Sarah Tishkoff

David and Lyn Silfen University Professor Departments of Genetics and Biology
428 Clinical Research Building
Genetics, Epigenetics, Genomics

Ph.D., Yale University, 1996

Research Interests: 


Human Evolutionary Genetics


We are interested in examining levels and patterns of genetic variation at the genome level among modern humans and non-human primates in order to elucidate the evolutionary forces (mutation, gene conversion/recombination, migration, drift, selection) that shape and maintain genetic variation in contemporary populations. These data are being used to reconstruct historical demographic and population differentiation events (including population expansion and contraction, subdivision, and migration) and to test hypotheses of modern human origins, including the possibility of introgression of archaic and modern human genomes.


African Genetic Diversity Project

Despite the fact that Africa plays a central role in human evolution, African populations have been greatly underrepresented in the study of human genetic diversity. Our goal is to establish a large database of genetic diversity among geographically, linguistically, and culturally diverse African populations. The study of African genetic diversity will be important for reconstructing modern human origins as well as recent African and African American population histories. The study of African genetic diversity will also be important for the identification of the genetic basis of diseases prevalent in African and African American populations (e.g. hypertension, diabetes, prostate cancer).


To achieve this goal, we and our collaborators have made several field expeditions to Africa to collect DNA samples from >7,000 individuals from > 100 ethnic groups. For many of these samples, we have collected phenotype data to be used for genotype/phenotype analyses. We are continuing to collect DNA samples and phenotype information from geographically diverse regions of Africa. Great care is taken to conduct this research in an ethical manner. An additional goal is to help train African scientists and to help build resources within Africa for doing human genetic research.


We are analyzing mtDNA, Y chromosome, and autosomal variation in these populations, including genome-wide analyses of resequencing data and of microsatellite, in/del, SNP, and CNV polymorphism data. From these studies, we will gain valuable knowledge of the genetic structure of African populations and the identification of markers that will be usefulness in gene mapping studies; we will learn about the correlation of environmental, cultural, linguistic, and genetic variation; we will be able to obtain highly accurate estimates of demographic parameters and to test hypotheses of modern human origins and more recent population migration and differentiation events.


Global patterns of linkage disequilibrium (LD) in the human genome

There is an increasing interest in identifying genes involved in complex disease (e.g. hypertension, diabetes, obesity, schizophrenia, and some types of cancer). Gene mapping approaches for complex disease often rely on the detection of association between marker and disease alleles within populations. The design and effectiveness of these studies will depend on underlying levels and patterns of LD in the populations of interest. Linkage disequilibrium will be influenced both by locus-specific factors (e.g. mutation and recombination rates, gene conversion, selection) as well as by population and demographic history (e.g. substructure, admixture, genetic drift, population expansion, and founder events). Patterns of LD are being examined among ethnically diverse populations in order to better understand how locus-specific effects as well as population and demographic history shape the distribution of LD in the human genome and to identify populations that will be particularly informative for genetic linkage and association studies.


The genetic basis of resistance to infectious disease

It is likely that infectious disease has played a major role in human evolution and in shaping genetic variation in the human genome. A current focus of my laboratory is the study of human genetic variation and the evolutionary history of genes involved in resistance against infectious disease. We are characterizing patterns of genetic variation in candidate genes for resistance/susceptibility to malaria in a set of globally diverse populations, but with an emphasis on African populations. Our goal is to identify functionally significant genetic variation that plays a role in susceptibility to infection. In addition, we are collaborating with laboratories that are studying genetic variation in Plasmodium falciparum in order to examine co-evolution of infectious agents and their human hosts.


The genetic basis of adaptation in humans

We currently know little about how changes at the genetic level correlate with phenotypic changes and adaptation to novel environments during recent human evolutionary history. Additionally, it has been hypothesized that genetic mutations associated with common complex diseases (e.g. hypertension, diabetes, obesity, asthma, arthritis, allergies, etc.) may be at high frequency in modern populations because they were adaptive in ancient environments. Thus, characterization of signatures of natural selection in genes that are of adaptive significance may be of use for identifying functionally significant variants, some of which may play a role in human disease. We are particularly interested in identifying local adaptation in culturally and geographically diverse Africans, because of the possibility that selective forces may be geographically restricted.


