AFRICAN GENETIC DIVERSITY: Implications for Human
Demographic History, Modern Human Origins, and Complex
Disease Mapping
Michael C. Campbell
1
and Sarah A. Tishkoff
1,2
1
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania 19107; mcam@mail.med.upenn.edu
2
Department of Biology, University of Pennsylvania, School of Arts and Sciences, Philadelphia,
Pennsylvania 19104; tishkoff@mail.med.upenn.edu
Abstract
Comparative studies of ethnically diverse human populations, particularly in Africa, are important
for reconstructing human evolutionary history and for understanding the genetic basis of phenotypic
adaptation and complex disease. African populations are characterized by greater levels of genetic
diversity, extensive population substructure, and less linkage disequilibrium (LD) among loci
compared to non-African populations. Africans also possess a number of genetic adaptations that
have evolved in response to diverse climates and diets, as well as exposure to infectious disease. This
review summarizes patterns and the evolutionary origins of genetic diversity present in African
populations, as well as their implications for the mapping of complex traits, including disease
susceptibility.
Keywords
disease susceptibility; African populations; genetic variation; human evolution; linkage
disequilibrium
INTRODUCTION
One of the “grand challenges” of the post-genome era is to “develop a detailed understanding
of the heritable variation in the human genome” (36). By characterizing genetic variation
among individuals and populations, we may gain a better understanding of differential
susceptibility to disease, differential response to pharmacological agents, human evolutionary
history, and the complex interaction of genetic and environmental factors in producing
phenotypes. Africa is an important region to study human genetic diversity because of its
complex population history and the dramatic variation in climate, diet, and exposure to
infectious disease, which result in high levels of genetic and phenotypic variation in African
populations. A better understanding of levels and patterns of variation in African genomes,
together with phenotype data on variable traits, including susceptibility to disease and drug
response, will be critical for reconstructing modern human origins, the genetic basis of
adaptation to diverse environments, and the development of more effective vaccines and other
Copyright © 2008 by Annual Reviews. All rights reserved
DISCLOSURE STATEMENT
The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.
NIH Public Access
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Annu Rev Genomics Hum Genet. 2008 ; 9: 403–433. doi:10.1146/annurev.genom.9.081307.164258.
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therapeutic treatments for disease. This information will also be important for identifying
variants that play a role in susceptibility to a number of complex diseases in people of recent
African ancestry (172,187,208).
HUMAN EVOLUTIONARY HISTORY IN AFRICA
Africa is a region of considerable genetic, linguistic, cultural, and phenotypic diversity. There
are more than 2000 distinct ethno-linguistic groups in Africa, speaking languages that
constitute nearly a third of the world’s languages (http://www.ethnologue.com/) (Figure 1).
These populations practice a wide range of subsistence patterns including various modes of
agriculture, pastoralism, and hunting-gathering. Africans also live in climates that range from
the world’s largest desert and second largest tropical rainforest to savanna, swamps, and
mountain highlands, and these climates have, in some cases, undergone dramatic changes in
the recent past (106,172).
According to the Out of Africa (OOA) model of modern human origins, anatomically modern
humans originated in Africa and then spread across the rest of the globe within the past
~100,000 years (206). The transition to modern humans within Africa was not sudden; rather,
the paleobiological record indicates an irregular mosaic of modern, archaic, and regional
morphological and behavioral traits that occurred over a substantial period of time and across
a broad geographic range within Africa (127). The earliest known derived suite of
morphological traits associated with modern humans appears in fossil remains from Ethiopia,
dated to ~150--190 kya (128,229). However, this finding does not rule out the existence of
modern morphological traits in other regions of Africa before 100 kya, particularly where
specimens may be less well preserved and/or where extensive archaeological and
paleobiological investigations have not been conducted (172). Indeed, a multiregional origin
model for modern humans within Africa is not as unlikely as it would be for global populations,
considering the greater potential for migration and admixture within a single continental region
(172,241). A more fully modern suite of traits appears in East Africa and Southwest Asia around
90 kya, followed by a rapid spread of modern humans throughout the rest of Africa and Eurasia
within the past 40,000--80,000 years (120,172) (Figure 2).
