Skip to main content
Genetics logoLink to Genetics
. 1999 Jul;152(3):921–932. doi: 10.1093/genetics/152.3.921

A general requirement for the Sin3-Rpd3 histone deacetylase complex in regulating silencing in Saccharomyces cerevisiae.

Z W Sun 1, M Hampsey 1
PMCID: PMC1460667  PMID: 10388812

Abstract

The Sin3-Rpd3 histone deacetylase complex, conserved between human and yeast, represses transcription when targeted by promoter-specific transcription factors. SIN3 and RPD3 also affect transcriptional silencing at the HM mating loci and at telomeres in yeast. Interestingly, however, deletion of the SIN3 and RPD3 genes enhances silencing, implying that the Sin3-Rpd3 complex functions to counteract, rather than to establish or maintain, silencing. Here we demonstrate that Sin3, Rpd3, and Sap30, a novel component of the Sin3-Rpd3 complex, affect silencing not only at the HMR and telomeric loci, but also at the rDNA locus. The effects on silencing at all three loci are dependent upon the histone deacetylase activity of Rpd3. Enhanced silencing associated with sin3Delta, rpd3Delta, and sap30Delta is differentially dependent upon Sir2 and Sir4 at the telomeric and rDNA loci and is also dependent upon the ubiquitin-conjugating enzyme Rad6 (Ubc2). We also show that the Cac3 subunit of the CAF-I chromatin assembly factor and Sin3-Rpd3 exert antagonistic effects on silencing. Strikingly, deletion of GCN5, which encodes a histone acetyltransferase, enhances silencing in a manner similar to deletion of RPD3. A model that integrates the effects of rpd3Delta, gcn5Delta, and cac3Delta on silencing is proposed.

Full Text

The Full Text of this article is available as a PDF (332.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allis C. D., Chicoine L. G., Richman R., Schulman I. G. Deposition-related histone acetylation in micronuclei of conjugating Tetrahymena. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8048–8052. doi: 10.1073/pnas.82.23.8048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aparicio O. M., Billington B. L., Gottschling D. E. Modifiers of position effect are shared between telomeric and silent mating-type loci in S. cerevisiae. Cell. 1991 Sep 20;66(6):1279–1287. doi: 10.1016/0092-8674(91)90049-5. [DOI] [PubMed] [Google Scholar]
  3. Aparicio O. M., Gottschling D. E. Overcoming telomeric silencing: a trans-activator competes to establish gene expression in a cell cycle-dependent way. Genes Dev. 1994 May 15;8(10):1133–1146. doi: 10.1101/gad.8.10.1133. [DOI] [PubMed] [Google Scholar]
  4. Boeke J. D., LaCroute F., Fink G. R. A positive selection for mutants lacking orotidine-5'-phosphate decarboxylase activity in yeast: 5-fluoro-orotic acid resistance. Mol Gen Genet. 1984;197(2):345–346. doi: 10.1007/BF00330984. [DOI] [PubMed] [Google Scholar]
  5. Braunstein M., Rose A. B., Holmes S. G., Allis C. D., Broach J. R. Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev. 1993 Apr;7(4):592–604. doi: 10.1101/gad.7.4.592. [DOI] [PubMed] [Google Scholar]
  6. Braunstein M., Sobel R. E., Allis C. D., Turner B. M., Broach J. R. Efficient transcriptional silencing in Saccharomyces cerevisiae requires a heterochromatin histone acetylation pattern. Mol Cell Biol. 1996 Aug;16(8):4349–4356. doi: 10.1128/mcb.16.8.4349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chen-Cleland T. A., Smith M. M., Le S., Sternglanz R., Allfrey V. G. Nucleosome structural changes during derepression of silent mating-type loci in yeast. J Biol Chem. 1993 Jan 15;268(2):1118–1124. [PubMed] [Google Scholar]
  8. De Rubertis F., Kadosh D., Henchoz S., Pauli D., Reuter G., Struhl K., Spierer P. The histone deacetylase RPD3 counteracts genomic silencing in Drosophila and yeast. Nature. 1996 Dec 12;384(6609):589–591. doi: 10.1038/384589a0. [DOI] [PubMed] [Google Scholar]
