. These smaller sequences are then realigned and organized into the BAC and PAC clones from which they originated. Ultimately, realigning these BAC and PAC clones determines the sequence of an entire chromosome. Celera used a different approach: ‘whole genome shotgun sequencing’. In this methodology, the entire genome is fragmented into small clones that are sequenced directly. While hierarchical sequencing provides exact information on the localization of each individual sequence in the entire chromosome, it is very laborious. Whole genome shotgun sequencing on the other hand requires a more elaborate bioinformatics support. Currently, the entire genome sequence is freely accessible through the internet. The major portal sites are: s Ensembl: www.ensembl.org s NCBI MapView: www.ncbi.nlm.nih.gov/mapview s UCSC Genome Browser: genome.ucsc.edu These browsers provide a graphical interface allowing a representation of the genomic content at various levels of resolution. For each level, different features can be visualised such as: the orientation and position of known genes, the raw sequence data, the presence of SNPs etc. The HGP lead to groundbreaking insights into the structure, organisation and function of the human genome. The relatively limited number of genes (~30 to 35.000) comprised a first marked observation. Gene sequences only cover 5% of the genome, while only 1.5% contains coding sequences. Of roughly 50% of the known and predicted genes the function is currently largely unknown. the human genome diversity project The sequence data of the HGP were derived from 5 different individuals from different ethnic origins. The implications of the HGP to the study of genetic variation therefore remained limited. As a consequence a parallel initiative, the ‘human genome diversity project’ (HGDP), was initiated. The results from a genetic characterization in different populations revealed that the human genetic diversity is remarkably low: only 11% of the genetic variation worldwide can be explained by genetic differences between populations. The genetic diversity between individuals is stronger and amounts to 83%. Mutations and variation in the human genome.
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chapter_1 - Mutations and variation in the human genome....

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