Two migration routes of modern humans out of Africa have been proposed. The presence of
modern humans in Oceania as early as ~50 kya (65,66), which predates their presence in Europe
~40 kya, has suggested a southern coastal route around the Indian Ocean in which modern
humans first left Africa (possibly via Ethiopia) by crossing the Bab-el-Mandeb strait at the
mouth of the Red Sea and then rapidly migrated to Southeast Asia and Oceania (62,172) (Figure
1). This migration model is supported by the presence of very old mtDNA haplotypes in South
Asia and their absence in the Levant (120,168,197). Other models have traditionally favored
a second (or single) northern route via the Sinai Peninsula into the Levant (62,172) (Figure 1).
Regardless of the route of migration of modern humans out of Africa, the shared patterns of
genetic diversity among non-African populations [e.g., at the CD4 locus (200)] and the
divergent patterns of genetic variation among African populations argue against repeated
sampling of African diversity from multiple source populations (172,200,206). However,
analyses of more independent loci and a larger number of African populations, particularly
from East Africa, will be necessary to better estimate the number and source of migration events
out of Africa (172). After modern humans migrated from Africa, there could have been some
admixture of modern humans with archaic populations in Eurasia, such as Neanderthals. This
hypothesis remains a topic of considerable interest and debate and is the subject of a number
of recent studies and reviews (46,59,71,73,
77
,
144
,
158
,172,184,185,224)
The migration of modern humans out of Africa is thought to be accompanied by a population
bottleneck. The size of the population(s) migrating out of Africa is estimated to be ~600
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effective founding females (i.e., census size of ~1800 females) on the basis of mtDNA evidence
(62,120), to be ~1000 effective founding males and females (i.e., census size of ~3000
individuals) based on the analysis of 783 autosomal microsatellites genotyped in the Center
d’Etude du Polymorphisme Humain (CEPH) human genome diversity panel (HGDP) (112),
and to be ~1500 (i.e., a census size of ~4500 individuals) based on a combined analysis of
mtDNA, Y chromosome, and X chromosome nucleotide diversity data (72). These estimates
imply that Eurasians must have rapidly expanded to a larger size to account for estimates of a
long-term effective population size (N
e
) of ~10,000 individuals (census size of ~30,000
individuals) for global populations (172,243). Indeed, several recent studies indicate a rapid
expansion of Eurasian populations within the past ~50,000 years, whereas Africans have
maintained a large effective population size (72,125,243).
PATTERNS OF GENETIC VARIATION IN AFRICA
The pattern of genetic variation in modern African populations is influenced by demographic
history (e.g., changes in population size, short- and long- range migration events, and
admixture) as well as locus-specific forces such as natural selection, recombination, and
mutation. For example, the migration of agricultural Bantu speakers from West Africa
throughout sub-Saharan Africa within the past ~4000 years and subsequent admixture with
indigenous populations has had a major impact on patterns of variation in modern African
populations (157,167,172,201,235a) (Figure 1). Although Africa is critical for understanding
modern human origins and genetic risk factors for disease, it has been under-represented in
human genetic studies. Much of what we currently know about genetic diversity is from a
limited number of the ~2000 ethno-linguistic groups in Africa, and the majority of these data
are from mtDNA and Y chromosome studies. Large-scale autosomal studies of African genetic
diversity are only now beginning to become available.
Mitochondrial DNA and Y Chromosome Variation
Phylogenetic analyses of both mtDNA and Y chromosome DNA indicate that the oldest
lineages are specific to Africa and have a Time to Recent Common Ancestry (TMRCA) of
~200 kya (75,206). Interestingly, the most ancient mtDNA lineage (L0d) [dated to ~106 kya
(75)], which is common in click-speaking southern African Khoisan (SAK) populations, has
recently been identified at low frequency (5%) in the click-speaking Sandawe population from
Tanzania (75,201). Maximum likelihood estimates for the time of divergence of these
populations based on all mtDNA lineages is ~44 kya, indicating that any common ancestry is
quite old. This finding supports studies of classical polymorphisms as well as archeological
data that suggest that Khoisan-speaking populations may have originated in eastern Africa and
subsequently migrated into southern Africa (26), although a southern African origin of
Khoisan-speakers cannot be ruled out.
