Trudy F.C. Mackay

William Neal Reynolds Professor of Genetics and Distinguished University Professor

 Ph.D., University of Edinburgh
 Postdoctoral, Dalhousie University

Dr. Mackay is one of the world's leading authorities in quantitative genetics and co-author of the widely used textbook "Introduction to Quantitative Genetics" by Falconer and Mackay. She has served on numerous editorial boards and advisory committees, including the Board of Scientific Councilors of the National Center for Biotechnology Information of the National Institutes of Health. She has served as treasurer of the Genetics Society of America, president of the Drosophila Board of Directors and is president-elecct of the American Genetics Association. She is the recipient of the 2004 O. Max Gardner award of the University of North Carolina. In 2006 she was elected Fellow of the Royal Society.
  

The genetic basis of quantitative variation

‘Quantitative' characters are traits for which variation among individuals in a population is continuous. This continuous variation is attributable to segregating genetic variation at multiple loci and environmental sensitivity of allelic effects at loci contributing to the trait phenotype. Most characters important to the study of evolution, applied livestock and crop breeding, and human disease are genetically complex quantitative traits; however, we know very little of the actual loci responsible for quantitative variation. The goal of research in my laboratory is to determine the genetic basis of quantitative variation.

A comprehensive understanding of the genetic architecture of quantitative traits requires that we know the answers to the following questions: What are the genetic loci (Quantitative Trait Loci, or QTL) at which segregating and mutational variation occurs? What are the effects of mutations and segregating alleles? That is, what are the homozygous, heterozygous and epistatic effects on the trait; pleiotropic effects on other characters, including fitness; and environmental sensitivities of QTL alleles? What is the molecular genetic basis of quantitative variation in nature - Quantitative Trait Nucleotide (QTN) polymorphism? What are the frequencies of QTN in nature? What are mutation rates at individual QTL?

Determining the answers to these questions is important from the perspectives of functional genomics and evolutionary quantitative genetics. QTL methods will prove to be important tools for gene discovery and analysis in this post-genomic era, in which we need to assess the subtle functional effects of variation at loci that have been identified by whole genome sequencing, but whose functions are unknown. Detailed knowledge of the genetic basis of variation for quantitative traits is essential if we are to address longstanding issues in evolutionary quantitative genetics, such as the nature of the forces maintaining variation for quantitative traits in natural populations, and whether the loci causing variation with populations are generally the same as those causing divergence between populations and species.

The detailed characterization of the genetic architecture we require is only feasible in genetically tractable model organisms. Further, the nature of genetic variation for quantitative traits is expected to differ depending on the relationship of the trait to fitness. We are currently studying two model organisms with a wealth of genetic resources and advanced whole-genome sequencing projects, Drosophila melanogaster and Arabidopsis thaliana. We study morphological, behavioral, physiological and life history characters spanning the gamut of relationships to fitness.

Drosophila sensory bristle numbers are morphological traits with high levels of naturally occurring genetic variation and which are thought to be under strong stabilizing selection in the wild. Only when we know what loci contribute to naturally segregating variation for bristle numbers and frequencies of functional allelic variants at these loci will we be able to infer what evolutionary forces lead to the maintenance of substantial genetic variation despite strong selection. Animals display rich behavioral repertoires of responses to environmental stimuli, yet almost nothing is known of the genes underlying quantitative genetic variation in behavioral traits. We are studying olfactory responses to chemicals, mating behavior and adult locomotor behavior in Drosophila to begin the genetic dissection of complex behaviors. We study longevity and resistance to starvation stress as model life history traits, whose genetic basis may be conserved across taxa, including humans. In Arabidopsis, we study morphological and life history inflorescence traits.

