Genome-Wide Identification of Human Functional DNA Using a Neutral Indel Model 英文参考文献.docVIP

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Genome-Wide Identification of Human Functional DNA Using a Neutral Indel Model 英文参考文献.doc

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Genome-Wide Identification of Human Functional DNA Using a Neutral Indel Model 英文参考文献

Genome-WideIdentificationofHuman FunctionalDNAUsingaNeutralIndelModel Gerton Lunter1,2*,Chris P.Ponting1,Jotun Hein2 1MRCFunctionalGeneticsUnit,DepartmentofHumanAnatomyandGenetics,UniversityofOxford,Oxford,UnitedKingdom,2DepartmentofStatistics,Bioinformatics Group,UniversityofOxford,Oxford,UnitedKingdom It has become clear that a large proportion of functional DNA in the human genome does not code for protein. Identification of this non-coding functional sequence using comparative approaches is proving difficult and has previously been thought to require deep sequencing of multiple vertebrates. Here we introduce a new model and comparative method that, instead of nucleotide substitutions, uses the evolutionary imprint of insertions and deletions (indels) to infer the past consequences of selection. The model predicts the distribution of indels under neutrality,andshowsanexcellentfittohuman–mouseancestralrepeatdata.Acrossthegenome,manyunusuallylong ungapped regions are detected that are unaccounted for by the neutral model, and which we predict to be highly enrichedinfunctionalDNAthathasbeensubjecttopurifyingselectionwithrespecttoindels.Weusethemodelto determine the proportion under indel-purifying selection to be between 2.56% and 3.25% of human euchromatin. Since annotated protein-coding genes comprise only 1.2% of euchromatin, these results lend further weight to the propositionthatmorethanhalfthefunctionalcomplementofthehumangenomeisnon-protein-coding.Themethod issurprisinglypowerfulatidentifyingselectedsequenceusingonlytwoorthreemammaliangenomes.Applyingthe method to the human, mouse, and dog genomes, we identify 90 Mb of human sequence under indel-purifying selection,atapredicted10%false-discoveryrateand75%sensitivity.Asexpected,mostoftheidentifiedsequence represents unannotated material, while the recovered proportions of known protein-coding and microRNA genes closelymatchthepredictedsensitivityofthemethod.Themethod’shighsensitivitytofunctionalsequencesuch