We are using a number of approaches to identify functionally significant variants (both coding and regulatory) involved in adaptation. The first approach is to resequence candidate genes likely to play a role in adaptation (for example, genes involved in food and drug metabolism, sensory perception, and infectious disease resistance) in a panel of ethnically diverse humans and non-human primates. We are also using whole-genome polymorphism data in these populations to identify candidate regions of the genome that may be targets of natural selection. Once targets of selection are identified, resequencing, genotype/phenotype association studies, and in vitro gene expression assays can be used to identify functionally significant variants in both coding and non-coding regions of the genome.


Genotype/Phenotype Association Studies

For many of the individuals for which we have obtained DNA, we also collected phenotype data for traits likely to play a role in adaptation, some of which demonstrate a complex pattern of inheritance and are likely influenced by multiple loci and environmental factors. In addition to case/control analyses of variation at candidate genes, we are using whole-genome association studies to identify novel genes that are associated with these traits. Together with collaborators, we are also developing methods for mapping complex traits (including disease) in highly structured African populations.



There are currently few studies of variation at drug metabolism genes across geographically and ethically diverse African populations. Many of these genes are likely to play an important role in metabolism of drugs that are used to treat infectious diseases in Africans (i.e. HIV, malaria, and TB). Such knowledge is critical for the development of more effective treatments for these devastating diseases that result in millions of deaths each year. Therefore, we are characterizing variation in Africans at regulatory and coding regions of genes that are likely to play an important role in metabolism of drugs used to treat HIV, malaria, and TB and are collaborating with clinicians to determine the effect of these variants on drug metabolism.

Selected Publications: 


Tishkoff, S.A, Gonder, M.K, Henn, B.M., Mortensen H., Fernandopulle, N., Gignoux C., Knight, A, Underhill, P.A., Ramakrishnan, U, Reed, F.A., Mountain, J.L. “History of click-speaking populations of Africa inferred from mtDNA and Y chromosome genetic variation”, Mol. Bio. Evol, 24(10):2180-95.2007


Gonder, Mary Katherine, Holly M. Mortensen, Floyd A. Reed, Alexandra de Sousa and Sarah A. Tishkoff. “Whole mtDNA Genome Sequence Analysis of Ancient African Lineages”, Mol. Biol. Evol, 24(3):757-68. 2007.


Shimada, Makoto.K, Karuna Panchapakesan, Sarah Tishkoff, Alejandro Q. Nato, Jr., and Jody Hey Divergent haplotypes and human history as revealed in a worldwide survey of X-linked DNA sequence variation, Mol. Bio. Evol, 24(3):687-98. 2007.


Tishkoff, S.A., Floyd A. Reed, Alessia Ranciaro, Benjamin F. Voight, Courtney C. Babbitt, Jesse S. Silverman, Kweli Powell, Holly Mortensen, Jibril. B. Hirbo, Maha Osman, Muntaser Ibrahim, Sabah A. Omar, Godfrey Lema, T. B. Nyambo, Jilur Ghori, Suzannah Bumpstead, Jonathan K. Pritchard, Gregory A. Wray, Panos Deloukas “Convergent adaptation of human lactase persistence in Africans and Europeans”, Nature Genetics, 39(1):31-40. 2007.


Lind JM, Hutcheson-Dilks HB, Williams SM, Moore JH, Essex M, Ruiz-Pesini E, Wallace DC, Tishkoff SA, O'brien SJ, Smith MW. “Elevated male European and female African contributions to the genomes of African American individuals.” Hum Genet. 120(5):713-22 2007.


Tishkoff, S.A. and M.K. Gonder “Human origins within and out of Africa” In: Anthropological Genetics, (M. Crawford, ed), Cambridge University Press, 2006.


Reed, F.A. and S.A. Tishkoff. “African human diversity, origins, and migrations”, Current Opinion in Genetics and Development, 16(6):597-605. 2006.


Verrelli BC, Tishkoff SA, Stone AC, Touchman JW. Contrasting Histories of G6PD Molecular Evolution and Malarial Resistance in Humans and Chimpanzees. Mol Biol Evol. Aug;23(8):1592-1601. 2006.


Awomoyi A, G. Sirugo, M.J. Newport, and S.A. Tishkoff “Global distribution of a novel trinucleotide microsatellite polymorphism (ATA)n in intron 8 of the SLC11A1 gene and susceptibility to pulmonary Tuberculosis”, European J. of Immunogenetics, 33(1):11-5. 2006.


