Role of Duplicate Genes in Robustness against Deleterious Human Mutations


It is now widely recognized that robustness is an inherent property of biological systems [1],[2],[3]. The contribution of close sequence homologs to genetic robustness against null mutations has been previously demonstrated in simple organisms [4],[5]. In this paper we investigate in detail the contribution of gene duplicates to back-up against deleterious human mutations. Our analysis demonstrates that the functional compensation by close homologs may play an important role in human genetic disease. Genes with a 90% sequence identity homolog are about 3 times less likely to harbor known disease mutations compared to genes with remote homologs. Moreover, close duplicates affect the phenotypic consequences of deleterious mutations by making a decrease in life expectancy significantly less likely. We also demonstrate that similarity of expression profiles across tissues significantly increases the likelihood of functional compensation by homologs.


Vyšlo v časopise: Role of Duplicate Genes in Robustness against Deleterious Human Mutations. PLoS Genet 4(3): e32767. doi:10.1371/journal.pgen.1000014
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000014

Souhrn

It is now widely recognized that robustness is an inherent property of biological systems [1],[2],[3]. The contribution of close sequence homologs to genetic robustness against null mutations has been previously demonstrated in simple organisms [4],[5]. In this paper we investigate in detail the contribution of gene duplicates to back-up against deleterious human mutations. Our analysis demonstrates that the functional compensation by close homologs may play an important role in human genetic disease. Genes with a 90% sequence identity homolog are about 3 times less likely to harbor known disease mutations compared to genes with remote homologs. Moreover, close duplicates affect the phenotypic consequences of deleterious mutations by making a decrease in life expectancy significantly less likely. We also demonstrate that similarity of expression profiles across tissues significantly increases the likelihood of functional compensation by homologs.


Zdroje

1. HartwellLHHopfieldJJLeiblerSMurrayAW 1999 From molecular to modular cell biology. Nature 402 C47 52

2. StellingJSauerUSzallasiZDoyleFJ3rdDoyleJ 2004 Robustness of cellular functions. Cell 118 675 685

3. WagnerA 2005 SH. LSS Robustness and Evolvability in Living Systems Princeton University Press

4. GuZSteinmetzLMGuXScharfeCDavisRW 2003 Role of duplicate genes in genetic robustness against null mutations. Nature 421 63 66

5. ConantGCWagnerA 2004 Duplicate genes and robustness to transient gene knock-downs in Caenorhabditis elegans. Proc Biol Sci 271 89 96

6. SteinmetzLMScharfeCDeutschbauerAMMokranjacDHermanZS 2002 Systematic screen for human disease genes in yeast. Nat Genet 31 400 404

7. PappBPalCHurstLD 2004 Metabolic network analysis of the causes and evolution of enzyme dispensability in yeast. Nature 429 661 664

8. DudleyAMJanseDMTanayAShamirRChurchGM 2005 A global view of pleiotropy and phenotypically derived gene function in yeast. Mol Syst Biol 1 2005 0001

9. WagnerA 2000 Robustness against mutations in genetic networks of yeast. Nat Genet 24 355 361

10. KafriRBar-EvenAPilpelY 2005 Transcription control reprogramming in genetic backup circuits. Nat Genet 37 295 299

11. Lopez-BigasNOuzounisCA 2004 Genome-wide identification of genes likely to be involved in human genetic disease. Nucleic Acids Res 32 3108 3114

12. YuePMoultJ 2006 Identification and analysis of deleterious human SNPs. J Mol Biol 356 1263 1274

13. McKusickV 1998 Mendelian inheritance in man. A catalog of human genes and genetic disorders The Johns Hopkins University Press

14. BairochAApweilerR 1996 The SWISS-PROT protein sequence data bank and its new supplement TREMBL. Nucleic Acids Res 24 21 25

