Comprehensive red blood cell and platelet antigen prediction from whole genome sequencing: proof of principle

William J Lane, Connie M Westhoff, Jon Michael Uy, Maria Aguad, Robin Smeland-Wagman, Richard M Kaufman, Heidi L Rehm, Robert C Green, Leslie E Silberstein, MedSeq Project, David W Bates, Alexis D Carere, Allison Cirino, Kurt D Christensen, Robert C Green, Carolyn Y Ho, Lily Hoffman-Andrews, Joel B Krier, William J Lane, Denise M Perry, Lisa Lehmann, Calum A MacRae, Cynthia C Morton, Christine E Seidman, Shamil Sunyaev, Jason L Vassy, Rebecca Walsh, Sandy Aronson, Ozge Ceyhan-Birsoy, Siva Gowrisankar, Matthew S Lebo, Ignat Leschiner, Kalotina Machini, Heather M McLaughlin, Danielle R Azzariti, Heidi L Rehm, Jennifer Blumenthal-Barby, Lindsay Zausmer Feuerman, Leila Jamal, Kaitlyn Lee, Amy L McGuire, Jill Oliver Robinson, Melody J Slashinski, Julia Wycliff, Philip Lupo, Stewart C Alexander, Shubhangi Arora, Kelly Davis, Christine Kirby, Peter A Ubel, Peter Kraft, J Scott Roberts, Judy E Garber, Dmitry Dukhovny, Tina Hambuch, Michael F Murray, Isaac Kohane, Sek Won Kong, William J Lane, Connie M Westhoff, Jon Michael Uy, Maria Aguad, Robin Smeland-Wagman, Richard M Kaufman, Heidi L Rehm, Robert C Green, Leslie E Silberstein, MedSeq Project, David W Bates, Alexis D Carere, Allison Cirino, Kurt D Christensen, Robert C Green, Carolyn Y Ho, Lily Hoffman-Andrews, Joel B Krier, William J Lane, Denise M Perry, Lisa Lehmann, Calum A MacRae, Cynthia C Morton, Christine E Seidman, Shamil Sunyaev, Jason L Vassy, Rebecca Walsh, Sandy Aronson, Ozge Ceyhan-Birsoy, Siva Gowrisankar, Matthew S Lebo, Ignat Leschiner, Kalotina Machini, Heather M McLaughlin, Danielle R Azzariti, Heidi L Rehm, Jennifer Blumenthal-Barby, Lindsay Zausmer Feuerman, Leila Jamal, Kaitlyn Lee, Amy L McGuire, Jill Oliver Robinson, Melody J Slashinski, Julia Wycliff, Philip Lupo, Stewart C Alexander, Shubhangi Arora, Kelly Davis, Christine Kirby, Peter A Ubel, Peter Kraft, J Scott Roberts, Judy E Garber, Dmitry Dukhovny, Tina Hambuch, Michael F Murray, Isaac Kohane, Sek Won Kong

Abstract

Background: There are 346 serologically defined red blood cell (RBC) antigens and 33 serologically defined platelet (PLT) antigens, most of which have known genetic changes in 45 RBC or six PLT genes that correlate with antigen expression. Polymorphic sites associated with antigen expression in the primary literature and reference databases are annotated according to nucleotide positions in cDNA. This makes antigen prediction from next-generation sequencing data challenging, since it uses genomic coordinates.

Study design and methods: The conventional cDNA reference sequences for all known RBC and PLT genes that correlate with antigen expression were aligned to the human reference genome. The alignments allowed conversion of conventional cDNA nucleotide positions to the corresponding genomic coordinates. RBC and PLT antigen prediction was then performed using the human reference genome and whole genome sequencing (WGS) data with serologic confirmation.

Results: Some major differences and alignment issues were found when attempting to convert the conventional cDNA to human reference genome sequences for the following genes: ABO, A4GALT, RHD, RHCE, FUT3, ACKR1 (previously DARC), ACHE, FUT2, CR1, GCNT2, and RHAG. However, it was possible to create usable alignments, which facilitated the prediction of all RBC and PLT antigens with a known molecular basis from WGS data. Traditional serologic typing for 18 RBC antigens were in agreement with the WGS-based antigen predictions, providing proof of principle for this approach.

Conclusion: Detailed mapping of conventional cDNA annotated RBC and PLT alleles can enable accurate prediction of RBC and PLT antigens from whole genomic sequencing data.

© 2015 The Authors Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.

Figures

Figure 1
Figure 1
Approach for mapping conventional cDNA reference sequence positions to genomic coordinates. (A) Process developed to convert conventional CDS positions to genomic coordinates with FY as an example. (B) CDS positions referenced to cDNA sequence. (C and D) Genome transcript and genomic coordinates according to the human reference genome. (E) UCSC genomic sequence in which each exon and intron is annotated as separate sequence entry preceded by the genomic coordinates. The sequence regions are colored: 3′ and 5′ (gray), CDS (green uppercase), and intron (blue lowercase). (F) FY gene conversion between genomic coordinates and cDNA reference sequence.
Figure 2
Figure 2
WGS‐based RBC and PLT gene sequencing. Circos plot61of the WGS data that has been filtered to only show the RBC and PLT genes with a circular plot of the sequence coverage (100‐bp bins).

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