We use several complementary approaches to identify QTL and determine their effects for each of the traits of interest. We are screening over 2000 random P transposable element insert lines, derived in an inbred background, for our panel of traits. We have discovered many unexpected pleiotropic effects of known genes on these quantitative phenotypes, and also have determined phenotypes of many predicted genes of unknown function, confirming the value of quantitative genetic analysis as a functional genomics tool. We map QTL causing spontaneous mutational and naturally occurring variation for our traits by linkage to polymorphic molecular markers, followed by quantitative deficiency mapping (in Drosophila), and quantitative complementation tests to mutations at all candidate genes in the region to which the QTL maps. We are using linkage disequilibrium, or association, between nucleotide and insertion/deletion polymorphisms at candidate genes with quantitative phenotypes in random breeding populations to assess the contribution of candidate genes to phenotypic variation, and to identify the causal QTN. We have constructed 500 second chromosome and 500 third chromosome substitution lines, in a highly inbred background, to improve the power of these tests. Since the effects of QTL alleles can be environment-specific, we incorporate ecologically relevant macro-environments in all the above studies. Finally, we are excited about the prospects for linking whole-genome expression studies with variation for quantitative traits, and have begun experiments to determine the extent to which quantitative phenotypic variation is mirrored by quantitative variation in transcription.

Research in my laboratory is funded by the National Institutes of Health, and the W. M. Keck Center for Behavioral Biology.

Recent Publications:

Jordan, K. W., Carbone, M. A., Yamamoto, A., Morgan, T. J. & Mackay, T. F. C. 2007. Quantitative genomics of locomotor behavior in Drosophila melanogaster. Genome Biology 8: R172. doi:10.1186/gb-2007-8-8-r172.

Lai, C. Q., Parnell, L., Lyman, R. F., Ordovas, J. M. & Mackay, T. F. C. 2007. Candidate genes affecting drosophila life span identified by integrating microarray gene expression analysis and QTL mapping. Mech. Ageing Dev. 128: 237-249.

Lai, C. Q., Leips, J. Zou, W. Roberts, J. F., Wollenberg, K. R., Parnell, L D., Zeng, Z. B., Ordovas, J. M. & Mackay, T. F. C. 2007. Speed-mapping quantitative trait loci using microarrays. Nat. Methods 10: 839-841. [pdf file]

Mackay, T. F. C. & Anholt, R. R. H. 2007. Ain’t misbehavin’? Genotype-environment interactions and the genetics of behavior. Trends Genet. 23: 311-314.

Morozova, T. V., Anholt, R. R. H. And Mackay, T. F. C. 2007. Phenotypic and transcriptional response to selection for alcohol sensitivity in Drosophila melanogaster. Genome Biology 8: R231. doi:10.1186/gb-2007-8-10-r231.

Riedl, C. A. L., Riedl, M., Mackay, T. F. C. & Sokolowski, M. B. 2007. Genetic and behavioral analysis of natural variation in Drosophila melanogaster pupation position. Fly 1: www.landesbioscience.com

Rollmann, S. M., Yamamoto, A., Goossens, T., Zwarts, L., Callaerts, P., Norga, K., Mackay, T. F. C. & Anholt, R. R. H. 2007. The early neurodevelopmental gene Semaphorin 5c is essential for olfactory behavior in adult Drosophila. Genetics 176: 947-956.

Wang, P., Lyman, R. F., Shabalina, S. A., Mackay, T. F. C. & Anholt, R. R. H. 2007. Functional evolution of odorant binding proteins in Drosophila melanogaster. Genetics 177: 1655-1665.

Carbone, M. A., Jordan, K. W., Lyman, R. F., Harbison, S. T., Leips, J., DeLuca, M., Awadalla, P. & Mackay, T. F. C. 2006. Phenotypic variation and natural selection at Catsup, a pleiotropic quantitative trait gene in Drosophila. Curr. Biol. 16: 912-919.

Edwards, A. C., Rollmann, S. M., Morgan, T. J. & Mackay, T. F. C. 2006. Quantitative genomics of aggressive behavior in Drosophila melanogaster. PLoS Genetics 2: No. 9, e154 doi:10.1371/journal.pgen.0020154.

