Modeling Complex Genetic Interactions in a Simple Eukaryotic Genome: Actin Displays a Rich Spectrum of Complex Haploinsufficiencies

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2006 Dec 15

PMID 17167106

Citations 52

Authors

Brian Haarer

Susan Viggiano

Mathew A Hibbs

Olga G Troyanskaya

David C Amberg

Affiliations

Soon will be listed here.

Abstract

Multigenic influences are major contributors to human genetic disorders. Since humans are highly polymorphic, there are a high number of possible detrimental, multiallelic gene pairs. The actin cytoskeleton of yeast was used to determine the potential for deleterious bigenic interactions; approximately 4800 complex hemizygote strains were constructed between an actin-null allele and the nonessential gene deletion collection. We found 208 genes that have deleterious complex haploinsufficient (CHI) interactions with actin. This set is enriched for genes with gene ontology terms shared with actin, including several actin-binding protein genes, and nearly half of the CHI genes have defects in actin organization when deleted. Interactions were frequently seen with genes for multiple components of a complex or with genes involved in the same function. For example, many of the genes for the large ribosomal subunit (RPLs) were CHI with act1Delta and had actin organization defects when deleted. This was generally true of only one RPL paralog of apparently duplicate genes, suggesting functional specialization between ribosomal genes. In many cases, CHI interactions could be attributed to localized defects on the actin protein. Spatial congruence in these data suggest that the loss of binding to specific actin-binding proteins causes subsets of CHI interactions.

Citing Articles

Ribosomal protein paralogues in ribosome specialization.

Milenkovic I, Novoa E Philos Trans R Soc Lond B Biol Sci. 2025; 380(1921):20230387.

PMID: 40045786 PMC: 11883438. DOI: 10.1098/rstb.2023.0387.

Loss of cytoplasmic actin filaments raises nuclear actin levels to drive INO80C-dependent chromosome fragmentation.

Hurst V, Gerhold C, Tarashev C, Challa K, Seeber A, Yamazaki S Nat Commun. 2024; 15(1):9910.

PMID: 39548059 PMC: 11568269. DOI: 10.1038/s41467-024-54141-0.

Purification of human β- and γ-actin from budding yeast.

Haarer B, Pimm M, De Jong E, Amberg D, Henty-Ridilla J J Cell Sci. 2023; 136(9).

PMID: 37070275 PMC: 10184827. DOI: 10.1242/jcs.260540.

From systems to structure - using genetic data to model protein structures.

Braberg H, Echeverria I, Kaake R, Sali A, Krogan N Nat Rev Genet. 2022; 23(6):342-354.

PMID: 35013567 PMC: 8744059. DOI: 10.1038/s41576-021-00441-w.

Cytoduction and Plasmiduction in Yeast.

Dorweiler J, Manogaran A Bio Protoc. 2021; 11(17):e4146.

PMID: 34604451 PMC: 8443334. DOI: 10.21769/BioProtoc.4146.

References

Ni L, Snyder M . A genomic study of the bipolar bud site selection pattern in Saccharomyces cerevisiae. Mol Biol Cell. 2001; 12(7):2147-70. PMC: 55669. DOI: 10.1091/mbc.12.7.2147. View

Dunn T, Shortle D . Null alleles of SAC7 suppress temperature-sensitive actin mutations in Saccharomyces cerevisiae. Mol Cell Biol. 1990; 10(5):2308-14. PMC: 360578. DOI: 10.1128/mcb.10.5.2308-2314.1990. View

Sanders S, Jennings J, Canutescu A, Link A, Anthony Weil P . Proteomics of the eukaryotic transcription machinery: identification of proteins associated with components of yeast TFIID by multidimensional mass spectrometry. Mol Cell Biol. 2002; 22(13):4723-38. PMC: 133885. DOI: 10.1128/MCB.22.13.4723-4738.2002. View

Boeckers T, Bockmann J, Kreutz M, Gundelfinger E . ProSAP/Shank proteins - a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease. J Neurochem. 2002; 81(5):903-10. DOI: 10.1046/j.1471-4159.2002.00931.x. View

