Complex SNP-related sequence variation in segmental genome duplications
Nat Genet, 36 (8):
861-866 (August 2004)Abstract
There is uncertainty about the true nature of predicted
single-nucleotide polymorphisms (SNPs) in segmental duplications
(duplicons) and whether these markers genuinely exist at increased
density as indicated in public databases. We explored these issues by
genotyping 157 predicted SNPs in duplicons and control regions in
normal diploid genomes and fully homozygous complete hydatidiform
moles. Our data identified many true SNPs in duplicon regions and few
paralogous sequence variants. Twenty-eight percent of the polymorphic
duplicon sequences we tested involved multisite variation, a new type
of polymorphism representing the sum of the signals from many
individual duplicon copies that vary in sequence content due to
duplication, deletion or gene conversion. Multisite variations can
masquerade as normal SNPs when genotyped. Given that duplicons
comprise at least 5\% of the genome and many are yet to be annotated in
the genome draft, effective strategies to identify multisite variation
must be established and deployed.
In conclusion, our study identifies MSVs as a new form of genome
polymorphism. Careful laboratory practice should often recognize MSVs
as aberrant markers, and MSVs may underlie the considerable fraction
of markers that fail HWE. But some MSVs are probably being interpreted
and used as unique SNPs, and HWE will not always identify these, even
if large sample numbers are used. More generally, MSVs (or rather
duplicon copy-number variation and duplicon gene conversion processes)
might underlie some common phenotypic differences between
individuals. We therefore suggest that MSVs should be specifically
targeted for evaluation in disease and pharmacogenomics research.