A fine-scale comparison of the human and chimpanzee genomes: linkage, linkage disequilibrium and sequence analysis
A fine-scale comparison of the human and chimpanzee genomes: linkage, linkage disequilibrium and sequence analysisB. Crouau-Roy1,2, S. Service1, M. Slatkin3 and N. Freimer1,4,5,*
1Neurogenetics Laboratory, University of California San Francisco, San Francisco, CA 94143, USA, 2CNRS, Centre d'Immunopathologie et de Genetique Humaine (CIGH), CHU Purpan, 31300 Toulouse, France, 3Department of Integrative Biology, University of California Berkeley, Berkeley, CA 94720, USA, 4Center for Neurobiology and Psychiatry, Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA and 5Programs in Genetics and Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA
Received March 20, 1996;Revised and Accepted May 6, 1996
We have performed a fine-scale comparative study of the human and chimpanzee genomes, using linkage, linkage disequilibrium and sequence analyses on microsatellite loci spanning a region of approximately 30 cM on human chromosome 4p. Our results extend the findings of previous studies that indicated virtually complete conservation between the human and chimpanzee genomes at the chromosomal and sub-chromosomal level and support the hypothesis, derived from previous analyses of mitochondrial DNA, that chimpanzee populations are more diverse than human ones. By sequencing several human and chimpanzee alleles of two microsatellites we showed that base substitutions that diminish the length of perfect repeats (but do not change allele sizes) are probably responsible for the low heterozygosity of these loci in chimpanzees; our results suggest that the evolutionary history of microsatellites should not be inferred from comparisons of mean allele lengths between populations or species.
Genetic comparisons of closely related species are of great value for elucidating evolutionary processes [for example, the degree of conservation of genome structure or the evolution of repeat sequences (1 )], and for studying phenomena, such as linkage disequilibrium (LD), which may be strongly influenced by population histories. The recent construction of high resolution human genetic maps using microsatellite repeats (2 ,3 ) permits such comparisons to be made between humans and their closest living relative, the chimpanzee (Pan troglodytes). Several studies have shown that most human microsatellites are conserved in chimpanzees, in the sense that human microsatellite primers can be used to amplify homologous polymorphic microsatellites in chimpanzees (4 -7 ). It has further been demonstrated that the structure of the human and chimpanzee genomes is highly conserved at the chromosomal and sub-chromosomal levels (8 -10 ), i.e. they are almost completely syntenous. We sought to investigate the conservation of human and chimpanzee genomes at a much higher level of resolution, by investigating a single chromosomal region (encompassing about 30 cM in proximal human 4p). We chose to study this region because at the initiation of previous related work (11 ) the human genetic and physical maps of chromosome 4p were particularly well-developed. Twelve contiguous human microsatellites were used for linkage and LD analyses in chimpanzees, and for direct sequence comparisons between human and chimpanzee samples. These evaluations permitted us to quantify the extent of genome conservation between these two species at the regional and sequence level, and to examine in detail the extent of LD between microsatellite loci in the two species. Furthermore, comparisons of microsatellite sequences in the two species, which have been separated for over 4 million years, may provide information about the evolution of these loci.
Using a sample of unrelated, haplotyped individuals drawn from the Finnish population, Peterson et al. (11 ) previously demonstrated that sets of contiguous microsatellites are useful for examining LD in anonymous genome regions and that such LD is positively highly correlated with a small physical distance between marker loci. Additionally, markers with low heterozygosity displayed less LD than those with high heterozygosity; this observation was predictable given the results of previous analyses conducted using diallelic markers, which are typically less informative than microsatellites (12 ). Slatkin (13 ) has shown that detection of LD in anonymous genome regions in random samples of unrelated individuals is influenced not only by the `genome-related' factors (e.g. physical and genetic distance and microsatellite heterozygosity) evaluated by Peterson et al. (11 ) but also by the demographic history of the population being studied. Computer simulations indicated that random samples from populations with a constant size are expected to have more LD between loci than random samples from populations that have experienced rapid growth (13 ). This is not to say that LD cannot be detected between closely linked loci in a population that has grown rapidly; in fact when looking at individuals selected for the presence of a disease phenotype, one expects LD between loci around a disease gene in descendents of a common ancestor in such populations [e.g. Hastbacka et al. (14 )]. However, population genetic theory predicts that in a random sample of individuals from rapidly growing populations, LD between closely linked loci in anonymous genome regions is not expected to arise because of mutation and genetic drift alone, whereas in such a sample from a population of constant size, LD between closely linked loci can be created by genetic drift (13 ).
