Mark L. Siegal

Associate Professor of Biology; Director, Undergraduate Studies


Areas of Research/Interest

evolutionary systems biology; robustness and evolution of complex traits


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)


    • PubMed Search Criteria: Siegal ML
    • Search Date: June 11 2017

Resolving the Complex Genetic Basis of Phenotypic Variation and Variability of Cellular Growth.
Genetics (2017 May 11) PMID: 28495957
Ziv N, Shuster BM, Siegal ML, Gresham D

Molecular genetics: Chaperone protein gets personal.
Nature (2017 May 04) PMID: 28424517
Siegal ML

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

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

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

A Philosophical Perspective on Evolutionary Systems Biology.
Biol Theory (2015 Mar 01) PMC4465572 free full-text archive
O'Malley MA, Soyer OS, Siegal ML

On the Nature and Evolutionary Impact of Phenotypic Robustness Mechanisms.
Annu Rev Ecol Evol Syst (2014 Nov 01) PMC4448758 free full-text archive
Siegal ML, Leu JY

Shifting sugars and shifting paradigms.
PLoS Biol (2015 Feb) PMC4331491 free full-text archive
Siegal ML

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

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

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

Precise estimates of mutation rate and spectrum in yeast.
Proc Natl Acad Sci U S A (2014 Jun 03) PMC4050626 free full-text archive
Zhu YO, Siegal ML, Hall DW, Petrov DA

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

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

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

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

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

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

Crouching variation revealed.
Mol Ecol (2013 Mar) PMID: 23437837
Siegal ML

Oh, the places they'll go: Female sperm storage and sperm precedence in Drosophila melanogaster.
Spermatogenesis (2012 Jul 01) PMC3469444 free full-text archive
Schnakenberg SL, Siegal ML, Bloch Qazi MC

The robustness continuum.
Adv Exp Med Biol (2012) PMID: 22821470
Levy SF, Siegal ML

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

Pausing on the path to robustness.
Dev Cell (2012 May 15) PMID: 22595664
Siegal ML, Rushlow C

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

Hsp90 depletion goes wild.
BMC Biol (2012 Feb 27) PMC3287126 free full-text archive
Siegal ML, Masel J

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

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

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

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

Robustness: mechanisms and consequences.
Trends Genet (2009 Sep) PMC2770586 free full-text archive
Masel J, Siegal ML

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

Network hubs buffer environmental variation in Saccharomyces cerevisiae.
PLoS Biol (2008 Nov 04) PMC2577700 free full-text archive
Levy SF, Siegal ML

Functional and evolutionary inference in gene networks: does topology matter?
Genetica (2007 Jan) PMID: 16897451
Siegal ML, Promislow DE, Bergman A

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

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

Evolutionary capacitance as a general feature of complex gene networks.
Nature (2003 Jul 31) PMID: 12891357
Bergman A, Siegal ML

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

Waddington's canalization revisited: developmental stability and evolution.
Proc Natl Acad Sci U S A (2002 Aug 06) PMC124963 free full-text archive
Siegal ML, Bergman A

The evolution of dosage-compensation mechanisms.
Bioessays (2000 Dec) PMID: 11084626
Marin I, Siegal ML, Baker BS

Application of Cre/loxP in Drosophila. Site-specific recombination and transgene coplacement.
Methods Mol Biol (2000) PMID: 10840736
Siegal ML, Hartl DL

Oviposition-site preference in Drosophila following interspecific gene transfer of the Alcohol dehydrogenase locus.
Behav Genet (1999 May) PMID: 10547927
Siegal ML, Hartl DL

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

Triple-ligation strategy with advantages over directional cloning.
Biotechniques (1996 Oct) PMID: 8891209
Siegal ML, Petrov DA, De Aguiar D

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