Annalise Paaby

Location

I am a postdoc 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
New York, NY 10003

Research

My research goal is to understand how quantitative traits evolve given the complexity of their genetic underpinnings. For example, how do genotype-genotype and genotype-environment interactions mediate the expression of allelic variants? Sequencing technology now provides near-complete resolution at the DNA level, revealing the molecular variants in populations. The major outstanding questions are which genetic variants matter and under what conditions. Answers to these questions define how natural populations respond to selection, and lie at the heart of applied research efforts in quantitative and human genetics. My work combines quantitative and developmental genetic approaches to characterize conditional relationships between genotype and phenotype in order to improve our understanding of complex trait architecture.

newfrontpic4Here different C. elegans wild isolates reveal cryptic variation in their ability to tolerate gene silencing of par-3, a critical component in early embryonic cell division. Following par-3 silencing, some strains exhibit low larval hatching (high lethality), while others show almost complete hatching.

Cryptic genetic variation

In my current research, I use genetic perturbations and high-throughput, high-replication methods to uncover conditional-effect mutations that are otherwise undetectable. I examined embryogenesis in wild C. elegans isolates and discovered a vast reserve of genetic variation that is conditionally functional—normally silent, but visible when specific genes are disrupted.

Normally, wild C. elegans isolates vary little in phenotype, and development proceeds with stereotyped precision. However, strains vary substantially in embryonic lethality after embryonic genes are silenced, providing evidence of pervasive “cryptic genetic variation” (CGV) in embryonic pathways. I observed especially strong evidence of CGV in the pathway that governs polarization of the early embryo.

The genetic architecture of CGV exhibits low pleiotropy, such that cryptic variants appear to reside in peripheral locations in embryonic gene networks. These findings indicate that the generally invariant, canalized process of early development can be destabilized to produce heritable differences in network function, and emphasize the importance of genetic background in characterizing gene function. CGV could be pivotal in the evolution of complex traits, and this work provides a model for the expression of conditionally functional effects that may be fundamental in the genetic basis of complex human disease.

This project is in collaboration with the labs of Fabio Piano and Kris Gunsalas at NYU, and was supported by an NIH NRSA fellowship and is now supported by a Revson Foundation fellowship.

Life history evolution

I was a graduate student in Paul Schmidt’s lab at the University of Pennsylvania, where I studied lifespan evolution in Drosophila melanogaster. (Knock yourself out: read my dissertation here.)

Flies that live longer tend to reproduce less and tolerate stress better, and we know that genetics underlie these differences. Others have found aging genes that, when knocked down, result in unusual lifespan extension. Could these genes vary in the wild, and contribute to the observed differences in life history? My work addressed this with two general questions:

1) Do aging genes show patterns of allelic variation across geography? A pattern of nucleotide variation across geography can indicate selection and identify possible functional polymorphisms.

2) Do candidate polymorphisms have functional effects on phenotype? Identifying nucleotide variants that affect phenotype can illuminate the genotype-phenotype relationship and explain which traits are visible to selection.

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

In flies collected along the U.S. east coast, I found evidence of long-term selection at the Insulin-like Receptor, InR, but not at chico, its substrate, even though knock-outs of both genes extend lifespan in the lab. I also found a polymorphism in the first exon of InR whose allele frequencies change with latitude in both North America and Australia, indicating recent selection. Functional tests showed that the high-latitude InR allele is associated with longer lifespan, reduced fecundity, and better tolerance to stress, and mediates these phenotypes via reduced insulin signaling. Work on methuselah, another aging gene, showed that naturally-occurring mth alleles also affect lifespan, fecundity and stress tolerance. Like InR, mth shows clinal variation in a polymorphism, located in its 5′ noncoding region and which appears to affect mth expression levels. These findings provide examples of genetic mechanisms for the evolution of life history tradeoffs in the wild.

Publications

PUBLISHED

White, A.G., B. Lees, H.L. Kao, P.G. Cipriani, E. Munarriz, A.B. Paaby, K. Erickson, S. Guzman, K. Rattanakorn, E. Sontag, D. Geiger, K.C. Gunsalus, F. Piano. 2013. DevStaR: High-throughput quantification of C. elegans developmental stages. IEEE Transactions on Medical Imaging 32(10): 1791-1803. HTML

Paaby, A.B. and M.V. Rockman. 2012. The many faces of pleiotropy. Trends in Genetics 29(2): 66-73. HTML

Zhang, J. and G.P. Wagner. 2013. On the definition and measurement of pleiotropy. Trends in Genetics 29(7): 383-384. HTML

Paaby, A.B. and M.V. Rockman. Pleiotropy: what do you mean? Reply to Zhang and Wagner. 2013. Trends in Genetics 29(7): 384. HTML

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

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 technician, lab of Paul Schmidt, University of Pennsylvania, 2002-2003
Research technician, lab of Steve DiNardo, University of Pennsylvania, 2000-2002

Awards
Senior Fellowship in Biomedical Science, Charles H. Revson Foundation, 2012
DeLill Nasser Professional Development Award, Genetics Society of America, 2012
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, 2005, 2006
Glenn Foundation/AFAR Scholarship, American Federation for Aging Research, 2004

Teaching experience
Guest lecturer, New York University, 2011, 2012
Guest lecturer, University of Pennsylvania, 2007, 2008, 2009
Teaching assistant, University of Pennsylvania, 2003-2008
Tutor for statistics, University of Pennsylvania, 2004-2005
Tutor for biology, Swarthmore College, 1999-2000

Blog

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