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Initial impact of the sequencing of the human genome

Abstract

The sequence of the human genome has dramatically accelerated biomedical research. Here I explore its impact, in the decade since its publication, on our understanding of the biological functions encoded in the genome, on the biological basis of inherited diseases and cancer, and on the evolution and history of the human species. I also discuss the road ahead in fulfilling the promise of genomics for medicine.

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Figure 1: Evolutionary conservation maps.
Figure 2: Chromatin state maps.
Figure 3: Disease association maps.
Figure 4: Cancer genome maps.
Figure 5: Positive selection maps.

References

  1. 1

    International Human Genome Sequencing Consortium . Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001)

    Google Scholar 

  2. 2

    Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001)

    ADS  CAS  Article  Google Scholar 

  3. 3

    International Human Genome Sequencing Consortium Finishing the euchromatic sequence of the human genome. Nature 431, 931–945 (2004)The draft sequences reported in refs 1 and 2 provided the first comprehensive look at 90% of the human genome; the finished sequence in ref. 3 increased the completeness to >99% and the accuracy to >99.999%, providing a solid foundation for biomedicine.

    ADS  Google Scholar 

  4. 4

    Mouse Genome Sequencing Consortium Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002)Comparison with the mouse genome led to the discovery that the vast majority of functional sequence in the human genome does not encode protein.

    Google Scholar 

  5. 5

    Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Rat Genome Sequencing Project Consoritum Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 428, 493–521 (2004)

    Google Scholar 

  7. 7

    Chimpanzee Sequencing and Analysis Consortium . Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69–87 (2005)

    Google Scholar 

  8. 8

    Mikkelsen, T. S. et al. Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences. Nature 447, 167–177 (2007)

    ADS  CAS  PubMed  Google Scholar 

  9. 9

    Green, R. E. et al. A draft sequence of the Neandertal genome. Science 328, 710–722 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Grice, E. A. et al. Topographical and temporal diversity of the human skin microbiome. Science 324, 1190–1192 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Gill, S. R. et al. Metagenomic analysis of the human distal gut microbiome. Science 312, 1355–1359 (2006)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Bentley, D. R. et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53–59 (2008)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Okou, D. T. et al. Microarray-based genomic selection for high-throughput resequencing. Nature Methods 4, 907–909 (2007)

    CAS  PubMed  Google Scholar 

  17. 17

    Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nature Methods 5, 621–628 (2008)

    CAS  PubMed  Google Scholar 

  18. 18

    Guttman, M. et al. Ab initio reconstruction of cell type-specific transcriptomes in mouse reveals the conserved multi-exonic structure of lincRNAs. Nature Biotechnol. 28, 503–510 (2010)

    CAS  Google Scholar 

  19. 19

    Yassour, M. et al. Ab initio construction of a eukaryotic transcriptome by massively parallel mRNA sequencing. Proc. Natl Acad. Sci. USA 106, 3264–3269 (2009)

    ADS  CAS  PubMed  Google Scholar 

  20. 20

    Gnerre, S. et al. High-quality draft assemblies of mammalian genomes from massively parallel sequence data. Proc. Natl Acad. Sci. USA 10.1073/pnas.1017351108 (27 December, 2010)

  21. 21

    Clamp, M. et al. Distinguishing protein-coding and noncoding genes in the human genome. Proc. Natl Acad. Sci. USA 104, 19428–19433 (2007)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Bejerano, G. et al. Ultraconserved elements in the human genome. Science 304, 1321–1325 (2004)

    ADS  CAS  PubMed  Google Scholar 

  23. 23

    Siepel, A. et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 15, 1034–1050 (2005)

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Pennacchio, L. A. et al. In vivo enhancer analysis of human conserved non-coding sequences. Nature 444, 499–502 (2006)

    ADS  CAS  PubMed  Google Scholar 

  25. 25

    King, M. C. & Wilson, A. C. Evolution at two levels in humans and chimpanzees. Science 188, 107–116 (1975)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Bejerano, G. et al. A distal enhancer and an ultraconserved exon are derived from a novel retroposon. Nature 441, 87–90 (2006)

    ADS  CAS  PubMed  Google Scholar 

  27. 27

    Pasquinelli, A. E. et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408, 86–89 (2000)

    ADS  CAS  Google Scholar 

  28. 28

    Lewis, B. P., Shih, I. H., Jones-Rhoades, M. W., Bartel, D. P. & Burge, C. B. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003)

    CAS  PubMed  Google Scholar 

  29. 29

    Kapranov, P. et al. Large-scale transcriptional activity in chromosomes 21 and 22. Science 296, 916–919 (2002)

    ADS  CAS  PubMed  Google Scholar 

  30. 30

    Carninci, P. et al. The transcriptional landscape of the mammalian genome. Science 309, 1559–1563 (2005)