Phylogenetic analysis indicates that the most recent African specific mtDNA haplogroup
lineage, L3, is the likely precursor of modern European and Asian mtDNA haplotypes (226).
Indeed a subset of this lineage (M1) is observed at high frequency in Ethiopian populations
(101,168) and may have expanded out of Africa ~60 kya (168). This observation adds strength
to the proposal that the dispersal of modern humans out of Africa may have occurred via
Ethiopia (117,200). However, more recent analysis of whole mtDNA genomes suggests that
the M1 lineage may have originated in southwestern Asia and then was introduced into East
Africa from Asia ~40--45 kya (150), whereas others have argued for a much more recent
introduction of the M1 lineage into Africa from the Middle East (63).
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Nucleotide and Haplotype Variation
The migration of modern humans out of Africa resulted in a population bottleneck and a
concomitant loss of genetic diversity (112,169). Numerous studies have shown higher levels
of nucleotide and haplotype diversity in Africans compared to non-Africans in both nuclear
and mitochondrial genomes (40,72,93,111,200,202,206,208). Non-African populations appear
to have a subset of the genetic diversity present in sub-Saharan Africa and more private alleles
and haplotypes are observed in Africa relative to other regions (38,93,111,169,
200
,202,206,
208,243) as expected under an OOA model. For example, a resequencing study of 3873 genes
in 154 chromosomes from European, Latino/Hispanic, Asian, and African American
populations observed that African Americans had the highest percentage of rare single
nucleotide polymorphisms (SNPs) (64%) and the lowest percentage of common SNPs (36%).
Additionally, 44% of all SNPs in this population were private (78). The high level of genetic
diversity in African populations is also consistent with a larger long-term effective population
size (N
e
) compared to non-Africans (72,195,196,202,
206
; N
e
is estimated to be ~15,000 for
Africans and ~7500 for non-Africans based on a resequencing analysis of several 10-kb regions
(243) (see Supplemental Material).
Structural Variation
Although most studies of genetic variation in humans have focused on nucleotide and
microsatellite diversity, a number of recent studies have demonstrated considerable amounts
of structural variation (SV) in the human genome, including both copy number variation (which
can include insertions and deletions as well as gene duplications) and inversions (17,37,191,
211) (http://projects.tcag.ca/variation/). Some of these structural variants are also associated
with phenotypic variability (37,171,193). For example, variation in copy number of the
amylase gene, which plays a role in digestion of starch, is correlated with enzyme activity level
and with diet in ethnically diverse human populations (156). Additionally, SVs may play an
important role in susceptibility to common disease (109,124). A recent study that used high-
resolution paired-end mapping to identify SVs in the genomes of a single African (Yoruba
from Nigeria) individual and an individual of European descent led to the identification of 1175
insertions/deletions (INDELs) and 122 inversions (103). By extrapolation, these researchers
predicted 761 and 887 SVs in the full genomes of these European and African individuals,
respectively. Additionally, 45% of the SVs were shared between these samples, suggesting
that a large proportion of SV events occurred prior to the divergence of African and non-African
populations. The majority of these SVs were less than 10 kb in size, but at least 15% were
larger than 100 kb and some SVs were predicted to be several megabases in size in both the
European and African sample, indicating that the genomes of healthy individuals may differ
by megabases of nucleotide sequence (103). To date, few population genetic studies of SVs
across ethnically diverse populations have been performed (37). Instead, most studies have
focused on the European, Japanese, Chinese, and African (Yoruba) HapMap populations
(37). A study of 67 common copy number variants (CNVs) in these populations indicated that
11% of the variation was due to differences among populations and that many of the variants
were shared among populations from different regions, further supporting the argument that
these variants existed prior to migration of modern humans out of Africa (171). There are
currently no studies of SV variability within and between ethnically diverse African
populations. Such knowledge will be informative for reconstructing human evolutionary
history and for understanding the role of SVs in normal phenotypic diversity and in
susceptibility to disease.
POPULATION STRUCTURE IN AFRICA
Measures of population structure on a global level indicate that only ~10%--16% (Wright’s
fixation index, F
ST
= 0.10--0.16) of observed genetic variation is due to differences among
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