Copyright 2003 by the Genetics Society of America
Low Nucleotide Diversity in Chimpanzees and Bonobos
Ning Yu,* Michael I. Jensen-Seaman,*,1Leona Chemnick,†Judith R. Kidd,‡Amos S. Deinard,§
Oliver Ryder,†Kenneth K. Kidd‡and Wen-Hsiung Li*,2
*Department of Ecology and Evolution, University of Chicago, Chicago, Illinois 60637,†Center for Reproduction of Endangered Species,
Zoological Society of San Diego, San Diego, California 92101,‡Department of Human Genetics, Yale University School of Medicine,
New Haven, Connecticut 06520-8005 and§School of Veterinary Medicine and Department of Anthropology,
University of California, Davis, California 95616
Manuscript received February 4, 2003
Accepted for publication April 16, 2003
Comparison of the levels of nucleotide diversity in humans and apes may provide much insight into
the mechanisms of maintenance of DNA polymorphism and the demographic history of these organisms.
In the past, abundant mitochondrial DNA (mtDNA) polymorphism data indicated that nucleotide diversity
(?) is more than threefold higher in chimpanzees than in humans. Furthermore, it has recently been
claimed, on the basis of limited data, that this is also true for nuclear DNA. In this study we sequenced
50 noncoding, nonrepetitive DNA segments randomly chosen from the nuclear genome in 9 bonobos
and 17 chimpanzees. Surprisingly, the ? value for bonobos is only 0.078%, even somewhat lower than
that (0.088%) for humans for the same 50 segments. The ? values are 0.092, 0.130, and 0.082% for East,
Central, and West African chimpanzees, respectively, and 0.132% for all chimpanzees. These values are
similar to or at most only 1.5 times higher than that for humans. The much larger difference in mtDNA
diversity than in nuclear DNA diversity between humans and chimpanzees is puzzling. We speculate that
it is due mainly to a reduction in effective population size (Ne) in the human lineage after the human-
chimpanzee divergence, because a reduction in Nehas a stronger effect on mtDNA diversity than on
nuclear DNA diversity.
zyme mapping (Ferris et al. 1981), it has been known
that the nucleotide diversity (?) in mtDNA is at least
threefold higher in chimpanzees than in humans. This
view has been confirmed by recent sequence data from
the control region (Wise et al. 1997) and from synony-
mous sites in the ND2 gene (Stone et al. 2002). On the
other hand, since the late 1970s it has been known
that the level of heterozygosity at protein coding loci
is higher in humans than in chimpanzees (King and
Wilson1975; Lucotte1983).Supportingthis viewthat
humans may have as much or greater diversity in the
nuclear genome was the observation that humans had
higher levelsof heterozygosityat microsatelliteloci than
chimpanzees (Wise et al. 1997), although such a differ-
ence seen in similar studies was potentially attributable
to ascertainment bias (Ellegren et al. 1995; Crouau-
INCE the discovery of extensive mitochondrial DNA
(mtDNA) polymorphism in apes by restriction en-
Roy et al. 1996). Therefore, it was commonly thought
that mtDNA and nuclear DNA gave different pictures of
polymorphism in humans and chimpanzees. However,
recent DNA polymorphism data from a 10-kb X-linked
noncoding region, two intergenic (HOXB6, DRD4, ?1 kb
each), two intronic (ADH1, ?600 bp; DRD2, ?300 bp)
regions, and 5.8-kb silent sites in genes at six nuclear
loci revealed a three- to fourfold higher nucleotide di-
versity in chimpanzees than in humans (Deinard and
et al. 2001; Satta 2001), leading to the view that, like
mtDNA, nuclear DNA sequence diversity is also much
higher in chimpanzees than in humans.
