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Resolving the Full Spectrum of Human Genome Variation using Linked-Reads

By Patrick Marks, Sarah Garcia, Alvaro Martinez Barrio, Kamila Belhocine, Jorge Bernate, Rajiv Bharadwaj, Keith Bjornson, Claudia Catalanotti, Josh Delaney, Adrian Fehr, Ian T. Fiddes, Brendan Galvin, Haynes Heaton, Jill Herschleb, Christopher Hindson, Esty Holt, Cassandra B. Jabara, Susanna Jett, Nikka Keivanfar, Sofia Kyriazopoulou-Panagiotopoulou, Monkol Lek, Bill Lin, Adam Lowe, Shazia Mahamdallie, Shamoni Maheshwari, Tony Makarewicz, Jamie Marshall, Francesca Meschi, Chris O’keefe, Heather Ordonez, Pranav Patel, Andrew Price, Ariel Royall, Elise Ruark, Sheila Seal, Michael Schnall-Levin, Preyas Shah, Stephen Williams, Indira Wu, Andrew Wei Xu, Nazneen Rahman, Daniel G. MacArthur, Deanna M. Church

Posted 08 Dec 2017
bioRxiv DOI: 10.1101/230946 (published DOI: 10.1101/gr.234443.118)

Large-scale population based analyses coupled with advances in technology have demonstrated that the human genome is more diverse than originally thought. Standard short-read approaches, used primarily due to accuracy, throughput and costs, fail to give a complete picture of a genome. They struggle to identify large, balanced structural events, cannot access repetitive regions of the genome and fail to resolve the human genome into its two haplotypes. Here we describe an approach that retains long range information while harnessing the power of short reads. Starting from only ~1ng of DNA, we produce barcoded short read libraries. The use of novel informatic approaches allows for the barcoded short reads to be associated with the long molecules of origin producing a novel datatype known as 'Linked-Reads'. This approach allows for simultaneous detection of small and large variants from a single Linked-Read library. We have previously demonstrated the utility of whole genome Linked-Reads (lrWGS) for performing diploid, de novo assembly of individual genomes (Weisenfeld et al. 2017). In this manuscript, we show the utility of reference based analysis using a single Linked-Read library for full spectrum genome analysis. We demonstrate the ability of Linked-Reads to reconstruct megabase scale haplotypes and to recover parts of the genome that are typically inaccessible to short reads, including phenotypically important genes such as STRC, SMN1 and SMN2. We demonstrate the ability of both lrWGS and Linked-Read Whole Exome Sequencing (lrWES) to identify complex structural variations, including balanced events, single exon deletions, and single exon duplications. The data presented here show that Linked-Reads provide a scalable approach for comprehensive genome analysis that is not possible using short reads alone.

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