Interview with Sarah Tishkoff- Perspectives for Genetic

Research ill African Populations

GIOV ANNI I
Sarah Tishkoff is the David and Lyn Silfen University Associate Professor in
Genetics and Biology at the University of Pennsylvania, holding appointments in
the Perelman School of Medicine and the School of Arts and Sciences. Dr.
Tishkoff studies genetic variation in ethnically diverse Africans in order 10
reconstruct modern human origins, African population hislOry, and processes of
adaptation. Her research examines how genetic variation inlluences normal
variable trait s as wel l as di sease susceptibility and drug response. Dr. Tishkoff
has long been an advocate for the need for populations in Africa 10 be represented
in human genetic studies so that they may benefit from knowledge about their
population history and development of more effective medical treatment s.
Dr. Tishkoff received her bachelor' s degree in anthropology and genetics
from the Uni versi ty of Cali fornia at Berkeley, and her masters of philosophy and
doctorate in genetics from Yale School of Medicine. She taught in the
Department of Bi ology at the Un iversity of Maryland at Coll ege Park from
2000- 2007 and became a facult y member at the Universit y of Pennsylvania in 2008.
Dr. Tishkoff is a fI.."Cipient of an NIH Pioneer Award, a Packard Career Award,
and a BUlToughslWellcome Fund Career Award. She is currently a member of the
editorial boards of Genome Research Journal and G3: Gelles Genomes Ge-
netics a nd is an assoc iate editor of Molewlar Biology alld EI'olution Journal
a nd The Quarterly Review of Biology. Her research is supported by grants
from the National Institutes of Health and the National Science Foundation.
Giovanni Deslro-Bisol: Sarah. a significant part of your research work focuses on
the genetics of human populations living south of the Sahara desert. Therefore, you
can probably explain, better than anyone else, why sub-Saharan Africa is such an
important and attractive area for researchers studyi ng human molecular evolution.
' Uni"crsin\ di Rom" - La Dip;mimento di Uiologia Roma. haly.
n,;s intc"'iew was COlld UC1Cd ill English by
l/,m",n Biolo!:-,". <xtober 2011. v. 00. 5. pp. 637-M4.
Copyright C 2011 Way"" Staid University Press. Detroit. Michigan -182011309
KEY WORDS: SUB-SAHARAN AFRICA, GENETIC VARIATION, HUMAN ORIGINS, GENETIC
EPIDIMIOLOGY, AFRI CAN ANCESTRY, NATURAL SELECTION, GENETIC STUDIES OF
FUNCTIONAL VARIANTS, UNILINEARL Y TRANSMln'ED I'OL YMORPHISMS, PHYLOGEOGRA-
I'HY, APPROXIMATE BA YES IAN COMPUTATION I>I ETHODS, NEXT GENERATION SEQUENC-
ING TECHNOLOGIES.
638 / OESTIW-UiSOL
Fi gure I. Sarah Tishkoff is the David and Lyn Silfen UniI'Crity Associate Professor in Genetics and
Biology at the University of Pennsylvania. !'holO counesy of Sadie Robinson.
Sarah Tishkoff: Africa is an important region 10 study for genetic variation for
a number of reasons. First is that Africa is thought to be the homeland of all
modern humans. If we want 10 learn more about human origins (e.g .. when and
where did modern humans evolve and how did they adapt 10 shifting environ-
ments?) Ihen we need to study diversily in Africa. Secondly, Africa is Ihe recent
homeland of millions of people whose ancestors were brought to the Americas
and elsewhere as slaves. Knowledge of genetic di versity across ethnically diverse
Africans will Ix: importanl for reconstructing ancestry in individuals of recent
African descent. Thirdly, study of genetic, phenotypic, and environmenlal
variation in Africa will be imponant for identifying the genetic and environmen-
lal factors Ihat playa role in bolh normal phenotypic variation as well as in
diseases common in Africa and in people of recent African descent (e.g.,
infeclious diseases such as malaria. TB, and H[V and other diseases such as
hypertension and prostate cancer). Additionally, lillie is currently known about
genelie varialion at genes Ihal playa role in drug resJXmse across ethnically
diverse Africans. Such knowledge will be important for the development of more
effective trealments in these populations. Lastly, because of high level s of
genetic, cull ural, and climalic diversity in Africa lhere has likely been local
adaptation within populations from different regions practicing diverse lifestyles.