15. Jimenez-SanchezGChildsBValleD 2001 Human disease genes. Nature 409 853 855

16. HubbardTAndrewsDCaccamoMCameronGChenY 2005 Ensembl 2005. Nucleic Acids Res 33 D447 453

17. AltschulSFMaddenTLSchafferAAZhangJZhangZ 1997 Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25 3389 3402

18. HurlesM 2002 Are 100,000 “SNPs” useless? Science 298 1509 author reply 1509

19. NguyenDQWebberCPontingCP 2006 Bias of selection on human copy-number variants. PLoS Genet 2 e20

20. ReichDESchaffnerSFDalyMJMcVeanGMullikinJC 2002 Human genome sequence variation and the influence of gene history, mutation and recombination. Nat Genet 32 135 142

21. SunyaevSKondrashovFABorkPRamenskyV 2003 Impact of selection, mutation rate and genetic drift on human genetic variation. Hum Mol Genet 12 3325 3330

22. LynchMConeryJS 2000 The evolutionary fate and consequences of duplicate genes. Science 290 1151 1155

23. GraurDLiHW 2000 Fundamentals of molecular evolution Sinauer Associates

24. SherrySTWardMHKholodovMBakerJPhanL 2001 dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29 308 311

25. BlankLMKuepferLSauerU 2005 Large-scale 13C-flux analysis reveals mechanistic principles of metabolic network robustness to null mutations in yeast. Genome Biol 6 R49

26. YangZ 1997 PAML: a program package for phylogenetic analysis by maximum likelihood. Comput Appl Biosci 13 555 556

27. HubbardTJAkenBLBealKBallesterBCaccamoM 2007 Ensembl 2007. Nucleic Acids Res 35 D610 617

28. KondrashovFAOgurtsovAYKondrashovAS 2004 Bioinformatical assay of human gene morbidity. Nucleic Acids Res 32 1731 1737

29. SmithNGEyre-WalkerA 2003 Human disease genes: patterns and predictions. Gene 318 169 175

30. HeXZhangJ 2006 Higher duplicability of less important genes in yeast genomes. Mol Biol Evol 23 144 151

31. GuZNicolaeDLuHHLiWH 2002 Rapid divergence in expression between duplicate genes inferred from microarray data. Trends Genet 18 609 613

32. MakovaKDLiWH 2003 Divergence in the spatial pattern of gene expression between human duplicate genes. Genome Res 13 1638 1645

33. SuAIWiltshireTBatalovSLappHChingKA 2004 A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A 101 6062 6067

34. KafriRLevyMPilpelY 2006 The regulatory utilization of genetic redundancy through responsive backup circuits. Proc Natl Acad Sci U S A 103 11653 11658

35. SjoblomTJonesSWoodLDParsonsDWLinJ 2006 The consensus coding sequences of human breast and colorectal cancers. Science 314 268 274

36. GreenmanCStephensPSmithRDalglieshGLHunterC 2007 Patterns of somatic mutation in human cancer genomes. Nature 446 153 158

37. FrazerKABallingerDGCoxDRHindsDAStuveLL 2007 A second generation human haplotype map of over 3.1 million SNPs. Nature 449 851 861

38. LiWHWuCILuoCC 1984 Nonrandomness of point mutation as reflected in nucleotide substitutions in pseudogenes and its evolutionary implications. J Mol Evol 21 58 71

39. MaedaNWuCIBliskaJRenekeJ 1988 Molecular evolution of intergenic DNA in higher primates: pattern of DNA changes, molecular clock, and evolution of repetitive sequences. Mol Biol Evol 5 1 20

40. FayJCWyckoffGJWuCI 2001 Positive and negative selection on the human genome. Genetics 158 1227 1234

41. WyckoffGJWangWWuCI 2000 Rapid evolution of male reproductive genes in the descent of man. Nature 403 304 309

42. CamonEMagraneMBarrellDLeeVDimmerE 2004 The Gene Ontology Annotation (GOA) Database: sharing knowledge in Uniprot with Gene Ontology. Nucleic Acids Res 32 D262 266

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Genetika Reprodukčná medicína
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