Location

I am a post-doc in Matt Rockman’s lab at New York University.

E-mail
Annalise Paaby

Lab phone
(212) 992-7541

Mailing address
NYU Biology
Center for Genomics & Systems Biology
12 Waverly Place, 8th Flr (regular mail) or Rm L2-17 (packages)
New York, NY 10003

Current Research

Cryptic genetic variation

Worms and their embryos in liquid culture. Colors not typical.

My current project examines early developmental phenotypes in the nematode Caenorhabditis elegans in order to uncover cryptic genetic variation for embryogenesis.

Cryptic genetic variation is allelic variation that affects phenotype, but only under genetic or environmental perturbation. Perturbations like spontaneous mutations or environmental fluctuations are common in nature, however, and genetics experiments have demonstrated that many gene effects are conditional. Consequently, cryptic genetic variation probably plays an important role in the determination of quantitative traits. Moreover, its existence can explain, at least in part, why quantitative traits are so difficult to study. In humans, for example, the risk of developing a genetic disease is frequently a quantitative trait. Despite much effort, few of the genes that underlie heritable human diseases have been identified—but like many quantitative phenotypes, complex diseases can be influenced by gene-by-gene and gene-by-environment interactions, which makes them identifiable only under certain conditions.

To better understand such complex phenotypes, we need improved methods for identifying the underlying genes, and strategies for understanding how those genes interact. Conventional approaches to discovering causal loci, such as linkage or association mapping, identify those genic elements that have additive effects on phenotype: effects which persist across the genomes of many individuals, for example. These approaches fail to discover genes with conditional effects, which may comprise the majority. Specifically searching for genetic variation that behaves cryptically, however, has the potential to identify these additional genes and characterize interactions among them. My work uses C. elegans embryogenesis as a model to better understand how quantitative traits are determined in general.

Large-scale screens have already identified the genes in the C. elegans genome that affect embryogenesis in a single genetic background. My work utilizes this knowledge, and a high-thoughput phenotyping platform developed by the Piano lab, to identify genes that affect embryogenesis in a cryptic manner. The genetic variation I am surveying for cryptic effects is derived from wild isolates, in the form of a panel of recombinant inbred lines (RILs). To induce perturbations and reveal cryptic genetic variation across the RILs, the genes already shown to be required for embryogenesis are being knocked down. Then, differences in embryonic phenotype between the RILs are mapped to the causal, “cryptic” loci. Eventually, I aim to characterize the architecture of cryptic genetic variation in C. elegans early embryogenesis, and identify novel genetic determinants in this developmental process.

This work is in collaboration with the labs of Fabio Piano and Kris Gunsalas at NYU, and is supported by an NIH NRSA fellowship.

Graduate Research

Life history evolution

I was a graduate student in Paul Schmidt’s lab at the University of Pennsylvania. My dissertation work examined microevolutionary forces in natural populations of the fruit fly Drosophila melanogaster. (If you like, you can read my dissertation here.)

In particular, I studied the evolution of lifespan. Flies from high latitude populations live longer than flies from low latitute populations; high latitude flies also show lower fecundity, higher stress tolerance, and a suite of other correlated life history traits. The Schmidt lab and others have shown that genetics underlie these variations in phenotype. My work took a gene-targeted approach to investigate how environmental variation imposes differential selection pressure on these life history traits to drive lifespan evolution.

Aging genes

Multiple candidate genes for aging have been identified in D. melanogaster, typically by extended longevity mutant phenotypes. Despite their long lifespan, aging gene mutants are not especially fit: most have compromised reproductive success, which explains why functional alleles that promote aging persist in the wild. Because genes that regulate lifespan are pleiotropic and because different environments may favor different life history strategies, genetic variation at some aging loci may be maintained by selection. My work characterized naturally-occurring allelic variation at several aging loci, by addressing two general questions:

1) Do aging genes show patterns of allelic variation across geography? Different environments exert different selection pressures, and a pattern of nucleotide variation across geography can indicate selection and identify possible functional polymorphisms.

2) Do candidate functional polymorphisms within aging loci demonstrate differences in phenotype? Identifying a specific nucleotide variant that affects phenotype can shed light on how genotypes are translated into phenotypes, and testing for effects on multiple traits can explain which traits are visible to selection.

InR and chico

A popular fruit fly habitat: the compost heap at Terhune Orchards in Princeton, NJ.

