Mark Siegal

The aim of our research is to understand phenotypic evolution by studying the processes by which the genetic networks underlying development diverge. A major feature of developmental networks is their robustness (Masel & Siegal 2009). That is, they are tolerant of both environmental and genetic perturbations. Our lab uses both experimental and computational approaches to understand the causes and evolutionary consequences of this robustness.

One major experimental focus in our lab is on the process of sexual differentiation in Drosophila melanogaster and related flies. Sexual differentiation is a powerful model system for studying the evolution of development because many aspects of sexual morphology, physiology and behavior differ between closely related species, thereby enabling high-resolution comparative analysis. Despite this rapid divergence, sexual traits are highly robust within species and indeed are often diagnostic of species. We are using genomic and genetic approaches to identify and characterize regulatory pathways involved in genital development and function in D. melanogaster (e.g., Chatterjee et al. 2011). This will lay the groundwork for determining how these robust pathways diverged between closely related species.

A second major experimental focus is on directly identifying and characterizing genes that contribute to robustness of many traits. We have screened the genome of the laboratory yeast, Saccharomyces cerevisiae, for genes whose deletion increases the variation in the morphologies of individual, genetically identical cells. Yeast is advantageous for this work because of its wealth of genetic and genomic resources, and because it lends itself to high-throughput analyses. Hundreds of yeast genes increase morphological variation when deleted, and these genes tend to be highly connected in cellular networks (Levy & Siegal 2008). We are currently testing whether the same genes also buffer genetic differences between cells, and whether the variation that is revealed by impairment of these genes is potentially beneficial. This work is complemented by theoretical investigations into the evolution of complex gene networks (e.g., Bergman & Siegal 2003; Siegal et al. 2007), as well as bioinformatic analyses of regulatory networks (e.g., Chen et al. 2010), which give us predictions to test experimentally.

• National Institutes of Health Grant 1R01GM086673 "Sources and consequences of phenotypic variation in complex regulatory networks" PI: Mark Siegal
• National Science Foundation CAREER Award IOS-0642999 "Phenotypic robustness and diversity: integrating theory and experiment in genomics research and teaching" PI: Mark Siegal
• United States - Israel Binational Science Foundation Grant 2009270 "The role of spermathecal secretory cells in reproduction" PIs: Mark Siegal & Yael Heifetz (Hebrew University)
• National Institutes of Health Grant 1R01GM097415 "Sequencing yeast lines to measure rates of neutral and deleterious mutations" PIs: Mark Siegal & Dmitri Petrov (Stanford University)

