  Despite much progress over the past decade, current Single Nucleotide
Polymorphism (SNP) genotyping technologies still offer an insufficient degree
of multiplexing when required to handle user-selected sets of SNPs. In this
paper we propose a new genotyping assay architecture combining multiplexed
solution-phase single-base extension (SBE) reactions with sequencing by
hybridization (SBH) using universal DNA arrays such as all $k$-mer arrays. In
addition to PCR amplification of genomic DNA, SNP genotyping using SBE/SBH
assays involves the following steps: (1) Synthesizing primers complementing the
genomic sequence immediately preceding SNPs of interest; (2) Hybridizing these
primers with the genomic DNA; (3) Extending each primer by a single base using
polymerase enzyme and dideoxynucleotides labeled with 4 different fluorescent
dyes; and finally (4) Hybridizing extended primers to a universal DNA array and
determining the identity of the bases that extend each primer by hybridization
pattern analysis. Our contributions include a study of multiplexing algorithms
for SBE/SBH genotyping assays and preliminary experimental results showing the
achievable tradeoffs between the number of array probes and primer length on
one hand and the number of SNPs that can be assayed simultaneously on the
other. Simulation results on datasets both randomly generated and extracted
from the NCBI dbSNP database suggest that the SBE/SBH architecture provides a
flexible and cost-effective alternative to genotyping assays currently used in
the industry, enabling genotyping of up to hundreds of thousands of
user-specified SNPs per assay.
