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Articles by C Alkan
Total Records ( 2 ) for C Alkan
  F Hormozdiari , C Alkan , E. E Eichler and S. C. Sahinalp
 

Recent studies show that along with single nucleotide polymorphisms and small indels, larger structural variants among human individuals are common. The Human Genome Structural Variation Project aims to identify and classify deletions, insertions, and inversions (>5 Kbp) in a small number of normal individuals with a fosmid-based paired-end sequencing approach using traditional sequencing technologies. The realization of new ultra-high-throughput sequencing platforms now makes it feasible to detect the full spectrum of genomic variation among many individual genomes, including cancer patients and others suffering from diseases of genomic origin. Unfortunately, existing algorithms for identifying structural variation (SV) among individuals have not been designed to handle the short read lengths and the errors implied by the "next-gen" sequencing (NGS) technologies. In this paper, we give combinatorial formulations for the SV detection between a reference genome sequence and a next-gen-based, paired-end, whole genome shotgun-sequenced individual. We describe efficient algorithms for each of the formulations we give, which all turn out to be fast and quite reliable; they are also applicable to all next-gen sequencing methods (Illumina, 454 Life Sciences [Roche], ABI SOLiD, etc.) and traditional capillary sequencing technology. We apply our algorithms to identify SV among individual genomes very recently sequenced by Illumina technology.

  K. J McKernan , H. E Peckham , G. L Costa , S. F McLaughlin , Y Fu , E. F Tsung , C. R Clouser , C Duncan , J. K Ichikawa , C. C Lee , Z Zhang , S. S Ranade , E. T Dimalanta , F. C Hyland , T. D Sokolsky , L Zhang , A Sheridan , H Fu , C. L Hendrickson , B Li , L Kotler , J. R Stuart , J. A Malek , J. M Manning , A. A Antipova , D. S Perez , M. P Moore , K. C Hayashibara , M. R Lyons , R. E Beaudoin , B. E Coleman , M. W Laptewicz , A. E Sannicandro , M. D Rhodes , R. K Gottimukkala , S Yang , V Bafna , A Bashir , A MacBride , C Alkan , J. M Kidd , E. E Eichler , M. G Reese , F. M De La Vega and A. P. Blanchard
 

We describe the genome sequencing of an anonymous individual of African origin using a novel ligation-based sequencing assay that enables a unique form of error correction that improves the raw accuracy of the aligned reads to >99.9%, allowing us to accurately call SNPs with as few as two reads per allele. We collected several billion mate-paired reads yielding ~18x haploid coverage of aligned sequence and close to 300x clone coverage. Over 98% of the reference genome is covered with at least one uniquely placed read, and 99.65% is spanned by at least one uniquely placed mate-paired clone. We identify over 3.8 million SNPs, 19% of which are novel. Mate-paired data are used to physically resolve haplotype phases of nearly two-thirds of the genotypes obtained and produce phased segments of up to 215 kb. We detect 226,529 intra-read indels, 5590 indels between mate-paired reads, 91 inversions, and four gene fusions. We use a novel approach for detecting indels between mate-paired reads that are smaller than the standard deviation of the insert size of the library and discover deletions in common with those detected with our intra-read approach. Dozens of mutations previously described in OMIM and hundreds of nonsynonymous single-nucleotide and structural variants in genes previously implicated in disease are identified in this individual. There is more genetic variation in the human genome still to be uncovered, and we provide guidance for future surveys in populations and cancer biopsies.

 
 
 
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