A Statistical Framework for SNP Calling, Mutation Discovery, Association Mapping and Population Genetical Parameter Estimation from Sequencing Data

Overview

Journal Bioinformatics

Publisher Oxford University Press

Specialty Biology

Date 2011 Sep 10

PMID 21903627

Citations 3183

Authors

Heng Li

Affiliations

Soon will be listed here.

Abstract

Motivation: Most existing methods for DNA sequence analysis rely on accurate sequences or genotypes. However, in applications of the next-generation sequencing (NGS), accurate genotypes may not be easily obtained (e.g. multi-sample low-coverage sequencing or somatic mutation discovery). These applications press for the development of new methods for analyzing sequence data with uncertainty.

Results: We present a statistical framework for calling SNPs, discovering somatic mutations, inferring population genetical parameters and performing association tests directly based on sequencing data without explicit genotyping or linkage-based imputation. On real data, we demonstrate that our method achieves comparable accuracy to alternative methods for estimating site allele count, for inferring allele frequency spectrum and for association mapping. We also highlight the necessity of using symmetric datasets for finding somatic mutations and confirm that for discovering rare events, mismapping is frequently the leading source of errors.

Availability: http://samtools.sourceforge.net.

Contact: hengli@broadinstitute.org.

Citing Articles

Comparative analysis of genotype imputation strategies for SNPs calling from RNA-seq.

Guo K, Zhong Z, Zeng H, Zhang C, Chitotombe T, Teng J BMC Genomics. 2025; 26(1):245.

PMID: 40082746 PMC: 11907794. DOI: 10.1186/s12864-025-11411-5.

Single-cell RNA-seq data have prevalent blood contamination but can be rescued by Originator, a computational tool separating single-cell RNA-seq by genetic and contextual information.

Unjitwattana T, Huang Q, Yang Y, Tao L, Yang Y, Zhou M Genome Biol. 2025; 26(1):52.

PMID: 40069819 PMC: 11895284. DOI: 10.1186/s13059-025-03495-9.

Integrated functional genomic analysis identifies regulatory variants underlying a major QTL for disease resistance in European sea bass.

Mukiibi R, Ferraresso S, Franch R, Peruzza L, Dalla Rovere G, Babbucci M BMC Biol. 2025; 23(1):75.

PMID: 40069747 PMC: 11899128. DOI: 10.1186/s12915-025-02180-4.

Advantages of Mutant Generation by Genome Rearrangements of Non-Conventional Yeast via Direct Nuclease Transfection.

Oda A, Yasukawa T, Tamura M, Sano A, Masuo N, Ohta K Genes Cells. 2025; 30(2):e70010.

PMID: 40065658 PMC: 11894362. DOI: 10.1111/gtc.70010.

A 6.49-Mb inversion associated with the purple embryo spot trait in potato.

Wang P, Cheng L, Pan J, Ma L, Hu X, Zhang Z aBIOTECH. 2025; 6(1):22-32.

PMID: 40060175 PMC: 11889318. DOI: 10.1007/s42994-025-00197-5.

References

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo Z, Pool J . Sequencing of 50 human exomes reveals adaptation to high altitude. Science. 2010; 329(5987):75-8. PMC: 3711608. DOI: 10.1126/science.1190371. View

Robison K . Application of second-generation sequencing to cancer genomics. Brief Bioinform. 2010; 11(5):524-34. DOI: 10.1093/bib/bbq013. View

Pleasance E, Cheetham R, Stephens P, McBride D, Humphray S, Greenman C . A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2009; 463(7278):191-6. PMC: 3145108. DOI: 10.1038/nature08658. View

Nielsen R, Paul J, Albrechtsen A, Song Y . Genotype and SNP calling from next-generation sequencing data. Nat Rev Genet. 2011; 12(6):443-51. PMC: 3593722. DOI: 10.1038/nrg2986. View

Hodgkinson A, Eyre-Walker A . Human triallelic sites: evidence for a new mutational mechanism?. Genetics. 2009; 184(1):233-41. PMC: 2815919. DOI: 10.1534/genetics.109.110510. View

Li Y, Willer C, Sanna S, Abecasis G . Genotype imputation. Annu Rev Genomics Hum Genet. 2009; 10:387-406. PMC: 2925172. DOI: 10.1146/annurev.genom.9.081307.164242. View

Danecek P, Auton A, Abecasis G, Albers C, Banks E, DePristo M . The variant call format and VCFtools. Bioinformatics. 2011; 27(15):2156-8. PMC: 3137218. DOI: 10.1093/bioinformatics/btr330. View

Bentley D, Balasubramanian S, Swerdlow H, Smith G, Milton J, Brown C . Accurate whole human genome sequencing using reversible terminator chemistry. Nature. 2008; 456(7218):53-9. PMC: 2581791. DOI: 10.1038/nature07517. View

10.

Ley T, Mardis E, Ding L, Fulton B, McLellan M, Chen K . DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008; 456(7218):66-72. PMC: 2603574. DOI: 10.1038/nature07485. View

11.

Nakamura K, Oshima T, Morimoto T, Ikeda S, Yoshikawa H, Shiwa Y . Sequence-specific error profile of Illumina sequencers. Nucleic Acids Res. 2011; 39(13):e90. PMC: 3141275. DOI: 10.1093/nar/gkr344. View

12.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View

13.

Ajay S, Parker S, Abaan H, Fajardo K, Margulies E . Accurate and comprehensive sequencing of personal genomes. Genome Res. 2011; 21(9):1498-505. PMC: 3166834. DOI: 10.1101/gr.123638.111. View

14.

Shah S, Morin R, Khattra J, Prentice L, Pugh T, Burleigh A . Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009; 461(7265):809-13. DOI: 10.1038/nature08489. View

15.

Schaid D, Rowland C, Tines D, Jacobson R, Poland G . Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet. 2002; 70(2):425-34. PMC: 384917. DOI: 10.1086/338688. View

16.

Kim S, Lohmueller K, Albrechtsen A, Li Y, Korneliussen T, Tian G . Estimation of allele frequency and association mapping using next-generation sequencing data. BMC Bioinformatics. 2011; 12:231. PMC: 3212839. DOI: 10.1186/1471-2105-12-231. View

17.

Conrad D, Keebler J, DePristo M, Lindsay S, Zhang Y, Casals F . Variation in genome-wide mutation rates within and between human families. Nat Genet. 2011; 43(7):712-4. PMC: 3322360. DOI: 10.1038/ng.862. View

18.

Abecasis G, Altshuler D, Auton A, Brooks L, Durbin R, Gibbs R . A map of human genome variation from population-scale sequencing. Nature. 2010; 467(7319):1061-73. PMC: 3042601. DOI: 10.1038/nature09534. View

19.

Li H, Durbin R . Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010; 26(5):589-95. PMC: 2828108. DOI: 10.1093/bioinformatics/btp698. View

20.

Li Y, Vinckenbosch N, Tian G, Huerta-Sanchez E, Jiang T, Jiang H . Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nat Genet. 2010; 42(11):969-72. DOI: 10.1038/ng.680. View