The large studies of human genetic variation have concentrated on understanding the pattern and nature of single- nucleotide differences within the human genome. There are larger polymorphisms for example insertions, deletions and inversions, Which leaves much to be studied .in human structural genetic variation. The National Human Genome Research Institute (NHGRI propose to sequence large-insert clones from many individuals, from all racially diverse groups systematically discovering and resolving the complex variants at the DNA sequence level.
The sequencing of the human genome has revolutionised human biology and genetic medicine. However it is anticipated that the sequencing of individual human genomes is necessary for a comprehensive genetic understanding of disease. The cost of such efforts is prohibitive.
The discovery of functionally important genetic variation lies at the core of these endeavours, and there has been considerable progress in understanding the common patterns of single-nucleotide polymorphism (SNP) in humans. Of the estimated 10-15 million common human SNPs, a significant fraction have now been identified and genotyped among population samples (Hap.Map release 21).
Understanding the structural variation in the human genome is less advanced .Structural variation can be defined as all genomic changes that are not single base-pair substitutions i.e. insertions, deletions, inversions, duplications and translocations of DNA sequences, and copy-number differences (also known as copy-number variants, CNVs. .Thee are large-scale (>100 kb), intermediate-scale (500 bp-100 kb) and fine-scale (1-500 bp) structural variations in the human genome. Structural changes are common, and frequently involve the rearrangement of genes. It is important to establish a baseline of normal structural variation to allow the discovery and characterization of disease-causing mutations in patients.
There are considerable variation between normal human genomes, with more than 1,447 copy-number variant regions spanning 12% of the reference DNA sequence. It still remains important to identify which specific DNA sequences have been altered, and the molecular events that have given rise to these structural genomic variants.
Previous methodology has been unable to show structural variation events that have arisen as a result of balanced chromosomal rearrangements (such as inversions or reciprocal translocations of chromosomal segments). The frequency of such balanced events is unknown, a guess is 1-20% of all structural variation may in fact be balanced and does not involve copy-number changes.
Such human genetic traits as such as colour blindness, rhesus blood group sensitivity, classical haemophilia and forms of beta- and alpha- thalassaemia result from complex structural alterations in genes and gene families Other traits involve large, structural rearrangements of chromosomes for example, Prader-Willi syndrome. Structural genetic variation can confer phenotypes through several mechanisms, gene dosage (copy-number variation); gene disruption; gene fusions at the junction; position effects in which the rearrangement alters the regulation of a nearby gene; and unmasking of recessive mutations or functional SNPs on the remaining allele. Another possible mechanism could occur through perturbations of gene expression that normally result from the pairing of homologous allele. .
Several common structural genetic variants (>1% minor allele frequency) have been shown to be important in both normal phenotypic variability and disease susceptibility.
These examples highlight the importance of structural variation to disease and disease susceptibility, and suggest several concepts of potentially broad relevance.
1., the number of copies of a given gene or family of genes can be a direct risk factor for specific diseases.
2. Copy number alone may not explain phenotypic differences caused by structural genetic variation. In rhesus blood group sensitivity, colour blindness and the alpha- and beta-thalassaemias, the precise DNA sequence structure (that is, the formation of fusion genes or the position of a gene with respect to functional promoters) provides the most meaningful associations between genotype and disease
3. Normal structural genetic variation can increase the risk of secondary, pathogenic rearrangement.
The Human Genome Structural Variation Working Group ( Eichler et al ) Nature 2007, vol 447, 99161-165
- Martin Eastwood