Reed FA, Tishkoff SA. Positive selection can create false hotspots of recombination. Genetics. 172(3):2011-4. 2006.


Wang J., L. Song, M. K. Gonder, S. Azrak, D. A. Ray, M. A. Batzer, S.A. Tishkoff and P. Liang “Whole genome computational comparative genomics: a fruitful approach for ascertaining Alu insertion polymorphisms.” Gene, 365:11-20. 2006.


Mekel-Bobrov N, Gilbert SL, Evans PD, Vallender EJ, Anderson JR, Hudson RR, Tishkoff S.A., and Lahn BT. “Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens”. Science, 309:1720 – 2. 2005.


Evans PD, Gilbert SL, Mekel-Bobrov N, Vallender EJ, Anderson JR, Vaez-Azizi LM, Tishkoff SA, Hudson RR, Lahn BT. “Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans”. Science, 309:1717-20. 2005.


Tarazona Santos, E. and S.A. Tishkoff ,“Divergent patterns of haplotype structure and linkage disequilibrium at Interleukin-13 (IL13) in globally diverse human populations”, Genes and Immunity, 6(1):53-65. 2005.


Shriver MD, Rui Mei, Esteban J. Parra, Vibhor Sonpar, Indrani Halder, Sarah A. Tishkoff, Theodore G. Schurr, Sergev I. Zhadanov, Ludmilla P. Osipova, Tom Brutsaert, Jonathan Friedlaender, Lynn B. Jorde, W. Scott Watkins, Michael J. Bamshad, Gerardo Gutierez, Halina Loi, Hajime Matsuzaki, George Argyropoulos, Jose Fernandez, Rick A. Kittles, Joshua M. Akey, and Keith Jones. "Large-scale SNP analysis reveals clustered and continuous patterns of human genetic variation", Human Genomics, 2:81-89. 2005.


Tishkoff S.A. and Kenneth K Kidd, “Biogeography of human populations: Implications for race and medicine”, Nature Genetics, Suppl 1:S21-7. 2004


Verrelli, B.J. and S.A. Tishkoff. “Signatures of selection and gene conversion associated with human color vision variation.” Am J Hum Genet. 75(3):363-75. 2004.


Drousiotou, Anthi, Elias Touma, Nicoletta Andreou, Jacques Loiselet, Michalis Angastiniotis, Brian Verrelli, Sarah Tishkoff. “Molecular characterization of G6PD deficiency in Cyprus”, Blood Cells Mol Dis. 33:25-30. 2004.


Smith MW, NJ Patterson, JA Lautenberger, AL Truelove, GJ McDonald, BD Kessing, Z Yi, G deThe, M. Essex, P. J. Kanki, JP Phair, JJ Goedert, D Vlahov, RE Ferrell, SM Williams, SA Tishkoff, CA Winkler, FM DeLaVega, T Woodage, D Altshuler, JJ Sninsky, DA Gilbert, DA Hafler, SJ O'Brien, and DE Reich. "A high density ancestry map for disease gene discovery in African Americans", Am J Hum Genet. 74(5):1001-13. 2004.


Tishkoff, S.A. and B.J. Verrelli “G6PD deficiency and malarial resistance in humans: insights from evolutionary genetic analyses” In: Evolutionary Aspects of Infectious Disease (K. Dronamraju, ed), Cambridge University Press, 2004.


Tishkoff, SA and B.J. Verrrelli, “Role of evolutionary history on haplotype block structure in the human genome: implications for disease mapping”, Curr Opin Genet Dev. 13(6):569-75. 2003.


Tishkoff, S.A. and B.J. Verrelli, “Patterns of human genetic diversity: Implications for human evolutionary history and human disease”, Ann. Rev. Genomics and Human Genetics 4:293-340. 2003.


Verrelli, B J. H. McDonald, G. Argyropoulos, G. Destro-Bisol, A. Froment, A. Drousiotou, G. Lefranc, A.N. Helal, J. Loiselet, S.A. Tishkoff, “Evidence for Balancing Selection from Nucleotide Sequence Analyses of Human G6PD”., Am J Hum Genet.;71(5):1112-1128,2002.


Tishkoff, S.A. and S.M. Williams, “Genetic Analysis of African populations: Human evolution and complex disease”, Nature Reviews Genetics, 3(8):611-21, 2002.