    ADS  CAS  PubMed  Google Scholar 

  31. 31

    ENCODE Project Consortium Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799–816 (2007)

    ADS  Google Scholar 

  32. 32

    Guttman, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458, 223–227 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Rinn, J. L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Zappulla, D. C. & Cech, T. R. RNA as a flexible scaffold for proteins: yeast telomerase and beyond. Cold Spring Harb. Symp. Quant. Biol. 71, 217–224 (2006)

    CAS  PubMed  Google Scholar 

  35. 35

    Heintzman, N. D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nature Genet. 39, 311–318 (2007)

    CAS  Google Scholar 

  36. 36

    Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Jones, P. A. & Baylin, S. B. The epigenomics of cancer. Cell 128, 683–692 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Dekker, J., Rippe, K., Dekker, M. & Kleckner, N. Capturing chromosome conformation. Science 295, 1306–1311 (2002)

    ADS  CAS  Google Scholar 

  39. 39

    Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Sachidanandam, R. et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409, 928–933 (2001)

    ADS  CAS  PubMed  Google Scholar 

  41. 41

    Daly, M. J., Rioux, J. D., Schaffner, S. F., Hudson, T. J. & Lander, E. S. High-resolution haplotype structure in the human genome. Nature Genet. 29, 229–232 (2001)

    CAS  PubMed  Google Scholar 

  42. 42

    International HapMap Consortium . A haplotype map of the human genome. Nature 437, 1299–1320 (2005)References 40–42 laid the foundation for genetic studies of common disease, which have so far identified more than 1,100 loci associated with diseases.

    ADS  Google Scholar 

  43. 43

    Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004)

    ADS  CAS  Google Scholar 

  44. 44

    McCarroll, S. A. Copy number variation and human genome maps. Nature Genet. 42, 365–366 (2010)

    CAS  PubMed  Google Scholar 

  45. 45

    International Schizophrenia Consortium . Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008)

    Google Scholar 

  46. 46

    Weiss, L. A. et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008)

    CAS  Google Scholar 

  47. 47

    Walsh, T. et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543 (2008)References 45–47 revealed an important role of rare genetic deletions in psychiatric diseases.

    ADS  CAS  PubMed  Google Scholar 

  48. 48

    Durbin, R. M. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Bilgüvar, K. et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467, 207–210 (2010)

    ADS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Habashi, J. P. et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312, 117–121 (2006)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Lander, E. S. The new genomics: global views of biology. Science 274, 536–539 (1996)

    ADS  CAS  PubMed  Google Scholar 

  52. 52

    Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996)

    ADS  CAS  PubMed  Google Scholar 

  53. 53

    Reich, D. E. & Lander, E. S. On the allelic spectrum of human disease. Trends Genet. 17, 502–510 (2001)

    CAS  Google Scholar 

  54. 54

    Altshuler, D., Daly, M. J. & Lander, E. S. Genetic mapping in human disease. Science 322, 881–888 (2008)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nature Genet. 42, 1118–1125 (2010)

    CAS  PubMed  Google Scholar 

  56. 56

    Uda, M. et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemia. Proc. Natl Acad. Sci. USA 105, 1620–1625 (2008)

    ADS  CAS  PubMed  Google Scholar 

  57. 57

    Voight, B. F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nature Genet. 42, 579–589 (2010)

    CAS  PubMed  Google Scholar 

  58. 58

    Lango Allen, H. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Stefansson, H. et al. Common variants conferring risk of schizophrenia. Nature 460, 744–747 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Purcell, S. M. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009)

    ADS  CAS  Google Scholar 

  61. 61

    Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Sebat, J., Levy, D. L. & McCarthy, S. E. Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet. 25, 528–535 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Cowles, C. R., Hirschhorn, J. N., Altshuler, D. & Lander, E. S. Detection of regulatory variation in mouse genes. Nature Genet. 32, 432–437 (2002)

    CAS  PubMed  Google Scholar 

  65. 65

    Yan, H., Yuan, W., Velculescu, V. E., Vogelstein, B. & Kinzler, K. W. Allelic variation in human gene expression. Science 297, 1143 (2002)

    ADS  CAS  PubMed  Google Scholar 

  66. 66

    Teslovich, T. M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Park, J. H. et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nature Genet. 42, 570–575 (2010)

    CAS  PubMed  Google Scholar 

  68. 68

    Yang, J. et al. Common SNPs explain a large proportion of the heritability for human height. Nature Genet. 42, 565–569 (2010)

    CAS  PubMed  Google Scholar 

  69. 69

    Cohen, J. et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9 . Nature Genet. 37, 161–165 (2005)

    CAS  PubMed  Google Scholar 

  70. 70

    Ji, W. et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nature Genet. 40, 592–599 (2008)

