Improving the Power of Structural Variation Detection by Augmenting the Reference.

Jan Schröder,Santhosh Girirajan,Paul Medvedev,Anthony T Papenfuss,Mikael Boden

doi:10.1371/journal.pone.0136771

Abstract

The uses of the Genome Reference Consortium’s human reference sequence can be roughly categorized into three related but distinct categories: as a representative species genome, as a coordinate system for identifying variants, and as an alignment reference for variation detection algorithms. However, the use of this reference sequence as simultaneously a representative species genome and as an alignment reference leads to unnecessary artifacts for structural variation detection algorithms and limits their accuracy. We show how decoupling these two references and developing a separate alignment reference can significantly improve the accuracy of structural variation detection, lead to improved genotyping of disease related genes, and decrease the cost of studying polymorphism in a population.

Highlights

The initial sequencing and assembly of a human reference genome allowed for the understanding of our genomic landscape in comparison to other species [1, 2]
We note that none of the Venter Novel Alleles (VNAs) are present in the database of genomic structural variation, except as entries from the HuRef study itself
The increased power offered by ref+ can help in genotyping variants of clinical importance, as some of the VNAs affect genes that play a role in disease

Summary

Introduction

The initial sequencing and assembly of a human reference genome allowed for the understanding of our genomic landscape in comparison to other species [1, 2]. It facilitated our understanding of polymorphism within the human species by providing a high-resolution coordinate system onto which variants could be mapped [2]. The uses of the human reference sequence can be roughly categorized into three related but distinct categories: as a representative species genome, as a coordinate system for identifying variants, and as an alignment reference for variation detection algorithms. One notable exception is the idea of a human pan-genome, which has been introduced [3] to distinguish the representative species genome from the GRC reference

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Results

Conclusion