Multiple Haplotype-resolved Genomes Reveal Population Patterns of Gene and Protein Diplotypes

Overview

Journal Nat Commun

Specialty Biology

Date 2014 Nov 27

PMID 25424553

Citations 19

Authors

Margret R Hoehe

George M Church

Hans Lehrach

Thomas Kroslak

Stefanie Palczewski

Katja Nowick

Sabrina Schulz

Eun-Kyung Suk

Thomas Huebsch

Affiliations

Soon will be listed here.

Abstract

To fully understand human biology and link genotype to phenotype, the phase of DNA variants must be known. Here we present a comprehensive analysis of haplotype-resolved genomes to assess the nature and variation of haplotypes and their pairs, diplotypes, in European population samples. We use a set of 14 haplotype-resolved genomes generated by fosmid clone-based sequencing, complemented and expanded by up to 372 statistically resolved genomes from the 1000 Genomes Project. We find immense diversity of both haploid and diploid gene forms, up to 4.1 and 3.9 million corresponding to 249 and 235 per gene on average. Less than 15% of autosomal genes have a predominant form. We describe a 'common diplotypic proteome', a set of 4,269 genes encoding two different proteins in over 30% of genomes. We show moreover an abundance of cis configurations of mutations in the 386 genomes with an average cis/trans ratio of 60:40, and distinguishable classes of cis- versus trans-abundant genes. This work identifies key features characterizing the diplotypic nature of human genomes and provides a conceptual and analytical framework, rich resources and novel hypotheses on the functional importance of diploidy.

Citing Articles

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Analysis of 1276 Haplotype-Resolved Genomes Allows Characterization of Cis- and Trans-Abundant Genes.

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Interrogating the Human Diplome: Computational Methods, Emerging Applications, and Challenges.

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HaplotypeTools: a toolkit for accurately identifying recombination and recombinant genotypes.

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References

Lo C, Liu R, Lee J, Robasky K, Byrne S, Lucchesi C . On the design of clone-based haplotyping. Genome Biol. 2013; 14(9):R100. PMC: 4053695. DOI: 10.1186/gb-2013-14-9-r100. View

Stephens J, Schneider J, Tanguay D, Choi J, Acharya T, Stanley S . Haplotype variation and linkage disequilibrium in 313 human genes. Science. 2001; 293(5529):489-93. DOI: 10.1126/science.1059431. View

Scheet P, Stephens M . A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am J Hum Genet. 2006; 78(4):629-44. PMC: 1424677. DOI: 10.1086/502802. View

Suk E, McEwen G, Duitama J, Nowick K, Schulz S, Palczewski S . A comprehensively molecular haplotype-resolved genome of a European individual. Genome Res. 2011; 21(10):1672-85. PMC: 3202284. DOI: 10.1101/gr.125047.111. View

Hoehe M, Kopke K, Wendel B, Rohde K, Flachmeier C, Kidd K . Sequence variability and candidate gene analysis in complex disease: association of mu opioid receptor gene variation with substance dependence. Hum Mol Genet. 2000; 9(19):2895-908. DOI: 10.1093/hmg/9.19.2895. View

Gimelbrant A, Hutchinson J, Thompson B, Chess A . Widespread monoallelic expression on human autosomes. Science. 2007; 318(5853):1136-40. DOI: 10.1126/science.1148910. View

Hoehe M . Haplotypes and the systematic analysis of genetic variation in genes and genomes. Pharmacogenomics. 2003; 4(5):547-70. DOI: 10.2217/14622416.4.5.547. View

Adzhubei I, Schmidt S, Peshkin L, Ramensky V, Gerasimova A, Bork P . A method and server for predicting damaging missense mutations. Nat Methods. 2010; 7(4):248-9. PMC: 2855889. DOI: 10.1038/nmeth0410-248. View

Kamburov A, Stelzl U, Lehrach H, Herwig R . The ConsensusPathDB interaction database: 2013 update. Nucleic Acids Res. 2012; 41(Database issue):D793-800. PMC: 3531102. DOI: 10.1093/nar/gks1055. View

10.

Duitama J, McEwen G, Huebsch T, Palczewski S, Schulz S, Verstrepen K . Fosmid-based whole genome haplotyping of a HapMap trio child: evaluation of Single Individual Haplotyping techniques. Nucleic Acids Res. 2011; 40(5):2041-53. PMC: 3299995. DOI: 10.1093/nar/gkr1042. View

11.

Nag A, Savova V, Fung H, Miron A, Yuan G, Zhang K . Chromatin signature of widespread monoallelic expression. Elife. 2014; 2:e01256. PMC: 3873816. DOI: 10.7554/eLife.01256. View

12.

Burgtorf C, Kepper P, Hoehe M, Schmitt C, Reinhardt R, Lehrach H . Clone-based systematic haplotyping (CSH): a procedure for physical haplotyping of whole genomes. Genome Res. 2003; 13(12):2717-24. PMC: 403814. DOI: 10.1101/gr.1442303. View

13.

Gerstein M, Bruce C, Rozowsky J, Zheng D, Du J, Korbel J . What is a gene, post-ENCODE? History and updated definition. Genome Res. 2007; 17(6):669-81. DOI: 10.1101/gr.6339607. View

14.

Samuelson D, Hesselson S, Aperavich B, Zan Y, Haag J, Trentham-Dietz A . Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk. Proc Natl Acad Sci U S A. 2007; 104(15):6299-304. PMC: 1847458. DOI: 10.1073/pnas.0701687104. View

15.

Abecasis G, Auton A, Brooks L, DePristo M, Durbin R, Handsaker R . An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491(7422):56-65. PMC: 3498066. DOI: 10.1038/nature11632. View

16.

Drysdale C, McGraw D, Stack C, Stephens J, Judson R, Nandabalan K . Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci U S A. 2000; 97(19):10483-8. PMC: 27050. DOI: 10.1073/pnas.97.19.10483. View

17.

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

18.

Peters B, Kermani B, Sparks A, Alferov O, Hong P, Alexeev A . Accurate whole-genome sequencing and haplotyping from 10 to 20 human cells. Nature. 2012; 487(7406):190-5. PMC: 3397394. DOI: 10.1038/nature11236. View

19.

Chess A . Mechanisms and consequences of widespread random monoallelic expression. Nat Rev Genet. 2012; 13(6):421-8. DOI: 10.1038/nrg3239. View

20.

Kaper F, Swamy S, Klotzle B, Munchel S, Cottrell J, Bibikova M . Whole-genome haplotyping by dilution, amplification, and sequencing. Proc Natl Acad Sci U S A. 2013; 110(14):5552-7. PMC: 3619281. DOI: 10.1073/pnas.1218696110. View