Biomedical Engineering Reference
In-Depth Information
Identification of Polymorphic
Markers for Genetic Mapping
Daniel C. Koboldt and Raymond D. Miller
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA
2.1 Introduction
Single nucleotide polymorphisms (SNPs) are the most prevalent form of DNA sequence
variation in humans. At the end of 2008, public databases contained more than 12 million
entries of genetic variants in humans, the vast majority of which are SNPs [1]. While the
incidence of SNPs in the human genome is roughly 1 per 1000 bp on average, SNPs tend to
cluster locally [2], creating regions of high SNP density with long stretches of 'SNP deserts'
in between [3]. While an SNP could conceivably have four alleles (A, C, G, T), most are
biallelic, with A/G the most common allele combination. Since DNA is a double helix,
the opposite strand has alleles T and C. Consequently, an A/G SNP can also be described
as a T/C SNP, depending upon orientation. An estimated 63% of known SNPs are A/G,
17% are A/C, 8% are C/G, 4% are A/T and the remaining 8% are single base insertions or
deletions [3].
Owing to their widespread distribution across the genome, and facilitated by development
of high-throughput genotyping technologies, SNPs have become important tools for genetic
association studies. In an effort to understand the underlying structure of genetic variation
in humans, the International HapMap Consortium [4, 5] characterized nearly 4 million SNPs
in four geographically diverse human populations: the Yoruba in Ibadan, Nigeria (YRI); the
CEPH population with European ancestry in Utah, USA (CEU); Han Chinese in Beijing,
China (CHB); and Japanese in Tokyo, Japan. These data enabled the construction of a
high-resolution haplotype map describing the block-like structure of linkage disequilibrium
(LD) in the human genome. Large-scale, genome-wide association studies made possible