Jordan, K. W. & Mackay, T. F. C. 2006. Quantitative trait loci for locomotor behavior in Drosophila melanogaster. Genetics 174: 271-284.

Leips, J., Gilligan, P. & Mackay, T. F. C. 2006. Quantitative trait loci with age-specific effects on fecundity in Drosophila melanogaster. Genetics 172: 1595-1605.

Mackay, T. F. C. & Anholt, R. R. H. 2006. Of flies and man: Drosophila as a model for human complex traits. Ann. Rev. Genomics Hum. Genetics 7: 339-367

Mackay, T. F. C., Roshina, N. V., Leips, J. W. & Pasyukova, E. G. 2006. Complex genetic architecture of Drosophila longevity. Pp. 181-216 in Handbook of the Biology of Aging, Sixth Edition, edited by E. J. Masaro and S. N. Austad.

Moehring, A. J., Llopart, A. Elwyn, S., Coyne, J. A. & Mackay, T. F. C. 2006. The genetic basis of prezygotic reproductive isolation between Drosophila santomea and D. yakuba due to mating preference. Genetics 173: 215-223.

Moehring, A. J., Ana Llopart, A., Elwyn, S., Coyne, J. A. & Mackay, T. F. C. 2006. The genetic basis of postzygotic reproductive isolation between Drosophila santomea and D. yakuba due to hybrid male sterility. Genetics 173: 225-233.

Morgan, T. J. & Mackay, T. F. C. 2006. Quantitative trait loci for thermotolerance phenotypes in Drosophila melanogaster. Heredity 96: 232-242.

Morozova, T.V., Anholt, R..R. H & Mackay, T. F. C. 2006. Transcriptional response to alcohol exposure in Drosophila melanogaster. Genome Biology 7: R95. doi:10.1186/gb-2006-7-10-r95. [pdf file]

Rollmann, S. M., Magwire, M. M., Morgan, T. J., Özsoy, E. D., Yamamoto, A., Mackay, T. F. C. & Anholt, R. R. H. 2006. Pleiotropic fitness effects of the Tre1/Gr5a region in DDrosophila. Nat. Genet. 38: 824-829.

Sambandan, D., Yamamoto, A., Fanara., J. J., Mackay, T. F. C. & Anholt, R. R. H. 2006. Dynamic genetic interactions determine odor-guided behavior in Drosophila melanogaster. Genetics 174: 1349–1363.

Wilson, R. H., Morgan, T. J. & Mackay, T. F. C. 2006. High resolution mapping of quantitative trait loci affecting increased life span in Drosophila melanogaster. Genetics 173: 1455-1463.

Carbone, M. A., Llopart, A., DeAngelis, M., Coyne, J. & Mackay. T. F. C. 2005. Quantitative trait loci affecting the difference in pigmentation between Drosophila yakuba and D. santomea. Genetics 171: 211-225.

Harbison, S. T., Chang, S., Kamdar, K. P. & Mackay, T. F. C. 2005. Quantitative genomics of starvation stress resistance in Drosophila. Genome Biology 6: R36 (doi: 10.1186/gb-2005-6-4-r36). [pdf file]

Lstibùrek, M., Mullin, T. J., Mackay, T. F. C., Huber D. A. & Li, B. 2005. Positive assortative mating with family size as a function of predicted parental breeding values. Genetics 171: 1311-1320.

Mackay, T. F. C., Heinsohn, S. L., Lyman, R. F., Moehring, A. J., Morgan, T. J. & Rollmann, S. M. 2005. Genetics and genomics of Drosophila mating behavior. Proc. Natl. Acad. Sci. USA. 102: 6622-6629. [pdf file]

Mackay, T. F. C., Lyman, R. F. & Lawrence, F. 2005. Polygenic mutation in Drosophila melanogaster: Mapping spontaneous mutations affecting sensory bristle number. Genetics 170: 1723-1735.