Therefore, lhe possibililY of geographically restricted rare, as well as common.
functional variants requires Ihc inclusion of a broad range of geographically and
ethnically diverse African populations in human genetic studies.
flue/lliew willi Sarah Tishkoff I 639
GO-S: There have been a number of studies of DNA polymorphisms published
in the literature which offer contrasting hypotheses regarding the geographi c
ori gin of anatomically modern humans. For example. your Science 2(X)9 paper
provides compelling evidence that modern human migration ori ginated in
southwestern Africa (Tishkoff et al. 20 10). However. a reccnt Y-chromosomal
study (Batini et al. 2011) seems to indicate Ihat southern Afri ca was an early
destination of ancicnt human migrations from olhcr regions. Moreover, it has
been suggested that eastern Africa was an important source of initial human
migrations, a fact support ed by evidence from mtDNA anal ysis and some studi es
of thc earl iest Homo sapiens foss il rcmains. How can we explain these
discrepancies and what could be the strat egy 10 overcome them?
ST: In our Science 2(X)9 paper we inferred a southwestern ori gi n of migration of
modern humans based on patterns of genetic diversity in modern populations and
an assumption that divcrsity is grcatest in anccstral populations and dccreases as
populations migrate inlO new regions. The southwestern origin inferred in our
paper likely reflects the ancestral variati on present in the modern San popUlations
in Ihe region. However, we also noted that the geographi c distribution of genetic
variation in modern popUlations may not refl ect the geographic distribution of
genet ic variat ion in the past. Indeed, I believe it is very li kel y that modern
humans may have originated in East Afri ca (all hough we must be cautious about
making inferences about the locati on of modern human origins based only on
fossil data since fossil s arc not as wcl l preserved in tropi cal regions). For
example, li nguisti c. archeological and geneti c data suggest that people who
spoke languages classified as Khocsan may have originated in eastern Africa and
then migrated into southern Arriea (Scoa:ari 1999; Cavalli-Sforza 1994).
However, a recent study of Y chromosome variation identifi ed some of the oldest
lineages 10 be present in central and northwestern Africa (Cruciani et al. 2011).
Identifyi ng the geographic location of modern human origins based on the
paHerns of genet ic variation in modern popUlations is goi ng 10 be extremely
chall enging due 10 the complex migration hi slOries of African populations. I
believe that accurate reconstruction of modern human ori gins in Africa will
require integration of genet ic data wi th other data from the ti elds of paleobiology.
archeology, li nguistics and cultural anthropology.
GO-S: Some of your studies have becn concerned with interdisciplinary aspects
(e.g., Schcinfcldt. Soi, and Tishkoff2010). showing that linguistic divcrsity is an
important predictor of genetic diversity within the Niger-Kordofanian and
NUo-Saharan language families. It must be acknowledged that studi es of
corrclation between genetic and linguistic variation in African populations have
produced valuable insights into the peopling processes of this area. But it has
been claimed that human popUlation genetic ists should do more to avoid
imprecision about the ethnolinguistic affiliation of individuals sampled and to
640 / OESTIW-UiSOL
take the specific histories of individual groups into account (Mitchell 2010).
What is your opinion?
ST: I believe that, idcally, we should be as prccise as possible about ethnolin-
guistic elassitications and about the history of populations as inferred from
interdisciplinary studies. For that reason, we collaborated with linguist and
historian Christopher Ehret from UCLA on our Science 2009 paper in order to
study correlations between linguistic, geographic, and genetic variation within
Africa and to reconstruct population histories. However. no single source of data
can accurately provide the "full picture." For example, there are many cases
where there has been linguistic exchange but no genetic exchange, and vice
versa. Geneticists can benefit from collaboration with linguists, historians, and
archeologists in order to develop testable hypotheses and integrative reconstruc-
tions of African population history.
GD-B: Turning to the research concerning natural selection in human popula-
tions, I am sure that most of Human Biology readers know your paper on the
convergem evolution of lactase persistence (LP) in Africa and Europe (Tishkoff
ct al. 2007). Although LP is now widely recognized as one of the best examples
of natural selection in humans, the search for additional lactase persistence-
associated variants is still ongoing. Using an interpolation approach, Iian et al.