Spring K, Ahangari F, Scott S, Waring P, Purdie D, Chen P . Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nat Genet. 2002; 32(1):185-90. DOI: 10.1038/ng958. View

Goss K, Risinger M, Kordich J, Sanz M, Straughen J, Slovek L . Enhanced tumor formation in mice heterozygous for Blm mutation. Science. 2002; 297(5589):2051-3. DOI: 10.1126/science.1074340. View

Kalinichenko V, Bhattacharyya D, Zhou Y, Gusarova G, Kim W, Shin B . Foxf1 +/- mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury. Hepatology. 2002; 37(1):107-17. DOI: 10.1053/jhep.2003.50005. View

Breitkreutz B, Stark C, Tyers M . Osprey: a network visualization system. Genome Biol. 2003; 4(3):R22. PMC: 153462. DOI: 10.1186/gb-2003-4-3-r22. View

Deutsch S, Rideau A, Bochaton-Piallat M, Merla G, Geinoz A, Gabbiani G . Asp1424Asn MYH9 mutation results in an unstable protein responsible for the phenotypes in May-Hegglin anomaly/Fechtner syndrome. Blood. 2003; 102(2):529-34. DOI: 10.1182/blood-2002-09-2783. View

10.

Kholmanskikh S, Dobrin J, Wynshaw-Boris A, Letourneau P, Ross M . Disregulated RhoGTPases and actin cytoskeleton contribute to the migration defect in Lis1-deficient neurons. J Neurosci. 2003; 23(25):8673-81. PMC: 6740411. View

11.

Huh W, Falvo J, Gerke L, Carroll A, Howson R, Weissman J . Global analysis of protein localization in budding yeast. Nature. 2003; 425(6959):686-91. DOI: 10.1038/nature02026. View

12.

Ghaemmaghami S, Huh W, Bower K, Howson R, Belle A, Dephoure N . Global analysis of protein expression in yeast. Nature. 2003; 425(6959):737-41. DOI: 10.1038/nature02046. View

13.

Szafraniec K, Wloch D, Sliwa P, Borts R, Korona R . Small fitness effects and weak genetic interactions between deleterious mutations in heterozygous loci of the yeast Saccharomyces cerevisiae. Genet Res. 2003; 82(1):19-31. DOI: 10.1017/s001667230300630x. View

14.

Baetz K, Krogan N, Emili A, Greenblatt J, Hieter P . The ctf13-30/CTF13 genomic haploinsufficiency modifier screen identifies the yeast chromatin remodeling complex RSC, which is required for the establishment of sister chromatid cohesion. Mol Cell Biol. 2004; 24(3):1232-44. PMC: 321452. DOI: 10.1128/MCB.24.3.1232-1244.2003. View

15.

Tong A, Lesage G, Bader G, Ding H, Xu H, Xin X . Global mapping of the yeast genetic interaction network. Science. 2004; 303(5659):808-13. DOI: 10.1126/science.1091317. View

16.

Ascough K . Endocytosis: Actin in the driving seat. Curr Biol. 2004; 14(3):R124-6. View

17.

Kellis M, Birren B, Lander E . Proof and evolutionary analysis of ancient genome duplication in the yeast Saccharomyces cerevisiae. Nature. 2004; 428(6983):617-24. DOI: 10.1038/nature02424. View

18.

WERTMAN K, Drubin D, Botstein D . Systematic mutational analysis of the yeast ACT1 gene. Genetics. 1992; 132(2):337-50. PMC: 1205140. DOI: 10.1093/genetics/132.2.337. View

19.

Welch M, Vinh D, Okamura H, Drubin D . Screens for extragenic mutations that fail to complement act1 alleles identify genes that are important for actin function in Saccharomyces cerevisiae. Genetics. 1993; 135(2):265-74. PMC: 1205633. DOI: 10.1093/genetics/135.2.265. View

20.

Vinh D, Welch M, Corsi A, WERTMAN K, Drubin D . Genetic evidence for functional interactions between actin noncomplementing (Anc) gene products and actin cytoskeletal proteins in Saccharomyces cerevisiae. Genetics. 1993; 135(2):275-86. PMC: 1205634. DOI: 10.1093/genetics/135.2.275. View