chromosome has a distinctive patterning of gains and losses
of DNA. Yellow points show chromosomal segments with no
copy number differences between people, whereas red and
green points represent losses and gains of DNA respectively.
The most structurally variable regions in the human genome
are those with a high density of red and green points.
[Credit: Matthew Hurles]
map of human genetic variation - International team identifies
sites of copy number variation across all human chromosomes
always knew that we each had our own, individual copy of The
Book of Life, where the spellings of our genetic code differed
ever so slightly. But a series of scientific studies published
today show that it's not only single letters but sentences,
paragraphs, and even whole pages that can be missing or duplicated.
In the leading publication in Nature, an international team
has produced a map of such changes among 270 copies of the
human genetic code that is already revealing new routes for
finding genes involved in disease.
Human Genome Project delivered a reference sequence for a
human genome. To identify genes involved in disease, many
focused studies, including the HapMap Project, have mapped
single-letter differences (called single nucleotide polymorphisms
or SNPs) between individuals and compared them to the human
reference DNA sequence.
the reference sequence has also provided the foundation for
an entirely new search for variation, one that was not readily
identifiable before. This is the search, not for single differences,
but for larger regions that are absent from, or duplicated
in different individuals. With this analysis of copy number
variation (CNV), a whole new vista of genetic variation with
dramatic implications for disease studies has been revealed.
one of us has a unique pattern of gains and losses of complete
sections of DNA," said Dr Matthew Hurles, one of the
projects leaders at the Wellcome Trust Sanger Institute, "and
one of the real surprises of these results was just how much
of our DNA varies in copy number. We estimate this to be at
least 12% of the genome, similar in extent to SNPs. This has
never been shown before."
copy number variation that researchers had seen before was
simply the tip of the iceberg, while the bulk lay submerged,
undetected. We now appreciate the immense contribution of
this phenomenon to genetic differences between individuals."
new map will change the way in which scientists search for
genes involved in disease. While the SNP maps produced by
the HapMap and other work are invaluable, most CNVs are missed
by these maps. One striking example is resistance to infection
by HIV, which is determined in part by multiple copies of
the gene CCL3L1, and is essentially invisible to SNP-based
maps of genomic variation.
examples of diseases resulting from changes in copy number
are emerging," commented Charles Lee, one of the projects
leaders from Brigham and Womens Hospital and Harvard Medical
School in Boston, USA. "A recent review lists 17 conditions
of the nervous system alone - including Parkinson's Disease
and Alzheimer Disease - that can result from such copy number
medical research will benefit enormously from this map, which
provides new ways for identifying genes involved in common
In comparing their results with the authoritative database
of disease-related genes Online Mendelian Inheritance in Man,
the team found that 10% of these genes were associated with
CNVs. Genes that are involved in the immune system and in
brain development and activity - two functions that have evolved
rapidly in humans - tend to be enriched in CNVs. By contrast,
genes that play a role in early development and some genes
involved in cell division, both critical to fundamental biology,
tend to be spared.
conclusions are dramatic: "I believe this paper will
change forever the field of human genetics," commented
Professor James R. Lupski, Vice Chair, Department of Molecular
and Human Genetics, Baylor College of Medicine, Houston, Texas.
"One can no longer consider human traits as resulting
primarily from single base-pair changes or influenced only
by SNPs. With all due respect to Watson and Crick, many Mendelian
and complex traits, as well as sporadic diseases, may indeed
result from structural variation of the genome."
global CNV map is transforming medical research in four areas.
The first and major area is in hunting genes underlying common
diseases, which have not looked at CNVs to date. Second, the
CNV map is being used in study of familial genetic conditions.
Third, there are thousands of severe developmental defects
caused by chromosomal rearrangements. The CNV map is being
used to exclude variation found in unaffected individuals,
helping researchers to home in on the region that might be
involved. Finally, as with HIV, it will be possible to find
variants that protect against other infectious diseases, such
some ways, the methods we have used are molecular microscopes,"
explained Dr Nigel Carter, another of the projects leaders
at the Wellcome Trust Sanger Institute, "which have transformed
the techniques used since the foundation of clinical genetics,
where researchers used microscopes to look for visible deletions
and rearrangements in chromosomes."
these new tools, we and our clinical colleagues are able to
find previously undetectable deletions or duplications of
the genome in a patient. The CNV map now allows us to identify
which of these changes are unique to the disease."
increase the value of the map to researchers, the Wellcome
Trust Sanger Institute and its partners have developed a database
of CNVs associated with clinical conditions. The database,
called DECIPHER, allows researchers around the world to submit
clinical information of patients with CNV details using the
patient information is then mapped onto the human genome in
the public ENSEMBL browser, which enables collaborative investigations
of these rare disorders. In this way, DECIPHER has already
helped in the identification of new syndromes with subsequent
improvements in care and genetic advice for affected individuals
and families. "The wide variation between individuals
in the number of repeated or deleted portions of our DNA has
not been appreciated until now," commented Dr Mark Walport,
Director of the Wellcome Trust.
important work will help identify genetic causes of many diseases.
All of the new data is in the public domain emphasizing the
commitment of research funders in making the results of research
accessible to all."
number variation is the result of several different mechanisms,
some of which remain poorly understood. Many studies to date
suggest that larger CNVs occur in regions of the human genome
that contain, or are flanked by, duplicated or repeated DNA
sequences. Such regions are prone to errors when chromosomes
are shuffledbefore being passed on from parent to child. Some
smaller CNVs are not to be dependent on these repeated sequences.
The new research identifies many more of these smaller CNVs
and will greatly advance our understanding of what is perhaps
the most poorly understood mutational process operating in
the human genome.
map also tells us something of our shared history. As a result
of our recent common origin in Africa, the vast majority of
copy-number variation - around 89% - is shared among the diverse
human populations studied.
the pattern of CNV that each of us inherits subtly reflects
our ancestry and can be used to infer in which of the three
continental populations our recent ancestry lies.
differences in regions of our genome between different continental
populations will define variants that have allowed different
populations to adapt to their different environments. One
example is the strikingly increased copy number of the HIV-related
CCL3L1 gene in African populations. An understanding of how
genetic variation is distributed among populations not only
tells us about human prehistory but also improves our ability
to find disease genes.