Queitsch Lab

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Research Interests

Wild-type phenotypes are remarkably robust to environmental and genetic variation, yet evolutionary novelty continues to arise. What are the molecular underpinnings of phenotypic robustness? How do novel shapes and functions evolve from a robust wild-type phenotype? Natural selection draws upon phenotypic variation among individuals. Although selection can only fix traits with an underlying genetic basis, phenotypic variance results from a complex interplay of genetic, epigenetic, and environmental factors. We seek to identify and understand molecular mechanisms that have the potential to rapidly generate selectable phenotypic variation. Currently, we focus on Hsp90-mediated genetic capacitance and the phenotypic consequences of length variability polymorphisms in conserved Tandem Repeats (TR).

Why Hsp90? The environmentally responsive chaperone Hsp90 assists the maturation of many key regulatory proteins ² and ensures correct protein folding. As an unexpected consequence, genetic variation can accumulate and remain phenotypically silent. Challenging HSP90 function uncovers such cryptic genetic variation and can therefore produce altered phenotypes. Moderate environmental change alone can reveal similar selectable cryptic genetic variants in plants and flies in the laboratory ^3-6. The presence of HSP90-dependent cryptic genetic variation with a plausible natural release mechanism has wide-ranging implications for phenotypic variation and possibly evolutionary change. We have recently shown that HSP90-buffered genetic variants are common in the plant Arabidopsis thaliana ⁷. However, the identity of the underlying Hsp90-sensitive alleles and their signature of selection remain unknown; both are essential to assess the importance of Hsp90 capacitance for evolutionary processes. Therefore, our current efforts center on fine-mapping these loci in several natural A. thaliana populations.

Why Tandem Repeats? Conserved TR can expand and contract through errors in replication and recombination. Such changes in TR length occur with higher frequency than random mutations and can affect phenotype through altered promoter regions or expression of proteins with differing length. Typically, for TR in coding regions changes occur in frame thereby increasing the chance that a functional protein is expressed. Phenotypic consequences for individual variable TRs have been previously reported in yeast, flies, dogs, and humans ^8-11. Together with K. Verstrepen and Matthieu Legendre, we have identified variable repeat-containing genes for Arabidopsis and rice genomes (see Links). We are currently investigating the phenotypic consequences of TR length polymorphisms in coding regions for selected genes.

What else?

The Molecular Bases of Phenotypic Robustness. We define robustness (or developmental stability) as the accuracy with which a given genotype produces consistent trait values for a given phenotype across a population. Using this measure, we recently identified genetic loci that influence trait variance rather than trait mean ¹². This finding lends support to the notion that evolving genetic networks may be stabilized through additional connections over time. We are currently fine-mapping these loci to understand how these alleles may affect developmental stability.

Hsp90 clients in Plants. Only a few Hsp90 substrates (clients) are known in plants. We set out to identify other Hsp90-interacting proteins in A. thaliana to understand the chaperone’s function in plants better and to possibly inform our mapping efforts of Hsp90-dependent polymorphisms. Aided by essential collaborations with several other groups, we are addressing this problem through a combination of genetics, biochemistry and computational biology.

Why work with plants? Although plants suffer from neither schizophrenia nor cancer, they are ideal experimental models to investigate the universally shared interplay between genetic variation and environment. First, due to their sessile life style, plants are more intricately linked to environmental cues than animals. For example, plant morphology and development is shaped through interactions with environmental stimuli such as light and temperature. Second, environmental response traits such as stem elongation or flowering time – which are quantitative, normally distributed traits – are amenable to standard statistical analyses and high-throughput experimental design. Third, A. thaliana normally inbreeds, unlike animal models such as Drosophila and the mouse, such that many genetically different inbred lines can be generated from diverse parents without noticeable inbreeding depression. Fourth, unlike with animal models, large sets of different inbred homozygous lines (recombinant inbred lines, RILs) can be tested under complex natural conditions in the field as well as under controlled laboratory conditions. As RILs are genotyped for polymorphic markers segregating between their parents, the genetic loci that underlie the phenotypic variation across an RIL population can be readily identified by statistically associating RIL genotypes with phenotypes.

References

1. Waddington C.H. Canalization of development and the inheritance of acquired characters. 1942. Nature 154, 563-65 (1942).

2. Young, J.C., Moarefi, I. & Hartl, F.U. Hsp90: a specialized but essential protein-folding tool. J Cell Biol 154, 267-73 (2001).

3. Sangster, T.A., Lindquist, S. & Queitsch, C. Under cover: causes, effects and implications of Hsp90-mediated genetic capacitance. Bioessays 26, 348-62 (2004).

4. Rutherford, S.L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336-42 (1998).

5. Queitsch, C., Sangster, T.A. & Lindquist, S. Hsp90 as a capacitor of phenotypic variation. Nature 417, 618-24 (2002).

6. Sollars, V. et al. Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution. Nat Genet 33, 70-4 (2003).

7. Sangster TA, Salathia N, Lee HN, Watanabe E, Schellenberg K, Morneau K, Wang H, Undurraga S, Queitsch C*, Lindquist S. HSP90-buffered genetic variation is common in Arabidopsis thaliana.Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2969-74. Epub 2008 Feb 19. (*co-corresponding author)

8. Verstrepen, K.J., Jansen, A., Lewitter, F. & Fink, G.R. Intragenic tandem repeats generate functional variability. Nat Genet 37, 986-90 (2005).

9. Warren, S.T. & Nelson, D.L. Trinucleotide repeat expansions in neurological disease. Curr Opin Neurobiol 3, 752-9 (1993).

10. Rosato, E., Peixoto, A.A., Gallippi, A., Kyriacou, C.P. & Costa, R. Mutational mechanisms, phylogeny, and evolution of a repetitive region within a clock gene of Drosophila melanogaster. J Mol Evol 42, 392-408 (1996).

11. Sawyer, L.A. et al. Natural variation in a Drosophila clock gene and temperature compensation. Science 278, 2117-20 (1997).

12. Sangster TA, Salathia N, Undurraga S, Milo R, Schellenberg K, Lindquist S, Queitsch C. HSP90 affects the expression of genetic variation and developmental stability in quantitative traits.Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2963-8. Epub 2008 Feb 19.