faculty photo

Sarah A. Tishkoff

David and Lyn Silfen University Professor
Department: Genetics

Contact information
428 Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6145
Office: 215-746-2670
Fax: 215-573-2326
B.S. (Anthropology & Genetics)
University of California, Berkeley, 1989.
M.Phil. (Human Genetics, Kenneth Kidd adviser)
Yale University, 1992.
Ph.D. (Genetics, Kenneth Kidd adviser)
Yale University, 1996.
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Description of Research Expertise

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

Lachance, J., Vernot, B., Elbers, C. C., Ferwerda, B., Froment, A., Bodo, J. M., Lema, G., Fu, W., Nyambo, T. B., Rebbeck, T. R., Zhang, K., Akey, J. M., Tishkoff, S. A.: Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse African hunter-gatherers. Cell 150(3): 457-69, 2012.

Campbell, M. C., Ranciaro, A., Froment, A., Hirbo, J., Omar, S., Bodo, J. M., Nyambo, T., Lema, G., Zinshteyn, D., Drayna, D., Breslin, P. A., Tishkoff, S. A.: Evolution of functionally diverse alleles associated with PTC bitter taste sensitivity in Africa. Molecular biology and evolution 29(4): 1141-53, 2012.

Scheinfeldt, L. B., Soi, S., Thompson, S., Ranciaro, A., Woldemeskel, D., Beggs, W., Lambert, C., Jarvis, J. P., Abate, D., Belay, G., Tishkoff, S. A.: Genetic adaptation to high altitude in the Ethiopian highlands. Genome biology 13(1): R1, 2012.

Jarvis, J. P., Scheinfeldt, L. B., Soi, S., Lambert, C., Omberg, L., Ferwerda, B., Froment, A., Bodo, J. M., Beggs, W., Hoffman, G., Mezey, J., Tishkoff, S. A.: Patterns of ancestry, signatures of natural selection, and genetic association with stature in Western African pygmies. PLoS genetics 8(4): e1002641, 2012.

Campbell, M.C., Ranciaro, A., Froment, A., Hirbo, J., Omar, S., Bodo, J.M, Nyambo, T., Lema, G., Zinshteyn, D., Drayna, D., Breslin, P., Tishkoff, S.A.: The Ongoing Evolution of Novel Functional Alleles Associated with PTC Bitter Taste Sensitivity in Africa. Molecular Biology and Evolution November 2011.

Mortensen, H.;Froment, A.; Lema, G.; Bodo, J.M.; Ibrahim, M.; Nyambo, T.B.; Omar, S.A.; Tishkoff, S.A.: Characterization of Genetic Variation and Natural Selection at the Arylamine N-Acetyltransferase (NAT) Genes In global human populations. Pharmacogenomics 12(11): 1545-58, November 2011.

Ko, W. Y., Kaercher, K. A., Giombini, E., Marcatili, P., Froment, A., Ibrahim, M., Lema, G., Nyambo, T. B., Omar, S. A., Wambebe, C., Ranciaro, A., Hirbo, J. B., Tishkoff, S. A.: Effects of Natural Selection and Gene Conversion on the Evolution of Human Glycophorins Coding for MNS Blood Polymorphisms in Malaria-Endemic African Populations. American Journal of Human Genetics 88(6): 741-54, June 2011.

Gonder, Mary Katherine, Locatelli, Sabrina, Ghobrial, Lora, Mitchell, Matthew W., Kujawski, Joseph T., Lankester, Felix J., Stewart, Caro-Beth, Tishkoff, Sarah A.: Evidence from Cameroon reveals differences in the genetic structure and histories of chimpanzee populations. Proceedings of the National Academy of Sciences 108(12): 4766-71, March 22 2011.

Bryc, K., Auton, A., Nelson, M.R., Oksenberg, J.R., Hauser, S.L., Williams, S., Froment, A., Bodo, J.M, Wambebe, C., Tishkoff*, S.A., and Bustamante, C.D.*: Genome-wide patterns of population structure and admixture in West Africans and African Americans. Proceedings of the National Academy of Sciences 107(2): 786-91, Jan 12 2010 Notes: * Contributed equally as co-senior authors.

Scheinfeldt, L. B., Soi, S., Tishkoff, S. A.: Colloquium paper: working toward a synthesis of archaeological, linguistic, and genetic data for inferring African population history. Proceedings of the National Academy of Sciences 107 Suppl 2: 8931-8, 2010.

Tishkoff, S. A., Reed, F. A., Friedlaender, F. R., Ehret, C., Ranciaro, A., Froment, A., Hirbo, J. B., Awomoyi, A. A., Bodo, J. M., Doumbo, O., Ibrahim, M., Juma, A. T., Kotze, M. J., Lema, G., Moore, J. H., Mortensen, H., Nyambo, T. B., Omar, S. A., Powell, K., Pretorius, G. S., Smith, M. W., Thera, M. A., Wambebe, C., Weber, J. L., Williams, S. M.: The genetic structure and history of Africans and African Americans. Science 324(5930): 1035-44, 2009.

Tishkoff, S. A., Reed, F. A., Ranciaro, A., Voight, B. F., Babbitt, C. C., Silverman, J. S., Powell, K., Mortensen, H. M., Hirbo, J. B., Osman, M., Ibrahim, M., Omar, S. A., Lema, G., Nyambo, T. B., Ghori, J., Bumpstead, S., Pritchard, J. K., Wray, G. A., Deloukas, P.: Convergent adaptation of human lactase persistence in Africa and Europe. Nature Genetics 39(1): 31-40, 2007.

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Last updated: 08/15/2014
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