Mackay, T. F. C. & Lyman, R. F. 2005. Drosophila bristles and the nature of quantitative genetic variation. Phil. Trans. R. Soc. B 360: 1513-1527.

Rollmann, S. M., Robinson, K. O., Mackay, T. F. C. & Anholt, R. R. H. 2005. Pinocchio, a novel protein expressed in the antenna, contributes to olfactory behavior in Drosophila melanogaster. J. Neurobiol. 63: 146-158. [pdf file]

Wayne, M. L., Korol, A. & Mackay, T. F. C. 2005. Microclinal variation for ovariole number and body size in Drosophila melanogaster. Genetica 123: 263-270.

Anholt, R.R. and Mackay, T.F.C. 2004. Quantitative genetic analyses of complex behaviours in Drosophila. Nat. Rev. Genet. 5: 838-849. [pdf file]

Geiger-Thornsberry, G. L. & Mackay, T. F. C. 2004. Quantitative trait loci affecting natural variation in Drosophila longevity. Mech. Ageing Dev. 125: 179-189. [pdf file]

Genissel, A., Pastinen, T., Dowell, A., Mackay, T. F. C. & Long, A. D. 2004. No evidence for an association between common nonsynonymous polymorphisms in Delta and bristle number variation in natural and laboratory populations of Drosophila melanogaster. Genetics 166: 291-306. [pdf file]

Harbison, S. T., Yamamoto, A. H., Fanara, J. J., Norga, K. K. & Mackay, T. F. C. 2004. Quantitative trait loci affecting starvation resistance in Drosophila melanogaster. Genetics 166: 1807-1823. [pdf file]

Hill, W. G. & Mackay, T. F. C. 2004. Douglas Falconer and Introduction to Quantitative Genetics. Genetics 167: 1529-1536. [pdf file]

Mackay, T. F. C. 2004. The genetic architecture of quantitative traits: lessons from Drosophila. Curr. Opin. Genet. Dev. 14: 253-257. [pdf file]

Mackay, T. F. C. 2004. Douglas Scott Falconer (1913-2004). Heredity 93: 119-121. [pdf file]

Mackay, T. F. C. 2004. Methods for genetic dissection of complex traits. Sci. Aging Knowl. Environ. 2004 (17), pe17. [DOI: 10.1126/sageke.2004.17.pe17]

Mackay, T. F. C. 2004. Complementing complexity. Nat. Genet. 36: 1145-1147. [pdf file]

Mackay, T. F. C. 2004. Genetic dissection of quantitative traits. Pp. 51-73 in The Evolution of Population Biology: Modern Synthesis, edited by. R. Singh and M. Uyenoyama. Cambridge University Press.

Moehring, A. J. & Mackay, T. F. C. 2004. The quantitative genetic basis of male mating behavior in Drosophila melanogaster. Genetics 167: 1249-1263. [pdf file]

Moehring, A. J., Li, J., Schug, M. D., Smith, S. G., DeAngelis M., Mackay, T. F. C. & Coyne, J. A., 2004. Quantitative trait loci for sexual isolation between Drosophila simulans and D. mauritiana. Genetics 167: 1265-1274. [pdf file]

Pasyukova, E. G., Nuzhdin, S. V., Morozova, T. V. & Mackay, T. F. C. 2004. Accumulation of transposable elements in the genome of Drosophila melanogaster is associated with a decrease in fitness. J. Heredity 95: 284-290. [pdf file]

Pasyukova, E. G., Roshina, N. V. & Mackay, T. F. C. 2004. shuttle craft: A candidate quantitative trait gene for Drosophila life span. Aging Cell 3: 297-307.

