12
disequilibrium patterns for many CNVs, and reveal marked variation in copy
number among populations. They also demonstrated the utility of this resource for
genetic disease studies. Of the 2,900 copy number variations, 285 are already known
to be associated with disease, including AIDS, infl ammatory bowel disease, lupus,
cataracts, arterial disease, and schizophrenia. The fi ndings could change the direc-
tion of future genetic disease research, which has primarily focused on SNPs. Some
diseases are caused by copy number variation rather than SNPs.
CNVs are still relatively under-ascertained. Tiling oligonucleotide microarrays,
comprising 42 million probes, were used to generate a comprehensive map of 11,700
CNVs greater than 443 base pairs, of which most have been validated independently
(Conrad et al. 2010 ). Reference genotypes were generated from 450 individuals of
European, African or East Asian ancestry. The predominant mutational mechanisms
differ among CNV size classes. Retrotransposition has duplicated and inserted some
coding and non-coding DNA segments randomly around the genome. Furthermore,
by correlation with known trait-associated SNPs, 30 loci with CNVs were identifi ed
that are candidates for infl uencing disease susceptibility. The results show that any
two genomes differ by more than 1,000 CNVs, or approximately 0.8 % of a person’s
genome sequence. Most of these CNVs are deletions, with a minority being duplica-
tions. Two consequences are particularly striking in this study of apparently healthy
people. First, 75 regions have jumped around in the genomes of these samples: sec-
ond, more than 250 genes can lose one of the two copies in our genome without
obvious consequences and a further 56 genes can fuse together potentially to form
new composite genes. This map complements the cataloguing of SNPs delineated in
the HapMap Project. In spite of the power of this map, the heritability void left by
genome-wide association studies will not be accounted for by common CNVs in
case of complex diseases such as diabetes or heart disease.
By analyzing short-read mapping depth for 159 human genomes, a study has
demonstrated accurate estimation of absolute copy number for duplications as small
as 1.9 kilobase pairs, ranging from 0 to 48 copies (Sudmant et al. 2010 ).
Approximately 4.1 million “singly unique nucleotide” positions were identifi ed,
which provided information for distinguishing specifi c copies, and were used to
genotype the copy and content of specifi c paralogs within highly duplicated gene
families. These data identify human-specifi c expansions in genes associated with
brain development, reveal extensive population genetic diversity, and detect signa-
tures consistent with gene conversion in the human species. This approach enables
access to ~1,000 genes for genetic studies of disease association.
CNV Association with Disease
CNVs not only contribute to the phenotypic diversity among humans, they have
been also been associated with disease susceptibility. Diseases associated with
CNVs include AIDS, infl ammatory bowel disease, lupus, cataracts, cardiovascular
diseases, neurological diseases, autism and schizophrenia. The fi ndings could
change the direction of future genetic disease research, which has primarily focused
on SNPs.
1 Basic Aspects