However, as the data are limited, this issue deserves
further investigation. In a recent study Yu et al. (2002)
sequenced 50 DNA segments randomly chosen from
the noncoding, nonrepetitive parts of the human ge-
nome in 30 humans from various localities around the
world. In the present study we have sequenced the same
50 segments in 9 bonobos and 17 chimpanzees from
East, Central, and West Africa. Unexpectedly, the new
data reveal a small difference between the levels of nu-
cleotide diversity in chimpanzees and humans. There-
fore, nuclear DNA and mtDNA actually give different
pictures of the levels of nucleotide diversity in humans
and chimpanzees. How this difference arose is a puz-
zling question and we will attempt to find an answer.
Sequence data from this article have been deposited with the Gen-
Bank Data Libraries under accession nos. AY275957–AY277244.
1Present address: Human and Molecular Genetics Center, Medical
College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI
sity of Chicago, 1101 E. 57th St., Chicago, IL 60637.
Genetics 164: 1511–1518 (August 2003)
1512 N. Yu et al.
MATERIALS AND METHODS
East, Central, and West Africa. The total number of nu-
cleotide sites sequenced, after exclusion of deletions and
insertions (mostly single nucleotide indels), is ?23,500.
A total of 186 single nucleotide polymorphisms (SNPs)
51 of them were observed only once (i.e., singletons)
and 15 only twice (doubletons). The number of variant
sites found was 54 in the 12 West African chimpanzee
(P. t. verus) sequences, 101 in the 10 Central African
chimpanzee (P. t. troglodytes) sequences, and 39 in the 4
East Africanchimpanzee (P. t.schweinfurthii) sequences.
Thus, many more variants were found in the Central
African subspecies than in the West and East African
subspecies, indicating a much higher DNA diversity in
the Central African subspecies. The numbers of single-
tons were 14, 58, and 27 in the West, Central, and East
African chimpanzee sequences, respectively. Thus, in
the Central and East African subspecies, more than half
of the variants were singletons, whereas in the West
African subspecies less than one-third of the variants
were singletons with an equal number of doubletons. A
there were 21 singletons and 11 doubletons. Clearly,
bonobos are less polymorphic than each of the three
Adequacy of the sample sizes: As our sample sizes are
relatively small, we need to consider the problem of
sampling bias. For this purpose, we consider the effect
of sampling on nucleotide diversity (?) because ? is the
quantity of our primary interest in this study; ? is de-
fined as the number of nucleotide differences per site
between two randomly chosen sequences in a popula-
tion. As noted in Yu et al. (2002), an estimation bias
may be detected by comparing within-individual ? val-
ues (?w) with between-individual ? values (?b). Ideally,
each sequence in a sample should be taken randomly
from the population, but we have included the two
sequences within each of the individuals sampled. The
two sequences in an individual are not completely inde-
pendent if the individual is “inbred” to some extent.
Anyway, the within-individual ? values (?w) should tend
to be smaller than the between-individual ? values (?b)
and their inclusion should tend to give an underesti-
mate of ?. However, if the average ?band ?wvalues are
similar, then the sampling scheme would seem largely
of ? should produce no substantial bias. To simplify the
analysis, we concatenate the segments in an individual
in a random manner into two continuous sequences
and these sequences are then used to compute the ?b
For the Central African chimpanzee sequences, the
distribution of ?bvalues, which ranges from 0.098 to
0.174%, is only somewhat wider than that of the five ?w
values, which ranges from 0.102 to 0.153%. Since the
average ?b(0.131%) is ?10% higher than the average
?w(0.121%), the sampling bias should not be strong.
Sample sources: DNA from nine bonobos (Pan paniscus) and
17 common chimpanzees (six P. troglodytes verus, five P. t.
troglodytes, two P. t. schweinfurthii, and four individuals of un-
known subspecies) was used in this study. The five P. t. troglo-
dytes individuals (named Cheetah, Dodo, Bakoumba, Julie,
and Noemie) were from J. Wickings, CIRMF, Gabon. Three
of the six P. t. verus individuals (Rinus, Anita, and Hannibal)
were from A. Prince, Vialab, Liberia, one (Herman) was from
the Lowery Zoo, and two (Bert and Tate) were from the New
Iberia Research Center; four individuals (Carl, Kasey, Harv,
and Tank) were of unknown geographic origin. The two P.
t. schweinfurthii individuals (Harriet and Kobi) were from J.