  9. Enomoto S., Berman J. Chromatin assembly factor I contributes to the maintenance, but not the re-establishment, of silencing at the yeast silent mating loci. Genes Dev. 1998 Jan 15;12(2):219–232. doi: 10.1101/gad.12.2.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fritze C. E., Verschueren K., Strich R., Easton Esposito R. Direct evidence for SIR2 modulation of chromatin structure in yeast rDNA. EMBO J. 1997 Nov 3;16(21):6495–6509. doi: 10.1093/emboj/16.21.6495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gietz R. D., Sugino A. New yeast-Escherichia coli shuttle vectors constructed with in vitro mutagenized yeast genes lacking six-base pair restriction sites. Gene. 1988 Dec 30;74(2):527–534. doi: 10.1016/0378-1119(88)90185-0. [DOI] [PubMed] [Google Scholar]
  12. Gottschling D. E., Aparicio O. M., Billington B. L., Zakian V. A. Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell. 1990 Nov 16;63(4):751–762. doi: 10.1016/0092-8674(90)90141-z. [DOI] [PubMed] [Google Scholar]
  13. Gottschling D. E. Telomere-proximal DNA in Saccharomyces cerevisiae is refractory to methyltransferase activity in vivo. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4062–4065. doi: 10.1073/pnas.89.9.4062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Grunstein M. Yeast heterochromatin: regulation of its assembly and inheritance by histones. Cell. 1998 May 1;93(3):325–328. doi: 10.1016/s0092-8674(00)81160-5. [DOI] [PubMed] [Google Scholar]
  15. Haas A., Reback P. M., Pratt G., Rechsteiner M. Ubiquitin-mediated degradation of histone H3 does not require the substrate-binding ubiquitin protein ligase, E3, or attachment of polyubiquitin chains. J Biol Chem. 1990 Dec 15;265(35):21664–21669. [PubMed] [Google Scholar]
  16. Hecht A., Laroche T., Strahl-Bolsinger S., Gasser S. M., Grunstein M. Histone H3 and H4 N-termini interact with SIR3 and SIR4 proteins: a molecular model for the formation of heterochromatin in yeast. Cell. 1995 Feb 24;80(4):583–592. doi: 10.1016/0092-8674(95)90512-x. [DOI] [PubMed] [Google Scholar]
  17. Henchoz S., De Rubertis F., Pauli D., Spierer P. The dose of a putative ubiquitin-specific protease affects position-effect variegation in Drosophila melanogaster. Mol Cell Biol. 1996 Oct;16(10):5717–5725. doi: 10.1128/mcb.16.10.5717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Henikoff S., Matzke M. A. Exploring and explaining epigenetic effects. Trends Genet. 1997 Aug;13(8):293–295. doi: 10.1016/s0168-9525(97)01219-5. [DOI] [PubMed] [Google Scholar]
  19. Huang H., Kahana A., Gottschling D. E., Prakash L., Liebman S. W. The ubiquitin-conjugating enzyme Rad6 (Ubc2) is required for silencing in Saccharomyces cerevisiae. Mol Cell Biol. 1997 Nov;17(11):6693–6699. doi: 10.1128/mcb.17.11.6693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ivy J. M., Klar A. J., Hicks J. B. Cloning and characterization of four SIR genes of Saccharomyces cerevisiae. Mol Cell Biol. 1986 Feb;6(2):688–702. doi: 10.1128/mcb.6.2.688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jaenisch R. DNA methylation and imprinting: why bother? Trends Genet. 1997 Aug;13(8):323–329. doi: 10.1016/s0168-9525(97)01180-3. [DOI] [PubMed] [Google Scholar]
  22. Kadosh D., Struhl K. Histone deacetylase activity of Rpd3 is important for transcriptional repression in vivo. Genes Dev. 1998 Mar 15;12(6):797–805. doi: 10.1101/gad.12.6.797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kadosh D., Struhl K. Repression by Ume6 involves recruitment of a complex containing Sin3 corepressor and Rpd3 histone deacetylase to target promoters. Cell. 1997 May 2;89(3):365–371. doi: 10.1016/s0092-8674(00)80217-2. [DOI] [PubMed] [Google Scholar]
  24. Kang X. L., Yadao F., Gietz R. D., Kunz B. A. Elimination of the yeast RAD6 ubiquitin conjugase enhances base-pair transitions and G.C----T.A transversions as well as transposition of the Ty element: implications for the control of spontaneous mutation. Genetics. 1992 Feb;130(2):285–294. doi: 10.1093/genetics/130.2.285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kaufman P. D., Kobayashi R., Stillman B. Ultraviolet radiation sensitivity and reduction of telomeric silencing in Saccharomyces cerevisiae cells lacking chromatin assembly factor-I. Genes Dev. 1997 Feb 1;11(3):345–357. doi: 10.1101/gad.11.3.345. [DOI] [PubMed] [Google Scholar]