    CAS  PubMed  Google Scholar 

  71. 71

    Galarneau, G. et al. Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nature Genet. 42, 1049–1051 (2010)

    CAS  PubMed  Google Scholar 

  72. 72

    Dulbecco, R. A turning point in cancer research: sequencing the human genome. Science 231, 1055–1056 (1986)

    ADS  CAS  PubMed  Google Scholar 

  73. 73

    Futreal, P. A. et al. A census of human cancer genes. Nature Rev. Cancer 4, 177–183 (2004)

    CAS  Google Scholar 

  74. 74

    Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002)The discovery of BRAF mutations in melanoma has led to new drugs for melanoma with high response rates.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004)

    CAS  PubMed  Google Scholar 

  76. 76

    Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Garraway, L. A. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005)

    ADS  CAS  PubMed  Google Scholar 

  81. 81

    Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Perou, C. M. et al. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc. Natl Acad. Sci. USA 96, 9212–9217 (1999)

    ADS  CAS  PubMed  Google Scholar 

  83. 83

    Golub, T. R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537 (1999)

    CAS  PubMed  Google Scholar 

  84. 84

    van’t Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002)

    Google Scholar 

  85. 85

    Lamb, J. et al. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313, 1929–1935 (2006)

    ADS  CAS  Google Scholar 

  86. 86

    Boehm, J. S. et al. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 129, 1065–1079 (2007)

    CAS  Google Scholar 

  87. 87

    Ley, T. J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Chapman, M. A. et al. Initial genome sequencing and analysis of multiple myeloma. Nature doi:10.1038/nature09837. (in the press)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Cavalli-Sforza, L. L., Menozzi, P. & Piazza, A. The History and geography of Human Genes 518, 541 (Princeton Univ. Press, 1994)

    MATH  Google Scholar 

  91. 91

    Sabeti, P. C. et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832–837 (2002)

    ADS  CAS  PubMed  Google Scholar 

  92. 92

    Grossman, S. R. et al. A composite of multiple signals distinguishes causal variants in regions of positive selection. Science 327, 883–886 (2010)

    ADS  CAS  PubMed  Google Scholar 

  93. 93

    Yi, X. et al. Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329, 75–78 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Pollard, K. S. et al. An RNA gene expressed during cortical development evolved rapidly in humans. Nature 443, 167–172 (2006)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Hartwell, L. H., Hopfield, J. J., Leibler, S. & Murray, A. W. From molecular to modular cell biology. Nature 402, C47–C52 (1999)

    CAS  PubMed  Google Scholar 

  96. 96

    Davidson, E. H. The Regulatory Genome: Gene Regulatory Networks in Development and Evolution (Academic, 2006)

    Google Scholar 

  97. 97

    Clemons, P. A. et al. Small molecules of different synthetic and natural origins have distinct distributions of structural complexity that correlate with protein-binding profiles. Proc. Natl Acad. Sci. USA 107, 18787–18792 (2010)

    ADS  CAS  PubMed  Google Scholar 

  98. 98

    Peck, D. et al. A method for high-throughput gene expression signature analysis. Genome Biol. 7, R61 (2006)

    PubMed  PubMed Central  Google Scholar 

  99. 99

    Yarrow, J. C., Feng, Y., Perlman, Z. E., Kirchhausen, T. & Mitchison, T. J. Phenotypic screening of small molecule libraries by high throughput cell imaging. Comb. Chem. High Throughput Screen. 6, 279–286 (2003)

    CAS  PubMed  Google Scholar 

  100. 100

    Musunuru, K. et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466, 714–719 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This review reflects collective ideas, insightful conversations and contributions shared by many colleagues at the Broad Institute and elsewhere. In particular, I wish to express my gratitude to D. Altshuler, J. Baldwin, B. Bernstein, B. Birren, C. Burge, F. Collins, M. Daly, M. DePristo, E. Eichler, A. Futreal, L. Garraway, T. Golub, E. Green, C. Gunter, M. Guyer, M. Guttman, D. Haussler, E. Hechter, J. Hirschhorn, D. Hung, D. Jaffe, S. Kathiresan, L. Kruglyak, E. Lieberman, R. Lifton, K. Lindblad-Toh, S. McCarroll, A. Meissner, T. Mikkelsen, R. Myers, R. Nicol, C. Nusbaum, L. Pennacchio, R. Plenge, A. Regev, D. Reich, J. Rinn, P. Sabeti, V. Sankaran, S. Schreiber, P. Sklar, M. Stratton, H. Varmus, P. Visscher, A. Wolf and O. Zuk. I also thank B. Wong and L. Gaffney for assistance with figures.

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Correspondence to Eric S. Lander.

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Lander, E. Initial impact of the sequencing of the human genome. Nature 470, 187–197 (2011). https://doi.org/10.1038/nature09792

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