Fritz, Arizona Primate Foundation. Although no geographical
information was available for the individuals housed at the
New Iberia Research Center, they were regarded as P. t. verus
on the basis of their mitochondrial D-loop sequences (Morin
et al. 1994), and the nuclear sequences generated from these
samples did not contradict this classification (Deinard and
Kidd 2000).Ofthenine P.paniscus individuals,two(Bosondjo
and Matata) were from the Atlanta Zoo/Yerkes Regional Pri-
mate Center; two (Lody and Maringa) from the Milwaukee
Zoo, and five (Kakowet, Lokalema, Charlie, Vernon, and
Linda) from the San Diego Zoo. However, all nine individuals
were originally caught in Zaire and all of them were chosen
to be independent.
PCR amplification and sequencing of DNA segments: The
50 noncoding, nonrepetitive genomic segments (each ?1 kb)
were originally selected randomly from the human genome
(Chen and Li 2001; Yu et al. 2002). All were chosen to avoid
coding regions or close linkage to any coding regions. In each
segment and its nearby regions there was no registered gene
in GenBank and no potential coding region was detected by
either GenScan or GRAIL-EXP.
Touchdown PCR (Don et al. 1991) was used and the reac-
tions were carried out following the conditions described in
Zhao et al. (2000). The PCR products were purified by Wizard
PCR Preps DNA purification resin kit (Promega, Madison,
WI). Sequencing reactions were performed according to the
protocol of the ABI Prism BigDye Terminator sequencing
kits (Perkin-Elmer, Norwalk, CT) modified by one-quarter
G-50 (DNA grade, Pharmacia, Piscataway, NJ) and run on an
ABI 377XL DNA sequencer using 4.25% gels (Sooner Scien-
tific). About 500 bp of each segment was sequenced in both
ABI DNA Sequence Analysis 3.0 was used for lane
ally and heterozygous sites were detected as double peaks.
The forward and reverse sequences were assembled automati-
cally in each individual using SeqMan (DNAStar, Madison,
WI). The assembled files were carefully checked by eye. Fluo-
rescent traces for each variant site were rechecked again in
all individuals. All singletons, which are variants that appear
only once in the entire sample, were verified by PCR reampli-
fication and resequencing of the PCR products in both direc-
Data analysis: The sequences were aligned by SeqMan. Nu-
cleotide diversity values were calculated using DNASP version
3.14 (Rozas and Rozas 1999) and the average percentage
distances between species were calculated using DAMBE (Xia
and Xie 2001).
RESULTS AND DISCUSSION
Distribution of SNPs: We sequenced 50 noncoding
segments in nine bonobos and 17 chimpanzees from
1513Nucleotide Diversity in Chimpanzees
of the within-individual (?w;
?) and between-individual
(?b; ?) nucleotide diversity
values in bonobos. (a) All
of the 18 sequences are in-
cluded. (b) One individ-
ual (Bosondjo) and one se-
quence (randomly chosen)
from each of three indi-
Linda) are excluded.
zee sample. There is one very low ?wvalue (0.051%)
and the average ?wvalue (0.072%) is ?10% lower than
the average ?bvalue (0.082%). The average ?wwithout
the outlier becomes 0.077%, which is not far from the
average ?b(0.082%). This comparison suggests that the
estimated ? value (0.082%) in this subspecies is proba-
bly somewhat biased downward. For the East African
chimpanzee sample, the average ?wvalue (0.088%) is
no substantial bias. However, because only two individu-
als were sampled, the estimate may not be reliable and
should be taken with caution.