  26. Kayne P. S., Kim U. J., Han M., Mullen J. R., Yoshizaki F., Grunstein M. Extremely conserved histone H4 N terminus is dispensable for growth but essential for repressing the silent mating loci in yeast. Cell. 1988 Oct 7;55(1):27–39. doi: 10.1016/0092-8674(88)90006-2. [DOI] [PubMed] [Google Scholar]
  27. Kuo M. H., Brownell J. E., Sobel R. E., Ranalli T. A., Cook R. G., Edmondson D. G., Roth S. Y., Allis C. D. Transcription-linked acetylation by Gcn5p of histones H3 and H4 at specific lysines. Nature. 1996 Sep 19;383(6597):269–272. doi: 10.1038/383269a0. [DOI] [PubMed] [Google Scholar]
  28. Kyrion G., Liu K., Liu C., Lustig A. J. RAP1 and telomere structure regulate telomere position effects in Saccharomyces cerevisiae. Genes Dev. 1993 Jul;7(7A):1146–1159. doi: 10.1101/gad.7.7a.1146. [DOI] [PubMed] [Google Scholar]
  29. Liebman S. W., Newnam G. A ubiquitin-conjugating enzyme, RAD6, affects the distribution of Ty1 retrotransposon integration positions. Genetics. 1993 Mar;133(3):499–508. doi: 10.1093/genetics/133.3.499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ma X. J., Wu J., Altheim B. A., Schultz M. C., Grunstein M. Deposition-related sites K5/K12 in histone H4 are not required for nucleosome deposition in yeast. Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6693–6698. doi: 10.1073/pnas.95.12.6693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Marshall M., Mahoney D., Rose A., Hicks J. B., Broach J. R. Functional domains of SIR4, a gene required for position effect regulation in Saccharomyces cerevisiae. Mol Cell Biol. 1987 Dec;7(12):4441–4452. doi: 10.1128/mcb.7.12.4441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Martínez-Balbás M. A., Tsukiyama T., Gdula D., Wu C. Drosophila NURF-55, a WD repeat protein involved in histone metabolism. Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):132–137. doi: 10.1073/pnas.95.1.132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Megee P. C., Morgan B. A., Mittman B. A., Smith M. M. Genetic analysis of histone H4: essential role of lysines subject to reversible acetylation. Science. 1990 Feb 16;247(4944):841–845. doi: 10.1126/science.2106160. [DOI] [PubMed] [Google Scholar]
  34. Moazed D., Johnson D. A deubiquitinating enzyme interacts with SIR4 and regulates silencing in S. cerevisiae. Cell. 1996 Aug 23;86(4):667–677. doi: 10.1016/s0092-8674(00)80139-7. [DOI] [PubMed] [Google Scholar]
  35. Monson E. K., de Bruin D., Zakian V. A. The yeast Cac1 protein is required for the stable inheritance of transcriptionally repressed chromatin at telomeres. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13081–13086. doi: 10.1073/pnas.94.24.13081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Panning B., Jaenisch R. RNA and the epigenetic regulation of X chromosome inactivation. Cell. 1998 May 1;93(3):305–308. doi: 10.1016/s0092-8674(00)81155-1. [DOI] [PubMed] [Google Scholar]
  37. Park E. C., Szostak J. W. Point mutations in the yeast histone H4 gene prevent silencing of the silent mating type locus HML. Mol Cell Biol. 1990 Sep;10(9):4932–4934. doi: 10.1128/mcb.10.9.4932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Parthun M. R., Widom J., Gottschling D. E. The major cytoplasmic histone acetyltransferase in yeast: links to chromatin replication and histone metabolism. Cell. 1996 Oct 4;87(1):85–94. doi: 10.1016/s0092-8674(00)81325-2. [DOI] [PubMed] [Google Scholar]
  39. Picologlou S., Brown N., Liebman S. W. Mutations in RAD6, a yeast gene encoding a ubiquitin-conjugating enzyme, stimulate retrotransposition. Mol Cell Biol. 1990 Mar;10(3):1017–1022. doi: 10.1128/mcb.10.3.1017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Prakash S., Sung P., Prakash L. DNA repair genes and proteins of Saccharomyces cerevisiae. Annu Rev Genet. 1993;27:33–70. doi: 10.1146/annurev.ge.27.120193.000341. [DOI] [PubMed] [Google Scholar]
