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Reads meet rotamers: structural biology in the age of deep sequencing.

ABSTRACT: Structure has traditionally been interrelated with sequence, usually in the framework of comparing sequences across species sharing a common fold. However, the nature of information within the sequence and structure databases is evolving, changing the type of comparisons possible. In particular, we now have a vast amount of personal genome sequences from human populations and a greater fraction of new structures contain interacting proteins within large complexes. Consequently, we have to recast our conception of sequence conservation and its relation to structure-for example, focusing more on selection within the human population. Moreover, within structural biology there is less emphasis on the discovery of novel folds and more on relating structures to networks of protein interactions. We cover this changing mindset here.

SUBMITTER: Sethi A

PROVIDER: S-EPMC4751031 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Reads meet rotamers: structural biology in the age of deep sequencing.

Sethi Anurag A Clarke Declan D Chen Jieming J Kumar Sushant S Galeev Timur R TR Regan Lynne L Gerstein Mark M

Current opinion in structural biology 20151201

Structure has traditionally been interrelated with sequence, usually in the framework of comparing sequences across species sharing a common fold. However, the nature of information within the sequence and structure databases is evolving, changing the type of comparisons possible. In particular, we now have a vast amount of personal genome sequences from human populations and a greater fraction of new structures contain interacting proteins within large complexes. Consequently, we have to recast ...[more]

PMID: 26658741

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Project description:BackgroundMassively parallel DNA sequencing technologies have enabled the sequencing of several individual human genomes. These technologies are also being used in novel ways for mRNA expression profiling, genome-wide discovery of transcription-factor binding sites, small RNA discovery, etc. The multitude of sequencing platforms, each with their unique characteristics, pose a number of design challenges, regarding the technology to be used and the depth of sequencing required for a particular sequencing application. Here we describe a number of analytical and empirical results to address design questions for two applications: detection of structural variations from paired-end sequencing and estimating mRNA transcript abundance.ResultsFor structural variation, our results provide explicit trade-offs between the detection and resolution of rearrangement breakpoints, and the optimal mix of paired-read insert lengths. Specifically, we prove that optimal detection and resolution of breakpoints is achieved using a mix of exactly two insert library lengths. Furthermore, we derive explicit formulae to determine these insert length combinations, enabling a 15% improvement in breakpoint detection at the same experimental cost. On empirical short read data, these predictions show good concordance with Illumina 200 bp and 2 Kbp insert length libraries. For transcriptome sequencing, we determine the sequencing depth needed to detect rare transcripts from a small pilot study. With only 1 Million reads, we derive corrections that enable almost perfect prediction of the underlying expression probability distribution, and use this to predict the sequencing depth required to detect low expressed genes with greater than 95% probability.ConclusionsTogether, our results form a generic framework for many design considerations related to high-throughput sequencing. We provide software tools http://bix.ucsd.edu/projects/NGS-DesignTools to derive platform independent guidelines for designing sequencing experiments (amount of sequencing, choice of insert length, mix of libraries) for novel applications of next generation sequencing.

Dataset Information

Reads meet rotamers: structural biology in the age of deep sequencing.

Publications

Reads meet rotamers: structural biology in the age of deep sequencing.

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