RT Journal Article
SR Electronic
T1 Resolving the Full Spectrum of Human Genome Variation using Linked-Reads
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 230946
DO 10.1101/230946
A1 Patrick Marks
A1 Sara Garcia
A1 Alvaro Martinez Barrio
A1 Kamila Belhocine
A1 Jorge Bernate
A1 Rajiv Bharadwaj
A1 Keith Bjornson
A1 Claudia Catalanotti
A1 Josh Delaney
A1 Adrian Fehr
A1 Brendan Galvin
A1 Haynes Heaton
A1 Jill Herschleb
A1 Christopher Hindson
A1 Esty Holt
A1 Cassandra B. Jabara
A1 Susanna Jett
A1 Nikka Keivanfar
A1 Sofia Kyriazopoulou-Panagiotopoulou
A1 Monkol Lek
A1 Bill Lin
A1 Adam Lowe
A1 Shazia Mahamdallie
A1 Shamoni Maheshwari
A1 Tony Makarewicz
A1 Jamie Marshall
A1 Francesca Meschi
A1 Chris O'keefe
A1 Heather Ordonez
A1 Pranav Patel
A1 Andrew Price
A1 Ariel Royall
A1 Elise Ruark
A1 Sheila Seal
A1 Michael Schnall-Levin
A1 Preyas Shah
A1 Stephen Williams
A1 Indira Wu
A1 Andrew Wei Xu
A1 Nazneen Rahman
A1 Daniel MacArthur
A1 Deanna M. Church
YR 2017
UL http://biorxiv.org/content/early/2017/12/08/230946.abstract
AB 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.