  41. Pérez-Martín J., Johnson A. D. Mutations in chromatin components suppress a defect of Gcn5 protein in Saccharomyces cerevisiae. Mol Cell Biol. 1998 Feb;18(2):1049–1054. doi: 10.1128/mcb.18.2.1049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Qian Z., Huang H., Hong J. Y., Burck C. L., Johnston S. D., Berman J., Carol A., Liebman S. W. Yeast Ty1 retrotransposition is stimulated by a synergistic interaction between mutations in chromatin assembly factor I and histone regulatory proteins. Mol Cell Biol. 1998 Aug;18(8):4783–4792. doi: 10.1128/mcb.18.8.4783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Renauld H., Aparicio O. M., Zierath P. D., Billington B. L., Chhablani S. K., Gottschling D. E. Silent domains are assembled continuously from the telomere and are defined by promoter distance and strength, and by SIR3 dosage. Genes Dev. 1993 Jul;7(7A):1133–1145. doi: 10.1101/gad.7.7a.1133. [DOI] [PubMed] [Google Scholar]
  44. Rine J., Herskowitz I. Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae. Genetics. 1987 May;116(1):9–22. doi: 10.1093/genetics/116.1.9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Roest H. P., van Klaveren J., de Wit J., van Gurp C. G., Koken M. H., Vermey M., van Roijen J. H., Hoogerbrugge J. W., Vreeburg J. T., Baarends W. M. Inactivation of the HR6B ubiquitin-conjugating DNA repair enzyme in mice causes male sterility associated with chromatin modification. Cell. 1996 Sep 6;86(5):799–810. doi: 10.1016/s0092-8674(00)80154-3. [DOI] [PubMed] [Google Scholar]
  46. Rothstein R. Targeting, disruption, replacement, and allele rescue: integrative DNA transformation in yeast. Methods Enzymol. 1991;194:281–301. doi: 10.1016/0076-6879(91)94022-5. [DOI] [PubMed] [Google Scholar]
  47. Rundlett S. E., Carmen A. A., Kobayashi R., Bavykin S., Turner B. M., Grunstein M. HDA1 and RPD3 are members of distinct yeast histone deacetylase complexes that regulate silencing and transcription. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14503–14508. doi: 10.1073/pnas.93.25.14503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Rundlett S. E., Carmen A. A., Suka N., Turner B. M., Grunstein M. Transcriptional repression by UME6 involves deacetylation of lysine 5 of histone H4 by RPD3. Nature. 1998 Apr 23;392(6678):831–835. doi: 10.1038/33952. [DOI] [PubMed] [Google Scholar]
  49. Sherman F. Getting started with yeast. Methods Enzymol. 1991;194:3–21. doi: 10.1016/0076-6879(91)94004-v. [DOI] [PubMed] [Google Scholar]
  50. Sikorski R. S., Hieter P. A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae. Genetics. 1989 May;122(1):19–27. doi: 10.1093/genetics/122.1.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Singer M. S., Kahana A., Wolf A. J., Meisinger L. L., Peterson S. E., Goggin C., Mahowald M., Gottschling D. E. Identification of high-copy disruptors of telomeric silencing in Saccharomyces cerevisiae. Genetics. 1998 Oct;150(2):613–632. doi: 10.1093/genetics/150.2.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Singh J., Goel V., Klar A. J. A novel function of the DNA repair gene rhp6 in mating-type silencing by chromatin remodeling in fission yeast. Mol Cell Biol. 1998 Sep;18(9):5511–5522. doi: 10.1128/mcb.18.9.5511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Singh J., Klar A. J. Active genes in budding yeast display enhanced in vivo accessibility to foreign DNA methylases: a novel in vivo probe for chromatin structure of yeast. Genes Dev. 1992 Feb;6(2):186–196. doi: 10.1101/gad.6.2.186. [DOI] [PubMed] [Google Scholar]