(2010) identified some areas where the estimated LP phenotype frequencies
cannot be apparently explained by the frequencies of LP-associated alleles. Do
you think this may be a useful approach to gain new insights into LP evolution
in human populations? And moreover, could it be extended to other candidate
genes for natural selection?
ST: TIlis is certainly a useful approach. This study, and others like it, has
demonstrated that there must be additional unidentified genetic variants that play
a role in the LP phenotype, particularly in pastoralist populations from West
Africa and the Middle East. By contrast, a recent in depth study in Central Asia
(Heyer 2011) indicates that the European associated variant explains much of the
phenotypic variation in that region. Certainly a similar approach could be
extended to other candidate genes that playa role in adaptation. The challenge is
going to be the identification of these variants, many of which are likely 10 be in
non-coding regions and could be located at different loci in different populations.
Additionally, just because a genetic variant is found to be associated with a trait
in one population does not mean that it wil1 be associated with that trait in another
population due to gene X gene and gene X environment interactions.
GD-B: In your study cited above, you successfully complemented the detection
of genetic signatures of selection with an in vitro transcription essay for
flue/lliew willi Sarah Tishkoff I 641
candida1e variatl1s. Personally speaking and even 1hough it has been not often
used so far, I believe that such double genetic/functional approach could really
help 10 identify genes under selection. What could be the reasons for the limited
spread of the methodology?
ST: I believe that the reason for the limited number of functional studies of
variants that appear to be targets of selection is due 10 technical limitations and
challenges. For example, we collaborated wi1h Greg Wray from Duke University
to study lhe effec1 of the LP associaled genetic variants that we identified on gene
expression in vitro (Tishkoff et al. 2007). We were fonunate that intestinal cell
lines were available which could be used for this assay, since the transcriptional
regulation of the lactase gene is highly restricted 10 cells in the inlesti ne. Indeed,
the cell line that we used was not "ideal"' because lactase is most highly expressed
in the brush border cells of the small intestine. However, those cells cannot easily
be cultured. There are likely to be cases where functional assays of varianL<;
associated with adaptive traits will need to bc studied in particular cell lines from
tissucs that may not be readily available or, if the trait is rcstricted to isolated
populations, where access to various tissues typically obtained in medical
biopsies, may be limited. Additionally, the nature of the regulatory mechanism
may be complex and may involve epigenetic modifications which can be
particularly challenging to study. In the future, the continued development of
methods for creatin iPS cells, and transforming into various tissue cell types in
vitro may facilitate functional studies.
GD-B: As exemplified in your recent papers, the attention 10 genome wide
approaches is continuously increasing in our research field (P5lsson 2008:
Destro-Bisol et al. 2010). Do you believe that these new possibilities can reshape
the field of human population genetics and to reduce the role of unilinear
polymorphisms, such as mtDNA and Y -chromosome? Otherwise, can we expect
a "peaceful" coexistence between old and new tools for the study of human
evolution at molecular level, a1 least for a certain limeframe?
ST: There is no doubt Ihat the development of high throughput SNP genOlyping
and next generation sequencing technologies, which facilitate a genome-wide
approach, is revolutionizing the tield of human population genetics. Because of
recombination, analyses of the nuclear genome can provide information about
tens of thousands of independent evolutionary histories at unlinked loci, which
can be particularly informative for reconstructing demographic parameters
inl1uencing genetic variation (ineluding ancient substructure). Additionally,
autosomal lineages which have more ancient TMRCAs relative to mtDNA and
the Y chromosome arc particularly inlormative for reconstructing human
evolutionary history prior to 200,(X)() yrs ao. However, recombination events in
the nuclear genome present challenges for reconstructing lineages and for
642 / OESTIW- Ui SOL
inferring ancienl population relationships. The study of mtDNA and Y chromo-
some lineages still remains extremely informative for reconstructing recent
migrat ion events in modern humans and for disti nguishing sex-specific migrat ion
patterns. The development of statistical approaches for reconstructing demo-
graphic hi story from mtDNA lineages, such as Bayesian skyline plots (Drum-
mond e\ a1. 2(05) has al so been informative for reconstructing shifts in
population size and examining correlation with cultural and climatic changes
(Gignoux 201 1). However. one must be cautious when studying mtDNA and Y
chromosome Ii neages since they each represent only a si ngle evolutionary hi story
and will be intluenced by forces such as natural selection.