For the bonobo sample, the distributions of ?wand
?bvalues are given in Figure 1a. Several ?wand ?bvalues
are ?0.04%, whereas most of the others are consider-
ably ?0.04%. This observation suggests that some of
the individuals are fairly closely related to each other
or inbred, although they were originally chosen to be
djo and Maringa (studbook numbers 64 and 60, respec-
tively) were only 0.034, 0.034, 0.038, and 0.047%. We
therefore excluded Bosondjo from comparison. More-
over, the ?wvalue is only 0.030% for Kakowet (studbook
no. 34) and 0.038% for Lody and Linda (studbook nos.
68 and 23). We therefore excluded one sequence (ran-
domly chosen) from each of these three individuals.
After the exclusion of these sequences, only 13 se-
1514N. Yu et al.
quences remain and the new distributions of ?wand ?b
sequences increases the average ? value from 0.075 to
0.078%. The latter value will be used as our estimate.
Nucleotide diversity: For the 50 DNA segments we
obtained, the range of ? is from 0 (14 segments) to
0.39% in the West African chimpanzee sample, from 0
(7 segments) to 0.46% in the Central African chimpan-
zee sample, from 0 (23 segments) to 0.45% in the East
African chimpanzee sample, and from 0 (3 segments)
to 0.46% in the entire chimpanzee sample (Table 1).
The range of ? is from 0 to 0.36% in the bonobo sample
and from 0 to 0.30% in the human sample (Table 1).
Such large fluctuations are not surprising because the
nucleotide diversity in a short DNA region is subject to
strong stochastic effects. In addition, variation in ? may
also arise from variation in mutation rate among geno-
Table 2 shows that Central African chimpanzees have
the highest average ? value (0.130%), followed by East
African chimpanzees (0.092%), and then West African
chimpanzees (0.082%). As mentioned above, the ?
value estimated from the East African chimpanzee sam-
ple may not be reliable because of a small sample size
and that from the West African chimpanzee sample
might be biased downward. We note further that in
previous studies the East African chimpanzee had a
greater ? at APOB and PABX but a smaller ? at the
HOXB6 intergenic region and at the mtDNA ND2 and
the mtDNA control region than did the West African
chimpanzee (Table 2; Wise et al. 1997; Deinard and
Kidd 2000; Stone et al. 2002). Therefore, further data
are needed to see whether the ? value for the East
African chimpanzee is actually higher than that for the
West African chimpanzee.
Surprisingly, the average ? value in bonobos (0.078%)
is somewhat lower than that in humans (0.088%; Table
2). The observation thatbonobos have lower nucleotide
diversity than humans is in agreement with the Xq13.3
data, but contrary to the HOXB6, DRD4, DRD2, and NRY
regions. Furthermore, the average ? values in the East
and West African chimpanzee subspecies (0.092 and
0.082%) are similar to that in humans. The Central
African chimpanzee is the only subspecies that has a ?
value (0.130%) higher than that in humans and the dif-
ference is only 50%. We note further that even the
highest ?bvalue for the concatenated sequences in the
Central African chimpanzee sample is only 0.174% (see
above), which is only two times the average ? value in
humans. When all chimpanzee sequences are consid-
ered together, the average ? value (0.132%) is again
only 50% higher than that in humans. Actually, if we
consider African humans only, the ? value for the 50
DNA segments becomes 0.115% (Yu et al. 2002), which
is only 13% lower than that for chimpanzees.