Reduction of insulin signaling promotes lifespan in flies, worms and mice, and the pathway can be disrupted at multiple independent points to achieve lifespan extension. However, members of the pathway may not be equally responsive to selection. We performed a survey for allelic variation at two insulin signaling genes and found significant patterns of polymorphism and divergence at the insulin receptor, InR, but not at the receptor substrate, chico. Moreover, a candidate functional polymorphism was identified at InR by its nonrandom distribution across geography. On both the North American and Australian continents, we and our collaborators found that the most common haplotype of an InR amino acid indel polymorphism increased with latitude while the second most common haplotype decreased with latitude. This pattern suggests that alternate alleles are being maintained by alternate life history regimes across a heterogeneous environment. Functional tests showed that the alleles are associated with predictable variations in phenotype and levels of insulin signaling, indicating that this polymorphism likely contributes to the evolution of life history in wild populations of D. melanogaster.

methuselah

The gene methuselah (mth) was the first aging gene identified in D. melanogaster. Later work showed that a haplotype, comprised of five SNPs and maintained by linkage disequilbrium within the mth coding region, exhibits a cline in frequency across the latitudinal gradient of the U.S. east coast that is suggestive of selection. Using a quantitative complementation test, I tested the functional significance of eight wild-derived mth alleles and found differences in lifespan, fecundity and tolerance to oxidative stress. We hypothesize that an unknown polymorphism at mth is contributing to differences in life history and is being maintained by alternate selection regimes across the latitudinal gradient. Evaluation of allelic variation in the mth 5′ noncoding region has identified a clinal indel polymorphism in linkage disequilibrium with the clinal haplotype in the coding region and which affects levels of mth expression. Future work may test whether this polymorphism affects the expression of life history traits that are targeted by selection in the natural environment.

Publications

In Preparation / In Review

Paaby, A.B. and P.S. Schmidt. In Preparation. Characterization of an adaptive polymorphism in the Drosophila insulin receptor.

Published / In Press

Paaby, A.B., M.J. Blacket, A.A. Hoffmann and P.S. Schmidt. 2010. Identification of a candidate adaptive polymorphism for Drosophila life history by parallel independent clines on two continents. Molecular Ecology 19(4): 760-774. HTML

Paaby, A.B. and P.S. Schmidt. 2009. Dissecting the genetics of longevity in Drosophila melanogaster. Fly 3(1): 29-38. HTML PDF (Invited Review)

Schmidt, P.S. and A.B. Paaby. 2008. Reproductive diapause and life history clines in North American populations of Drosophila melanogaster. Evolution 62(5): 1204-1215. HTML PDF

Paaby, A.B. and P.S. Schmidt. 2008. Functional significance of allelic variation at methuselah, an aging gene in Drosophila. PLoS ONE 3(4): e1987. HTML PDF (Cited as a F1000 “Must Read”)

Schmidt, P.S., A.B. Paaby and M.S. Heschel. 2005. Genetic variance for diapause expression and associated life histories in Drosophila melanogaster. Evolution 59(12): 2616-2625. HTML PDF

Walters, J.P., C.X. Muñoz, A.B. Paaby and S. DiNardo. 2005. Serrate-Notch signaling defines the scope of the initial denticle field by modulating EGFR activation. Developmental Biology 286: 415-426. HTML PDF

Articles reporting on this work

Blackman, B.K. 2010. Connecting genetic variation to phenotypic clines. Molecular Ecology 19(4): 621-623. HTML

Ratneshwar, P. The Evolution of Aging. SAS Frontiers May 2009. HTML

Evolution of Aging. Penn Arts & Sciences Magazine Spring/Summer 2009, p 9. PDF

CV in brief

Education
University of Pennsylvania, Ph.D. in Biology, 2009
Swarthmore College, B.A. in Biology, 2000

Research positions
Postdoctoral researcher, lab of Matt Rockman, New York University, 2009-
Research assistant, lab of Paul Schmidt, University of Pennsylvania, 2006-2007
Research technician, lab of Paul Schmidt, University of Pennsylvania, 2002-2003
Research technician, lab of Steve DiNardo, University of Pennsylvania, 2000-2002

Teaching experience
Guest lecturer, University of Pennsylvania, 2007-2009
Teaching assistant, University of Pennsylvania, 2003-2008
Tutor for statistics, University of Pennsylvania, 2004-2005
Tutor for biology, Swarthmore College, 1999-2000

Awards
Ruth L. Kirschstein National Research Service Award Post­doctoral Fellowship, NIH, 2009
University of Pennsylvania SAS Dissertation Completion Fellowship, 2008
Binns-Williams Scholarship, University of Pennsylvania, 2006 & 2005
Glenn Foundation/AFAR Scholarship, 2004
Miles White Memorial Scholarship, 1996
Jonathan K. Taylor Scholarship to Swarthmore College, 1996

Blog

I write once upon a time wrote the blog thinkevolution.net/blog, which explores scientific and popular issues in evolutionary biology.