Office Address: CLSC 401
Telephone number: 773 834 1037
Our group aims to characterize the amount and patterns of genetic variation in human populations, and to elucidate the forces that shape and maintain this variation. Forces such as demographic change or population structure exert genome-wide effects, while others such as natural selection result in locus-specific effects. As greater attention is focused on dissecting the genetic bases of common diseases, an understanding of the patterns of human sequence variation is recognized as a critical step toward improved approaches to disease mapping. Our group takes advantage of the diverse intellectual environment at the University of Chicago to integrate the knowledge from population genetics and disease mapping studies.
Our work on these questions began with the analysis of mitochondrial DNA sequence and microsatellite variation, and led us to propose that ancestral human populations experienced a major demographic expansion. More recently, we have been taking advantage of the proliferation of new genetic tools for population studies, to test increasingly complex and, thus, more realistic scenarios of population growth; for example, we can survey sequence variation and linkage disequilibrium in a number of independent regions of the human genome. Our survey includes ethnically diverse populations so that the effect of population structure on genetic variation may also be assessed. Our empirical work is complemented by extensive modeling of demography and population structure by computer simulations based on coalescent theory (in collaboration with R. R. Hudson - University of Chicago).
More recently, we are studying the evolution of a polymorphic variant contributing to type 2 diabetes susceptibility. This variant was identified in the laboratory of our collaborators, G. I. Bell and N. J. Cox (University of Chicago). An attractive hypothesis, called the "thrifty genotype" hypothesis, proposes that diabetes variants have evolved under the effect of positive natural selection. Because natural selection leaves a distinctive signature on the amount and pattern of sequence variation and linkage disequilibrium in the region linked to the selected site, we have designed a survey to detect this. It involves quantitative comparison of both sequence and haplotype variation, and the degree and pattern of inter-population differentiation, at this site versus that at neutrally evolving loci. In addition, we will investigate the degree and pattern of inter-population differentiation at this site and ask whether it differs from those observed at other neutrally evolving loci in the human genome.
We are also interested in pharmacogenetic polymorphisms. Drug metabolizing enzymes (DMEs) are particularly interesting subjects for evolutionary biologists, because of their role as mediators between the organism and the environment. Their function in the detoxification of xenobiotics implies that variability at these genes is under strong selective pressures and, because the chemical environment varies significantly with diet, climate, lifestyle, etc., a great deal of inter-ethnic differentiation is expected (and in fact observed) for DME polymorphisms. Carcinogens are also metabolized by DMEs; thus, variability at DME genes is likely to result in varying susceptibility to cancer. Our efforts in this area so far have concentrated on a common polymorphism in the promoter of the UGT1A1 gene which encodes the major bilirubin glucuronidation enzyme. This enzyme also detoxifies the active metabolite of a commonly-used anticancer agent (irinotecan). Based on a worldwide survey of variability at the UGT1A1 promoter, we detected extensive variability across the major ethnic groups which may underlie the variability of response to the anticancer agent. We are currently investigating whether UGT1A1 polymorphisms contribute to the susceptibility to different types of cancer and surveying sequence variation for evolutionary analyses. We anticipate that these studies will provide a better understanding of the role of glucuronidation in drug response and in the gene-by-environment interactions that underlie cancer susceptibility.
Admixture facilitates genetic adaptations to high altitude in Tibet. Jeong C, Alkorta-Aranburu G, Basnyat B, Neupane M, Witonsky DB, Pritchard JK, Beall CM, Di Rienzo A (2014) Nat Commun. 2014;5:3281. doi: 10.1038/ncomms4281. 24513612
Gene expression of peripheral blood cells reveals pathways downstream of glucocorticoid receptor antagonism and nab-paclitaxel treatment. Maranville JC, Nanda R, Fleming GF, Skor MN, Di Rienzo A, Conzen SD (2014 Sep) Pharmacogenet Genomics. 2014 Sep;24(9):451-8. doi: 10.1097/FPC.0000000000000077.25000515 (Full Text)
Adaptations to local environments in modern human populations. Jeong C, Di Rienzo A (2014 Aug) Curr Opin Genet Dev. 2014 Aug 14;29C:1-8. doi: 10.1016/j.gde.2014.06.011. 25129844
In vitro sensitivity assays and clinical response to glucocorticoids in patients with inflammatory bowel disease. Maranville JC, Micic D, Hanauer SB, Di Rienzo A, Kupfer SS (2014 Jul) J Crohns Colitis. 2014 Jul 19. pii: S1873-9946(14)00210-4. doi: 10.1016/j.crohns.2014.06.013.25052346