Previous reports have suggested that chimpanzees
have two to four times greater amounts of ? than hu-
mans at several autosomal nuclear loci, including the
noncoding intergenic regions near HOXB6 and DRD4
(Deinard and Kidd 1999; Jensen-Seaman et al. 2001),
the intronic regions of DRD2 and AHD1 (Deinard and
sites at six protein coding loci (Satta 2001). Similar
results were also observed at the X chromosomal locus
NRY locus (Stone et al. 2002). However, since our data
set has a much wider genomic representation, it should
be more reliable. The stochastic effects of examining
only a small number of loci can be seen, for example,
in that in one-third (17 of 50) of the segments that we
examined chimpanzees had more than three times
higher ? than humans (Table 1), which is approxi-
mately the value that was found by others when looking
at a single locus (Table 2; Deinard and Kidd 1999;
Kaessmann et al. 1999). Thus, the difference in nucleo-
tide diversity between humans and chimpanzees is con-
siderably smaller for nuclear DNA than for mtDNA data
(Table 2). The disparity in using mtDNA vs. nuclear
was originally pointed out by Wise et al. (1997), who
in further comparisons to other nonhuman primates
suggested that humans, not chimpanzees, were unusual
in possessing such low levels of mtDNA diversity relative
to that of the nuclear genome.
Another measure of genetic variability is the number
of segregating alleles in the sample. However, because
the sample sizes are different for different populations,
we consider ? ? 4Neu, where Neis the effective popula-
tion size and u is the mutation rate per site per genera-
tion. The ? values estimated from the numbers of segre-
are given in Table 2. We note that, compared to the
difference in ? (0.088 vs.0.078%) between humans and
bonobos, the difference in ? (0.123 vs. 0.082%) is even
larger (Table 2), probably reflecting an increase in low-
frequency alleles due to a recent population expansion
in humans. The highest ? value for the three chimpan-
panzees, but it is only 24% higher than that for humans.
When all chimpanzee sequences are considered to-
gether, ? becomes 0.194%, which is only 50% higher
than that in humans.
Effective population sizes: To estimate effective pop-
ulation size (Ne) we estimate the mutation rate per nu-
cleotide site per generation (u) by using the sequence
divergence (d) between species (Table 3) and assuming
that the divergence time between the human and chim-
panzee-bonobo lineages is 6 MY (Brunet et al. 2002;
Vignaud et al. 2002). Since we are interested in the
long-term effective population size, we use Tajima’s esti-
mator, ? ? 4Neu (Tajima 1983), and we assume that
the generation time is 15 years for chimpanzees and
bonobos and 20 years for humans. The Nefor humans
is estimated to be 10,500 (Table 2), which is similar to
1515Nucleotide Diversity in Chimpanzees
Nucleotide diversity in each of the 50 DNA segments studied in chimpanzees, bonobos, and humans
Nucleotide diversity (%)
ahe human data are from Yu et al. (2002).
bP.t.v., West African chimpanzee; P.t.t., Central African chimpanzee; P.t.s., East African chimpanzee.
1516N. Yu et al.
Average nucleotide diversity in chimpanzees, bonobos, and humans and effective population sizes
estimated from ?
50 segments (noncoding)
mtDNA ND2 (synonymous)
mtDNA control region (partial 342 bp)
H. sapiens (340 bp)
References: 1, present study; 2, Deinard and Kidd (1999); 3, Kaessmann et al. (1999); 4, Kaessmann et al.
(2001); 5, Stone et al. (2002); 6, Wise et al. (1997); 7, Horai et al. (1992); 8, Ingman et al. (2000); 9, Deinard
and Kidd (2000). Abbreviations of chimpanzee subspecies follow those of Table 1. s, segregating site.
aGeneration lengths are assumed to be 15 and 20 years for apes and humans, respectively.
and Graur 1984; Takahata et al. 1995; Zhao et al.
2000), while that for bonobos (12,400) is only slightly
larger and that for the Central African chimpanzees
(20,900), or for the entire species of chimpanzees, is
about twice as large.
Causes for different patterns of nuclear DNA and
mtDNA diversity: As noted above, for nuclear DNA the
nucleotide diversity in humans is only 50% lower than
that in chimpanzees, whereas previous studies have
found the mtDNA nucleotide diversity in humans to be
at most only one-third of that found in chimpanzees
(Wise et al. 1997; Stone etal. 2002). What are the causes
for this sharp contrast? A highly plausible cause is a
reduction in the effective population size in the human
lineage since the human-chimp divergence. There is
strong evidence for this putative reduction (Ruvolo
1997; Harpending et al. 1998; Chen and Li 2001). As
noted by Fay and Wu (1999), a reduction in Necauses
for nuclear DNA. This follows from the theory that the
effect of a bottleneck on ? is proportional to T/N1,
where T is the time since the bottleneck and N1is the
new effective population size, and from the fact that the
1517 Nucleotide Diversity in Chimpanzees
?2 million bp (Chen et al. 2001; Ebersberger et al.