Date of these PubMed search results: March 24 2020
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1. A standardized nomenclature and atlas of the male terminalia of Drosophila melanogaster.
   Fly (Austin) (2019 Mar - Dec) PMC6988887 free full-text archive
   Rice G, David JR, Kamimura Y, Masly JP, Mcgregor AP, Nagy O, Noselli S, Nunes MDS, O'Grady P, Sanchez‑Herrero E, Siegal ML, Toda MJ, Rebeiz M, Courtier‑Orgogozo V, Yassin A
2. Feed-forward regulation adaptively evolves via dynamics rather than topology when there is intrinsic noise.
   Nat Commun (2019 Jun 3) PMC6546794 free full-text archive
   Xiong K, Lancaster AK, Siegal ML, Masel J
3. Author Correction: Testing the key assumption of heritability estimates based on genome-wide genetic relatedness.
   J Hum Genet (2019 Jun) PMID: 30940889
   Conley D, Siegal ML, Domingue BW, Harris KM, McQueen MB, Boardman JD
4. Control of nongenetic heterogeneity in growth rate and stress tolerance of Saccharomyces cerevisiae by cyclic AMP-regulated transcription factors.
   PLoS Genet (2018 Nov) PMC6241136 free full-text archive
   Li S, Giardina DM, Siegal ML
5. Decanalizing thinking on genetic canalization.
   Semin Cell Dev Biol (2019 Apr) PMC6252154 free full-text archive
   Geiler‑Samerotte K, Sartori FMO, Siegal ML
6. Correction: A sibling method for identifying vQTLs.
   PLoS One (2018) PMC5929535 free full-text archive
   Conley D, Johnson R, Domingue B, Dawes C, Boardman J, Siegal ML
7. A sibling method for identifying vQTLs.
   PLoS One (2018) PMC5884517 free full-text archive
   Conley D, Johnson R, Domingue B, Dawes C, Boardman J, Siegal ML
8. Deep sequencing of natural and experimental populations of Drosophila melanogaster reveals biases in the spectrum of new mutations.
   Genome Res (2017 Dec) PMC5741049 free full-text archive
   Assaf ZJ, Tilk S, Park J, Siegal ML, Petrov DA
9. Resolving the Complex Genetic Basis of Phenotypic Variation and Variability of Cellular Growth.
   Genetics (2017 Jul) PMC5500157 free full-text archive
   Ziv N, Shuster BM, Siegal ML, Gresham D
10. Molecular genetics: Chaperone protein gets personal.
    Nature (2017 May 4) PMID: 28424517
    Siegal ML
11. Selection Transforms the Landscape of Genetic Variation Interacting with Hsp90.
    PLoS Biol (2016 Oct) PMC5074785 free full-text archive
    Geiler‑Samerotte KA, Zhu YO, Goulet BE, Hall DW, Siegal ML
12. Sibling genes as environment: Sibling dopamine genotypes and adolescent health support frequency dependent selection.
    Soc Sci Res (2015 Nov) PMID: 26463544
    Rauscher E, Conley D, Siegal ML
13. Engineering and Biology: Counsel for a Continued Relationship.
    Biol Theory (2015 Mar) PMC4465806 free full-text archive
    Calcott B, Levy A, Siegal ML, Soyer OS, Wagner A
14. A Philosophical Perspective on Evolutionary Systems Biology.
    Biol Theory (2015 Mar 1) PMC4465572 free full-text archive
    O'Malley MA, Soyer OS, Siegal ML
15. On the Nature and Evolutionary Impact of Phenotypic Robustness Mechanisms.
    Annu Rev Ecol Evol Syst (2014 Nov 1) PMC4448758 free full-text archive
    Siegal ML, Leu JY
16. Shifting sugars and shifting paradigms.
    PLoS Biol (2015 Feb) PMC4331491 free full-text archive
    Siegal ML
17. Essential gene disruptions reveal complex relationships between phenotypic robustness, pleiotropy, and fitness.
    Mol Syst Biol (2015 Jan 21) PMC4332149 free full-text archive
    Bauer CR, Li S, Siegal ML
18. Reply to Chen and Zhang: On interpreting genome-wide trends from yeast mutation accumulation data.
    Proc Natl Acad Sci U S A (2014 Sep 30) PMC4191808 free full-text archive
    Zhu YO, Siegal ML, Hall DW, Petrov DA
19. The genetics of sex: exploring differences.
    G3 (Bethesda) (2014 Jun 17) PMC4065266 free full-text archive
    Arbeitman MN, Kopp A, Siegal ML, Van Doren M
20. Precise estimates of mutation rate and spectrum in yeast.
    Proc Natl Acad Sci U S A (2014 Jun 3) PMC4050626 free full-text archive
    Zhu YO, Siegal ML, Hall DW, Petrov DA
21. Testing the key assumption of heritability estimates based on genome-wide genetic relatedness.
    J Hum Genet (2014 Jun) PMC4126504 free full-text archive
    Conley D, Siegal ML, Domingue BW, Mullan Harris K, McQueen MB, Boardman JD
22. Histone variant HTZ1 shows extensive epistasis with, but does not increase robustness to, new mutations.
    PLoS Genet (2013) PMC3749942 free full-text archive
    Richardson JB, Uppendahl LD, Traficante MK, Levy SF, Siegal ML
23. Genetic and nongenetic determinants of cell growth variation assessed by high-throughput microscopy.
    Mol Biol Evol (2013 Dec) PMC3840306 free full-text archive
    Ziv N, Siegal ML, Gresham D
24. Heritability and the equal environments assumption: evidence from multiple samples of misclassified twins.
    Behav Genet (2013 Sep) PMID: 23903437
    Conley D, Rauscher E, Dawes C, Magnusson PK, Siegal ML