Tishkoff, S.A., R. Varkonyi, N. Cahinhinan, S. Abbes, G. Argyropolous, G. Destro-Bisol, A. Drousiotou, B. Dangerfield, G. LeFranc, J. Loiselet, A. Piro, M. Stoneking, A. Tagarelli, G. Tagarelli, E. Touma, S. Williams, A.G. Clark, “Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance”, Science. Jul 20; 293:455-62. 2001.


Tishkoff SA, Pakstis AJ, Stoneking M, Kidd JR, Destro-Bisol G, Sanjantila A, Lu R, Deinard AS, Sirugo G, Jenkins T, Kidd KK, and Clark AG, “Short Tandem-Repeat Polymorphism/Alu Haplotype Variation at the PLAT Locus: Implications for Modern Human Origins”, Am J Hum Genet. Oct;67(4):901-925., 2000.


Tishkoff, S.A., A.J. Pakstis, S. Michalatos-Beloin, G. Ruano, and K.K. Kidd, “A comparison of molecular and statistical methods for estimating haplotype frequencies as illustrated by highly polymorphic STRP data”, Am. J. Hum. Genet. Aug;67(2):518-22, 2000.


Destro-Bisol, G., R. Maviglia, A. Caglia, I. Boschi, G. Spedini, V. Pascali, A.G. Clark, and S.A. Tishkoff, “Estimating European admixture in an African American population using microsatellites and a microsatellite haplotype (CD4/Alu)”, Hum. Genet., 104:149-157, 1999.


Zietkiweicz, E., V. Yotova, M. Jarnik, M. Korab-Laskowska, K.K. Kidd, D. Modiano, R. Scozzari, M. Stoneking, S. Tishkoff, M. Batzer, and D. Labuda, “Genetic structure of the ancestral population of modern humans”, J. Mol. Evol. 47:146-155, 1998.


Tishkoff, S.A., A. Goldman, F. Calafell, W.C. Speed, B. Bonné-Tamir, J.R. Kidd, A.J. Pakstis, T. Jenkins, and K.K. Kidd, “A global haplotype analysis of the DM locus: implications for the evolution of modern humans and the origin of myotonic dystrophy mutations”, Am. J. Hum Genet. 62(6):1389-1402, 1998.


Zietkiewicz, E., V. Yotova, M. Jarnik, M. Korab-Laskowska, K.K. Kidd, D. Modiano, R. Scozzari, M. Stoneking, S. Tishkoff, M. Batzer, and D. Labuda, “Nuclear DNA variability data support a recent common origin of Homo sapiens”, Gene (205):161-171, 1997.


Michalatos-Beloin, S., S.A. Tishkoff, K.L. Bentley, K.K. Kidd, and G. Ruano, “Molecular haplotyping of genetic markers 10kb apart by allele-specific long range PCR” Nuc. Acids Res. 24:4841-4843, 1996. (S. Michalotos-Beloin and S.A. Tishkoff contributed equally to this paper).


Risch, N., K.K. Kidd, and S.A. Tishkoff, “Genetic data and the African origin of humans”, Science 274:1548-1549, Nov. 29, 1996.


Tishkoff, S.A., K.K. Kidd, and N. Risch, “Interpretations of Multiregional Evolution”, Science 274, Nov. 1, 1996.


Tishkoff, S.A., E. Dietzsch, W. Speed, A.J. Pakstis, K. Cheung, J.R. Kidd, B. Bonné-Tamir, A.S. Santachiara-Benerecetti, P. Moral, E. Watson, M. Krings, S. Pääbo, N. Risch, T. Jenkins, and K.K. Kidd, "Global patterns of linkage disequilibrium at the CD4 locus and modern human origins", Science 271(5254):1380-7, 1996.


Tishkoff, S.A., G. Ruano, J.R. Kidd, and K.K. Kidd, "Distribution and frequency of a polymorphic Alu insertion at the PLAT locus in humans", Human Genetics 97(6):759-64, 1996.


Ruano, G., A.S. Deinard, S. Tishkoff, and K.K. Kidd, "Detection of DNA sequence variation via deliberate heteroduplex formation from genomic DNAs amplified En Masse in 'population tubes'" PCR Methods and Applications 3:225-231, 1994.


NSF Sloan Postdoctoral fellowship in molecular evolution 1996-1998


Burroughs/Wellcome Fund Career Award in the Biomedical Sciences1998-2005


David and Lucile Packard Career Award in Science and Engineering 2001-2006