2002; Fujiyama et al. 2002). The sequence divergence
between the human and the bonobo (1.30%) is some-
panzee, probably because the bonobo has a smaller
effective population size than the chimpanzee and so
has been subject to a stronger effect of random drift.
These data also provide the largest and most compre-
hensive estimate of divergence time between chimpan-
zees and bonobos, estimated here to be 1.8 MYA, assum-
ing a 6-MYA Homo-Pan split (Brunet et al. 2002;
Vignaud et al. 2002). This estimate is the same as that
by Stone et al. (2002), based on their data from the
nonrecombing regionof Y,and isintermediate between
published data using mtDNA (2.5 MYA; Gagneux et al.
1999) and X chromosomal DNA (0.9 MYA; Kaessmann
etal. 1999).Also, thedate ofthe formationof theCongo
River, which currently prevents contact between these
species, has been estimated from geological and limno-
logical evidence to have formed ?1.5 MYA (Beadle
1981). Perhaps the formation of the Congo River initi-
This was also a timeof potentially large climatic changes
in the African climate and changes in vegetation pat-
terns, proposed by some to have catalyzed the origins of
several hominid species and human innovations (Vrba
Average sequence divergence (%) between taxa estimated
from the 50 DNA segments studied
Species P.t.s.P.t.t.P.t.v.Chimp Bonobo
Abbreviations of chimpanzee subspecies follow those of
effective population size for mtDNA is usually smaller
than that for nuclear DNA (Takahata 1993). An addi-
tion time in the human lineage, which leads to a higher
mutation rate per generation and also to a higher ex-
pected ? value in the case of nuclear DNA but to little
increase in the case of mtDNA because of maternal
inheritance and limited germ cell divisions per genera-
tion in the female germline.
Another possibility is that population subdivision
might have been stronger in humans than in chimpan-
in humans than in chimpanzees, so that the effective pop-
ulation size for mtDNA is considerably smaller in hu-
mans than in chimpanzees (Birky et al. 1989). Evidence
to support this argument may come from the observa-
tion that chimpanzee females uniformly disperse from
their natal troop, in contrast to the typical mammalian
(and primate) pattern of female philopatry with male
dispersal (Greenwood 1980). The potential for high
rates of female migration in chimpanzees is seen in the
long-distance (?900 km) sharing of mtDNA haplotypes
(Morin et al. 1994; Goldberg and Ruvolo 1997).
Divergences between subspecies and species: The
average sequence divergence (d; average nucleotide dif-
ferences per site) between chimpanzee subspecies is the
smallest between the West and East African chimpan-
it should be the largest. The smaller divergence occurs
because the levels of nucleotide diversity in the East and
West African chimpanzees are smaller than that in the
value is the largest betweenthe Central and East African
subspecies. The between-subspecies d values are only
slightly higher than the within-subspecies ? values, indi-
cating a small separation between subspecies.
The sequence divergence between the bonobo and
the nucleotide diversity within the chimpanzee species
(0.132%), indicating a much longer separation time
between the two species than between the chimpanzee
subspecies. The sequence divergence between the hu-
man and the chimpanzee is 1.22% (Table 3), which is
similar to the values (?1.2%) obtained on the basis of
We thank the zoos, research organizations, and individuals listed
in materials and methods for the generous donation of DNA or
bloodsamples usedinthisstudy. Thisstudywassupported byNational
Institutes of Health grants GM-55759 and GM-30998.
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Communicating editor: N. Takahata