Pilot study demonstrating potential association between breast cancer image-based risk phenotypes and genomic biomarkers. Li H, Giger ML, Sun C, Ponsukcharoen U, Huo D, Lan L, Olopade OI, Jamieson AR, Brown JB, Di Rienzo A (2014 Mar) Med Phys. 2014 Mar;41(3):031917. doi: 10.1118/1.4865811. 24593735 (Full Text)
Discovery and functional assessment of gene variants in the vascular endothelial growth factor pathway. Pare-Brunet L, Glubb D, Evans P, Berenguer-Llergo A, Etheridge AS, Skol AD, Di Rienzo A, Duan S, Gamazon ER, Innocenti F (2014 Feb) Hum Mutat. 2014 Feb;35(2):227-35. doi: 10.1002/humu.22475. Epub 2013 Nov 27.24186849 (Full Text)
Comparison of cellular and transcriptional responses to 1,25-dihydroxyvitamin d3 and glucocorticoids in peripheral blood mononuclear cells. Kupfer SS, Maranville JC, Baxter SS, Huang Y, Di Rienzo A (2013) PLoS One. 2013 Oct 8;8(10):e76643. doi: 10.1371/journal.pone.0076643. eCollection 2013.24116131 (Full Text)
Genetic mapping with multiple levels of phenotypic information reveals determinants of lymphocyte glucocorticoid sensitivity. Maranville JC, Baxter SS, Witonsky DB, Chase MA, Di Rienzo A (2013 Oct) Am J Hum Genet. 2013 Oct 3;93(4):735-43. doi: 10.1016/j.ajhg.2013.08.005. Epub 2013 Sep 19. 24055111 (Full Text)
Inter-ethnic differences in lymphocyte sensitivity to glucocorticoids reflect variation in transcriptional response. Maranville JC, Baxter SS, Torres JM, Di Rienzo A (2013 Apr) Pharmacogenomics J. 2013 Apr;13(2):121-9. doi: 10.1038/tpj.2011.55. Epub 2011 Dec 13.22158329 (Full Text)
SNP discovery, expression and cis-regulatory variation in the UGT2B genes. Sun C, Southard C, Huo D, Hernandez RD, Witonsky DB, Olopade OI, Di Rienzo A (2012 Aug) Pharmacogenomics J. 2012 Aug;12(4):287-96. doi: 10.1038/tpj.2011.2. Epub 2011 Mar 1.21358749
Interactions between glucocorticoid treatment and cis-regulatory polymorphisms contribute to cellular response phenotypes. Maranville JC, Luca F, Richards AL, Wen X, Witonsky DB, Baxter S, Stephens M, Di Rienzo A (2011 Jul) PLoS Genet. 2011 Jul;7(7):e1002162. doi: 10.1371/journal.pgen.1002162. Epub 2011 Jul 7.21750684 (Full Text)
A reduced representation approach to population genetic analyses and applications to human evolution. Luca F, Hudson RR, Witonsky DB, Di Rienzo A (2011 Jul) Genome Res. 2011 Jul;21(7):1087-98. doi: 10.1101/gr.119792.110. Epub 2011 May 31.21628451 (Full Text)
Adaptations to climate-mediated selective pressures in humans. Hancock AM, Witonsky DB, Alkorta-Aranburu G, Beall CM, Gebremedhin A, Sukernik R, Utermann G, Pritchard JK, Coop G, Di Rienzo A (2011 Apr) PLoS Genet. 2011 Apr;7(4):e1001375. doi: 10.1371/journal.pgen.1001375. Epub 2011 Apr 21. 21533023 (Full Text)
Allele-specific down-regulation of RPTOR expression induced by retinoids contributes to climate adaptations. Sun C, Southard C, Witonsky DB, Kittler R, Di Rienzo A (2010 Oct) PLoS Genet. 2010 Oct 28;6(10):e1001178. doi: 10.1371/journal.pgen.1001178. 21060808(Full Text)
Adaptation - not by sweeps alone. Pritchard JK, Di Rienzo A (2010 Oct) Nat Rev Genet. 2010 Oct;11(10):665-7. doi: 10.1038/nrg2880. Epub 2010 Sep 14.20838407
Using environmental correlations to identify loci underlying local adaptation. Coop G, Witonsky D, Di Rienzo A, Pritchard JK (2010 Aug) Genetics. 2010 Aug;185(4):1411-23. doi: 10.1534/genetics.110.114819. Epub 2010 Jun 1.20516501 (Full Text)
Colloquium paper: human adaptations to diet, subsistence, and ecoregion are due to subtle shifts in allele frequency. Hancock AM, Witonsky DB, Ehler E, Alkorta-Aranburu G, Beall C, Gebremedhin A, Sukernik R, Utermann G, Pritchard J, Coop G, Di Rienzo A (2010 May) Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8924-30. doi: 10.1073/pnas.0914625107. Epub 2010 May 5. 20445095 (Full Text)
Adaptations to climate in candidate genes for common metabolic disorders. Hancock AM, Witonsky DB, Gordon AS, Eshel G, Pritchard JK, Coop G, Di Rienzo A (2008 Feb) PLoS Genet. 2008 Feb;4(2):e32. doi: 10.1371/journal.pgen.0040032. 18282109 (Full Text)
Interrogating multiple aspects of variation in a full resequencing data set to infer human population size changes. Voight BF, Adams AM, Frisse LA, Qian Y, Hudson RR, Di Rienzo A (2005 Dec) Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18508-13. Epub 2005 Dec 13. 16352722(Full Text)
An evolutionary framework for common diseases: the ancestral-susceptibility model. Di Rienzo A, Hudson RR (2005 Nov) Trends Genet. 2005 Nov;21(11):596-601. Epub 2005 Sep 8. 16153740
CYP3A variation and the evolution of salt-sensitivity variants. Thompson EE, Kuttab-Boulos H, Witonsky D, Yang L, Roe BA, Di Rienzo A (2004 Dec) Am J Hum Genet. 2004 Dec;75(6):1059-69. Epub 2004 Oct 18. 15492926 (Full Text)
Comparative linkage-disequilibrium analysis of the beta-globin hotspot in primates. Wall JD, Frisse LA, Hudson RR, Di Rienzo A (2003 Dec) Am J Hum Genet. 2003 Dec;73(6):1330-40. Epub 2003 Nov 18. 14628290 (Full Text)
Gene conversion and different population histories may explain the contrast between polymorphism and linkage disequilibrium levels. Frisse L, Hudson RR, Bartoszewicz A, Wall JD, Donfack J, Di Rienzo A (2001 Oct) Am J Hum Genet. 2001 Oct;69(4):831-43. Epub 2001 Aug 29. 11533915 (Full Text)