Anholt, R.R.H., Dilda, C.L., Chang, S., Fanara, J.J., Kulkarni, N.H., Ganguly, I., Rollmann, S.M., Kamdar, K.P. & Mackay, T.F.C. 2003. The genetic architecture of odor-guided behavior in Drosophila: Epistasis and the transcriptome. Nature Genetics 35: 180-184. [pdf file]

Borrás, T., Morozova, T.V., Heinsohn, S.L., Lyman, R.F., Mackay, T.F.C. & Anholt, R.R.H. 2003. Transcription profiling in Drosophila eyes that overexpress the human glaucoma-associated TIGR/MYOC protein. Genetics 163: 637-645. [pdf file]

De Luca, M., Roshina, N.V., Geiger-Thornsberry, G.L., Lyman, R.F., Pasyukova, E.G. & Mackay, T.F.C. 2003. Dopa-decarboxylase affects variation in Drosophila longevity. Nature Genetics 34: 429-433. [pdf file]

Ganguly, I., Mackay, T.F.C. & Anholt, R.R.H. 2003. Scribble is essential for olfactory behavior in Drosophila. Genetics 164: 1447-1457. [pdf file]

Norga, K.K., Gurganus, M.C., Dilda, C.L., Yamamoto, A., Lyman, R.F., Patel, P.H., Mackay, T.F.C. & Bellen, H.J. 2003. Quantitative analysis of bristle number in Drosophila mutants identifies genes involved in neural development. Curr. Biol. 13: 1388-1397. [pdf file]

Ungerer, M.C., Halldorsdottir, S.S., Purugganan, M.D., and Mackay, T.F. 2003. Genotype-environment interactions at Quantitative Trait Loci affecting inflorescence development in Arabidopsis thaliana. Genetics 165: 353-365. [pdf file]

Weinig, C., Dorn, L.A., Kane, N.C., German, Z.M., Halldorsdottir, S.S., Ungerer, M.C., Toyonaga, Y., Mackay, T.F., Purugganan, M.D., and Schmitt, J. 2003. Heterogeneous selection at specific loci in natural environments in Arabidopsis thaliana. Genetics. 165:321-329. [pdf file]

Ungerer, M.C., Halldorsdottir, S.S., Modliszewski, J.L., Mackay, T.F.C., Purugganan, M.D. 2002. Quantitative trait loci for inflorescence development in Arabidopsis thaliana. Genetics 160:1133-1151. [Abstract]

Kulkarni, N.H., Yamamoto, A.H., Robinson, K.O., Mackay, T.F.C., Anholt, R.R. 2002. The DSC1 channel, encoded by the smi60E locus, contributes to odor-guided behavior in Drosophila melanogaster. Genetics 161:1507-1516. [Abstract]

Geiger-Thornsberry, G.L. and Mackay, T.F.C. 2002. Association of single-nucleotide polymorphisms at the Delta locus with genotype by environment interaction for sensory bristle number in Drosophila melanogaster. Genet Res. 79:211-218. [Abstract]

Leips, J. and Mackay, T.F.C. 2002. The complex genetic architecture of Drosophila life span. Exp. Aging Res. 28:361-390. [Abstract]

Robin, C., Lyman, R.F., Long, A.D., Langley, C.H. and Mackay, T.F.C. 2002. hairy. A quantitative trait locus for Drosophila sensory bristle number. Genetics. 162:155-164. [Abstract]

Mackay, T. F. C. 2002. The nature of quantitative genetic variation for Drosophila longevity. Mech. Age. Dev. 123: 95-104. [Abstract]

Mackay, T.F.C. 2001. The genetic architecture of quantitative traits: Inferences from Drosophila sensory bristle number. In The Character Concept in Evolutionary Biology, edited by G.P. Wagner. pp. 389-409. Academic Press, San Diego, CA.

Anholt, R. R. H., Fanara, J. J., Fedorowicz, G. M., Ganguly, I., Kulkarni, N., Mackay, T. F. C. & Rollmann, S. M. 2001. Functional genomics of odor-guided behavior in Drosophila melanogaster. Chem. Senses 26: 215-221. [Abstract]

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