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there are variants in which part of a gene is deleted or sequences from two genes
are fused together without destroying the cellular activity with which they are asso-
ciated. These fi ndings show that the parts list of the human genome may be more
variable and fl exible than previously considered. The discovery of CNVs in our
genomes has dramatically changed our perspective on DNA structural variation
and disease.
Mapping and Sequencing of Structural Variation from Human Genomes
The fi rst high-resolution map showing the structural variants (SVs) that exists in the
human genome has been published (Kidd et al. 2008 ). Using a clone-based method,
the complete DNA sequences of eight people of diverse geographic ancestry was
examined: four of African descent, two of Asian descent, and two of western
European descent. The DNA sequence of those eight persons was compared to the
DNA sequence derived from the Human Genome Project, which is known as the
reference sequence. This map provides a comprehensive picture of the normal pat-
tern of SV present in these genomes, refi ning the location of 1,695 SVs that more
than about 6,000 base pairs long; 50 % of these were seen in more than one indi-
vidual and lay outside regions of the genome previously described as structurally
variant. The researchers discovered 525 new insertion sequences, ranging in size
from a few thousand to 130,000 base pairs, which are not present in the human
reference genome, and many of these are variable in copy number between indi-
viduals. Complete sequencing of 261 SVs revealed considerable locus complexity
and provides insights into the different mutational processes that have shaped the
human genome.
In various parts of human genome, some people have segments of DNA sequence
that other people do not have. Large genetic regions may be fl ipped in one person
compared with another and these differences can infl uence a person’s susceptibility
to various diseases. These data provide a standard for genotyping platforms and a
prelude to future individual genome sequencing projects. The results also indicate
that the human genome sequence is still incomplete that sequencing of additional
genomes will be required to fi ll the remaining gaps. The eight people studied are
part of a much larger group whose genomes will be sequenced as part of the 1,000
Genomes Project, an international effort to sequences the genomes of people from
around the world.
In order to understand structural variation, it is also essential to develop new
technologies designed to detect genetic differences among people. For example,
SNP biochips, whether used in research or in clinical applications, need to refl ect
this structural variation to fi nd links between particular gene variants and diseases.
Currently available biochips would miss an association for nearly half of these sites.
Besides their potential applications, the new results provide a wealth of data to
explore hypotheses and make discoveries as we now have eight new reference
human genomes.
1 Basic Aspects