  54. Smith J. S., Brachmann C. B., Pillus L., Boeke J. D. Distribution of a limited Sir2 protein pool regulates the strength of yeast rDNA silencing and is modulated by Sir4p. Genetics. 1998 Jul;149(3):1205–1219. doi: 10.1093/genetics/149.3.1205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Smith J. S., Caputo E., Boeke J. D. A genetic screen for ribosomal DNA silencing defects identifies multiple DNA replication and chromatin-modulating factors. Mol Cell Biol. 1999 Apr;19(4):3184–3197. doi: 10.1128/mcb.19.4.3184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Smith S., Stillman B. Stepwise assembly of chromatin during DNA replication in vitro. EMBO J. 1991 Apr;10(4):971–980. doi: 10.1002/j.1460-2075.1991.tb08031.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Sobel R. E., Cook R. G., Allis C. D. Non-random acetylation of histone H4 by a cytoplasmic histone acetyltransferase as determined by novel methodology. J Biol Chem. 1994 Jul 15;269(28):18576–18582. [PubMed] [Google Scholar]
  58. Sobel R. E., Cook R. G., Perry C. A., Annunziato A. T., Allis C. D. Conservation of deposition-related acetylation sites in newly synthesized histones H3 and H4. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):1237–1241. doi: 10.1073/pnas.92.4.1237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Sung P., Prakash S., Prakash L. The RAD6 protein of Saccharomyces cerevisiae polyubiquitinates histones, and its acidic domain mediates this activity. Genes Dev. 1988 Nov;2(11):1476–1485. doi: 10.1101/gad.2.11.1476. [DOI] [PubMed] [Google Scholar]
  60. Sussel L., Shore D. Separation of transcriptional activation and silencing functions of the RAP1-encoded repressor/activator protein 1: isolation of viable mutants affecting both silencing and telomere length. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7749–7753. doi: 10.1073/pnas.88.17.7749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Taunton J., Hassig C. A., Schreiber S. L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science. 1996 Apr 19;272(5260):408–411. doi: 10.1126/science.272.5260.408. [DOI] [PubMed] [Google Scholar]
  62. Thompson J. S., Ling X., Grunstein M. Histone H3 amino terminus is required for telomeric and silent mating locus repression in yeast. Nature. 1994 May 19;369(6477):245–247. doi: 10.1038/369245a0. [DOI] [PubMed] [Google Scholar]
  63. Turner B. M., Birley A. J., Lavender J. Histone H4 isoforms acetylated at specific lysine residues define individual chromosomes and chromatin domains in Drosophila polytene nuclei. Cell. 1992 Apr 17;69(2):375–384. doi: 10.1016/0092-8674(92)90417-b. [DOI] [PubMed] [Google Scholar]
  64. Vannier D., Balderes D., Shore D. Evidence that the transcriptional regulators SIN3 and RPD3, and a novel gene (SDS3) with similar functions, are involved in transcriptional silencing in S. cerevisiae. Genetics. 1996 Dec;144(4):1343–1353. doi: 10.1093/genetics/144.4.1343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Verreault A., Kaufman P. D., Kobayashi R., Stillman B. Nucleosome assembly by a complex of CAF-1 and acetylated histones H3/H4. Cell. 1996 Oct 4;87(1):95–104. doi: 10.1016/s0092-8674(00)81326-4. [DOI] [PubMed] [Google Scholar]
  66. Wakimoto B. T. Beyond the nucleosome: epigenetic aspects of position-effect variegation in Drosophila. Cell. 1998 May 1;93(3):321–324. doi: 10.1016/s0092-8674(00)81159-9. [DOI] [PubMed] [Google Scholar]
  67. Wang L., Liu L., Berger S. L. Critical residues for histone acetylation by Gcn5, functioning in Ada and SAGA complexes, are also required for transcriptional function in vivo. Genes Dev. 1998 Mar 1;12(5):640–653. doi: 10.1101/gad.12.5.640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Zhang Y., Iratni R., Erdjument-Bromage H., Tempst P., Reinberg D. Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex. Cell. 1997 May 2;89(3):357–364. doi: 10.1016/s0092-8674(00)80216-0. [DOI] [PubMed] [Google Scholar]
  69. Zhang Y., Sun Z. W., Iratni R., Erdjument-Bromage H., Tempst P., Hampsey M., Reinberg D. SAP30, a novel protein conserved between human and yeast, is a component of a histone deacetylase complex. Mol Cell. 1998 Jun;1(7):1021–1031. doi: 10.1016/s1097-2765(00)80102-1. [DOI] [PubMed] [Google Scholar]
  70. Zhu Y., Peterson C. L., Christman M. F. HPR1 encodes a global positive regulator of transcription in Saccharomyces cerevisiae. Mol Cell Biol. 1995 Mar;15(3):1698–1708. doi: 10.1128/mcb.15.3.1698. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES