Whole-genome genotyping

Overview

Between 2003 and 2005, Giulia Kennedy’s Affymetrix groups published the methods that made it practical to genotype a human sample at tens, then hundreds of thousands of positions on an oligonucleotide array. The sequence opened with “Large-scale genotyping of complex DNA” in Nature Biotechnology (volume 21, pages 1233–1237, 2003), with Kennedy as first author and Hajime Matsuzaki and Shoulian Dong among the co-authors.¹ The paper addressed genetic studies that need many thousands of single-nucleotide polymorphisms genotyped across large numbers of individuals to understand complex human phenotypes.

Research

The 2004 Genome Research paper, “Parallel Genotyping of Over 10,000 SNPs Using a One-Primer Assay on a High-Density Oligonucleotide Array”, lists Kennedy twelfth of nineteen authors and describes the platform: restriction digestion to fractionate the genome, amplification of a specific fractionated subset, and allele-specific hybridization to the array.²³ An erratum correcting a sequence followed in July 2004. The same year, “Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays” appeared in Nature Methods (volume 1, pages 109–111): 116,204 SNPs scored with call rates above 99%, reproducibility above 99.97% and accuracy, measured by inheritance in trios and concordance with the HapMap Project, above 99.7%.⁴⁵

Reading the arrays needed algorithms as much as chemistry. She is a co-author of “Algorithms for large-scale genotyping microarrays” (Bioinformatics, 2003)⁶ and of the 2005 Bioinformatics paper on dynamic-model-based algorithms for screening and genotyping over 100K SNPs,⁷ whose Dynamic Model algorithm became the default Affymetrix used to decide genotype calls.⁸

Impact

Trade press summarised the run as “Kennedy et al. publishing in Nature Biotech in 2003 and Matsuzaki et al. publishing in Genome Research and Nature Methods in 2004”.⁹ By June 2006 an NHGRI primer for the HapMap era was citing “Kennedy et al, Nature Biotech, 2003” as the reference for the Affymetrix GeneChip Mapping Assay.¹⁰ The habit formed here, of validating a high-dimensional assay with explicit performance numbers, is the one she carried to Veracyte.

Facts

First author of "Large-scale genotyping of complex DNA", Nature Biotechnology 21, 1233–1237 (2003), with Hajime Matsuzaki, Shoulian Dong and colleagues.¹⁹¹⁰

Co-author of "Parallel Genotyping of Over 10,000 SNPs Using a One-Primer Assay on a High-Density Oligonucleotide Array", Genome Research 14, 414–425 (2004), which fractionates the genome by restriction digestion, amplifies a specific subset and reads alleles by hybridization to the array.²³

Co-author of "Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays", Nature Methods 1, 109–111 (2004), which scored 116,204 SNPs with call rates above 99%, reproducibility above 99.97% and accuracy above 99.7%.⁴⁵⁹

Co-author of "Algorithms for large-scale genotyping microarrays", Bioinformatics 19(18), 2397–2403 (2003), and of "Dynamic model based algorithms for screening and genotyping over 100K SNPs on oligonucleotide microarrays", Bioinformatics 21(9), 1958–1963 (2005).⁶⁷

The Dynamic Model algorithm described in the 2005 paper was the default algorithm applied by Affymetrix to decide genotype calls.⁸

A 2006 NHGRI primer cites "Kennedy et al, Nature Biotech, 2003" as the reference for the Affymetrix GeneChip Mapping Assay.¹⁰

Research