25. Beyond orchids and dandelions: testing the 5-HTT "risky" allele for evidence of phenotypic capacitance and frequency-dependent selection.
    Biodemography Soc Biol (2013) PMC3690663 free full-text archive
    Conley D, Rauscher E, Siegal ML
26. The details in the distributions: why and how to study phenotypic variability.
    Curr Opin Biotechnol (2013 Aug) PMC3732567 free full-text archive
    Geiler‑Samerotte KA, Bauer CR, Li S, Ziv N, Gresham D, Siegal ML
27. Crouching variation revealed.
    Mol Ecol (2013 Mar) PMID: 23437837
    Siegal ML
28. Oh, the places they'll go: Female sperm storage and sperm precedence in Drosophila melanogaster.
    Spermatogenesis (2012 Jul 1) PMC3469444 free full-text archive
    Schnakenberg SL, Siegal ML, Bloch Qazi MC
29. The robustness continuum.
    Adv Exp Med Biol (2012) PMID: 22821470
    Levy SF, Siegal ML
30. Polygenic cis-regulatory adaptation in the evolution of yeast pathogenicity.
    Genome Res (2012 Oct) PMC3460188 free full-text archive
    Fraser HB, Levy S, Chavan A, Shah HB, Perez JC, Zhou Y, Siegal ML, Sinha H
31. Pausing on the path to robustness.
    Dev Cell (2012 May 15) PMID: 22595664
    Siegal ML, Rushlow C
32. Bet hedging in yeast by heterogeneous, age-correlated expression of a stress protectant.
    PLoS Biol (2012) PMC3348152 free full-text archive
    Levy SF, Ziv N, Siegal ML
33. Hsp90 depletion goes wild.
    BMC Biol (2012 Feb 27) PMC3287126 free full-text archive
    Siegal ML, Masel J
34. Sperm-storage defects and live birth in Drosophila females lacking spermathecal secretory cells.
    PLoS Biol (2011 Nov) PMC3210755 free full-text archive
    Schnakenberg SL, Matias WR, Siegal ML
35. The female-specific doublesex isoform regulates pleiotropic transcription factors to pattern genital development in Drosophila.
    Development (2011 Mar) PMID: 21343364
    Chatterjee SS, Uppendahl LD, Chowdhury MA, Ip PL, Siegal ML
36. Everything you always wanted to know about sex ... in flies.
    Sex Dev (2010) PMC3701886 free full-text archive
    Arbeitman MN, Kopp A, Siegal ML, Van Doren M
37. Correlating gene expression variation with cis-regulatory polymorphism in Saccharomyces cerevisiae.
    Genome Biol Evol (2010) PMC2953268 free full-text archive
    Chen K, van Nimwegen E, Rajewsky N, Siegal ML
38. Robustness: mechanisms and consequences.
    Trends Genet (2009 Sep) PMC2770586 free full-text archive
    Masel J, Siegal ML
39. Reexamining microRNA site accessibility in Drosophila: a population genomics study.
    PLoS One (2009 May 25) PMC2682560 free full-text archive
    Chen K, Maaskola J, Siegal ML, Rajewsky N
40. Network hubs buffer environmental variation in Saccharomyces cerevisiae.
    PLoS Biol (2008 Nov 4) PMC2577700 free full-text archive
    Levy SF, Siegal ML
41. Functional and evolutionary inference in gene networks: does topology matter?
    Genetica (2007 Jan) PMID: 16897451
    Siegal ML, Promislow DE, Bergman A
42. Functional conservation and divergence of intersex, a gene required for female differentiation in Drosophila melanogaster.
    Dev Genes Evol (2005 Jan) PMID: 15645316
    Siegal ML, Baker BS
43. A genomic analysis of Drosophila somatic sexual differentiation and its regulation.
    Development (2004 May) PMID: 15056610
    Arbeitman MN, Fleming AA, Siegal ML, Null BH, Baker BS
44. Evolutionary capacitance as a general feature of complex gene networks.
    Nature (2003 Jul 31) PMID: 12891357
    Bergman A, Siegal ML
45. intersex, a gene required for female sexual development in Drosophila, is expressed in both sexes and functions together with doublesex to regulate terminal differentiation.
    Development (2002 Oct) PMID: 12361959
    Garrett‑Engele CM, Siegal ML, Manoli DS, Williams BC, Li H, Baker BS
46. Waddington's canalization revisited: developmental stability and evolution.
    Proc Natl Acad Sci U S A (2002 Aug 6) PMC124963 free full-text archive
    Siegal ML, Bergman A
47. The evolution of dosage-compensation mechanisms.
    Bioessays (2000 Dec) PMID: 11084626
    Marin I, Siegal ML, Baker BS
48. Application of Cre/loxP in Drosophila. Site-specific recombination and transgene coplacement.
    Methods Mol Biol (2000) PMID: 10840736
    Siegal ML, Hartl DL
49. Oviposition-site preference in Drosophila following interspecific gene transfer of the Alcohol dehydrogenase locus.
    Behav Genet (1999 May) PMID: 10547927
    Siegal ML, Hartl DL
50. An experimental test for lineage-specific position effects on alcohol dehydrogenase (Adh) genes in Drosophila.
    Proc Natl Acad Sci U S A (1998 Dec 22) PMC28074 free full-text archive
    Siegal ML, Hartl DL
51. Triple-ligation strategy with advantages over directional cloning.
    Biotechniques (1996 Oct) PMID: 8891209
    Siegal ML, Petrov DA, De Aguiar D
52. Transgene Coplacement and high efficiency site-specific recombination with the Cre/loxP system in Drosophila.
    Genetics (1996 Oct) PMC1207562 free full-text archive
    Siegal ML, Hartl DL