GD-D: A second factor, which is goi ng to deeply modify our research field, is
linked to the diffusion of computational methods intended to test complex
evolutionary scenarios and allow more robust inferences of demographi c
parameters, a fact well demonstrated by the growing usc of Approximate
Bayesian computational tL'Chniques. What do you cxpect from their inevitahle
competition with classical phylogeographic approaches?
ST: I do not think these arc competitive approaches. Rather, I believe that they are
complementary. Phylogeographic appro..1ches arc infomlative for analyzing the
geographic distribution of genetic variation and. in many cases, can be informative
for tracing historic migration and popUlation differentiation event s. However, ABC
methods, and other methods which are based on computer simulation, arc particu-
larly informative for inferring demographic parameters and for testing models of
IXlPulation hi story. However. those methods often depend on having an underlying
model to test (otherwise they are computationally intractable). Phylogeographic
approaches, together with data from other fields such as archeology, can be
infonnative for narrowing down the models used in ABC simulations. Additionally,
methods that incorporate infonnation about geography togethcr with computer
simulations (e.g., si mulations of "allele surfing" in spatially expanding populations;
Ray and Excoffier 2009; Excofiier 2009) will be particularly informative.
GO-D: Looking at the future. what further developments do you expect in human
population genetics over the next decade from both a theoretical and method-
ological point of view?
ST: l ne biggest challenge in the future is going to be developing methods for
analyzing the massive data scts Ihat will be generated using next generation
S/.."quencing technologies. It is now possible to sequence entire human genomes at
hi gh coverage for lcss than $5000. Within the next several years the cost will likely
approach $1000. Of course, there are still limitations of the h..'Chnology, including our
flue/lliew willi Sarah Tishkoff I 643
ability to accurately identify structural variants such as inversion polymorphisms, and
to do de 1101'0 sequence assembly without a reference genome (which is panicularJy
imponant for African populations which may be highly divergent from current
reference genomes). However, once these technical barriers arc overcome, we will be
able to generate largc ~ a l e population genomic data sets. There are a number of
computational challenges that will need to be addressed in order to analyze these
data. For example, there will be a need to develop computational and statistical
methods for inferring demographic histories under complex models involving, for
example, ancient admixture between multiple source populations. Another challenge
will be to develop computational and biological approaches for identifying functional
variants. including those that playa role in gene rcgulation.
GD-B: How do you think you will develop your research activity in the
near future?
ST: I n the future, my research activities will focus on using an integrative
genomics approach, incorporating genomic, transcriptomic, and epigenomic
data, to test models of modern human origins and to identify genetic variants that
playa role in adaptation to diverse environments. I am particularly interested in
studying the role of environment and culture, together with genomic variation, in
shaping phenotypic variation in Africa. For example, we arc interested in
studying how populations have adapted to diverse diets. We arc also interested
in studying the genetic and environmental factors thai playa role in disease
susceptibility, with an emphasis on infectious disease. We will continue to
collaborate with linguists, historians, and anthropologists to help reconstruct both
recent and ancient African population history. Lastly, I believe that it is important
to build resources and infra-structure in Africa so that Africans can conduct
genomics research on the continent and my laboratory is actively involved in
training African scientists, bOlh in Africa and in our lab in the U.S.
GO-S: Finally, on the basis of your experience, what should bc thc priorities for
young rescarchers in human population genetics in their future carecrs?
ST: I would recommend that young researchers interested in human popUlation
genetics should get a solid foundation in core tields such as anthropology,
evolutionary theory, genelics, and genomics. However, training in the fields of
bioinfonllatics, computational biology, and statistical genetics will be critical. Those
skills will be in high demand as we movc into the genomics era and will be essential
for reconstructing human dcmographic history and testing models of human origins.
Receil'ed II Augusl 2011; accepled for IJllblicaliol! 11 Augusl 2011.
644 / OESTIW- Ui SOL
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