In the current study we sought to evaluate this prediction by genotyping a chimpanzee population sample with a subset of the chromosome 4 markers previously used by Peterson et al. (11 ) in their study of a Finnish sample. Finland has a well-documented demographic history (15 ); its present-day population is thought to descend from approximately 1000 founders who settled the southwestern portion of the country 2000 years ago. This founding population has grown exponentially, with little further admixture, to its present size of approximately 5 million (14 ). The demographic history of chimpanzee populations is less well known, however mtDNA analyses provide substantial inferential information. In particular, they indicate that, historically, there has been substantial gene flow among populations and that it is unlikely that these populations have expanded in recent times (16 ). We therefore assume that chimpanzee population sizes have remained relatively constant (or have contracted) over the period of time that the Finnish population has rapidly expanded. Examining the degree of sequence-level genome conservation between these two species, with very different population histories, enables us to elucidate the contributions of both genome-related and population-related factors to the detection and maintenance of LD in anonymous genome regions.
All 12 dinucleotide repeat loci amplified in the chimpanzee samples, despite the fact that these microsatellites were designed for analysis in humans. Distribution of allele frequencies of these markers in the human and chimpanzee samples show that, although there is substantial variation in allelic frequencies within each locus and the modal alleles are different, the distribution of allele sizes overlap for all but two loci (Table 1). We noted similar, high heterozygosities for both species except for three markers (D4S404, D4S885 and D4S190) which display low heterozygosities in the chimpanzee. For the other nine markers, heterozygosity in the chimpanzee exceeds 0.7. For seven of these nine markers we observed higher (although not statisically significant) heterozygosity in the chimpanzee than in the human despite the fact that nearly twice the number of chromosomes were examined in the human sample as compared to the chimpanzee. The heterozygosities for humans shown in Table 1 are from the Finnish sample described in Peterson et al. (11), however the chimpanzee sample also displayed greater heterozygosity for these loci in comparison with the mixed European sample of the CEPH database (data not shown). Two loci, D4S391 and D4S174, with 13 and 17 alleles, respectively, have heterozygosities greater than 0.95 in the chimpanzee. For these two markers, the mean number of repeats in the chimpanzee is always lower than that observed in humans, however the variance in the number of repeats is two and four times higher than in the human, respectively. The average repeat number and the range in allele size are similar for most of the markers except for the three markers which display low heterozygosity in the chimpanzee ( Table 2 ).
To address the origin of the low heterozygosity of two markers in the chimpanzee sample, we determined the sequences of the various alleles of D4S404 and D4S885 (Fig. 1 ). The structure of the D4S404 CA repeat is imperfect in humans and chimpanzees, with the four same substitutions. In both species, variation at this marker is attributable to differences in the number of CAs in the longest uninterrupted repeat. This uninterrupted repeat at D4S404 is much shorter in all of the chimpanzee alleles sequenced compared to the human alleles, and the most common allele in the chimpanzee is the one which contains the smallest number of repeats (eight CA repeats). For D4S885, the repeat structure differs between human and chimpanzee: in humans there is a long perfect AC repeat, while in the chimpanzee this repeat is interrupted by an AT substitution. Additionally, there is a deletion of a dinucleotide (CA) in the 3' flanking region of the long AC repeat in the chimpanzee, but not in the human. We also observed several substitutions in the regions flanking the repeat (between and within species); these changes (underlined in Fig. 1 ) did not alter allele lengths.
. Results of linkage analyses for marker pairs that resulted in Lod scores >2.0 in the chimpanzee pedigree
Marker pair
Lod score
D4S419-D4S418
4.20
D4S425-D4S391
4.20
D4S551-D4S425
4.018
D4S230-D4S418
3.96
D4S391-D4S418
3.84
D4S425-D4S418
3.59
D4S616-D4S391
3.3
D4S419-D4S425
3.26
D4S551-D4S230
3.25
D4S174-D4S405
3.02
D4S418-D4S174
2.95
D4S391-D4S230
2.89
D4S551-D4S418
2.85
D4S419-D4S174
2.72
D4S551-D4S391
2.70
D4S230-D4S174
2.50
D4S391-D4S174
2.40
D4S425-D4S230
2.38
D4S419-D4S391
2.25
D4S551-D4S616
2.17
D4S419-D4S230
2.13
This threshold for linkage was chosen based on the prior expectation that the loci would be linked. The maximum likelihood estimate of the inter-marker recombination fraction was <0.10 for all comparisons, indicating the loci to be tightly linked.
LD in the chimpanzee sample was evaluated using 48 chromosomes for which haplotypes could be reconstructed. There are 66 pairwise comparisons of the 12 loci studied, and LD was detected for 23 of these comparisons (Table 3 ). Two loci with low heterozygosity in the chimpanzee (D4S404 and D4S190) are involved in the majority of comparisons in which associations are detected (17 out of 23). These associations appear to derive from sharing of rare haplotypes that include rare alleles at these loci. For example, a rare allele (of 83 bp in length) for D4S404 was present in two haplotypes; these haplotypes (for which we have no evidence of common ancestry) also share rare alleles at several of the other markers tested. In the human population, a total of six pairwise comparisons were in disequilibrium (Table 3 ). Comparison of the LD results in the two species shows that three of the same marker pairs are in disequilibrium in both human and chimpanzee. The pairwise comparisons for two additional pairs of loci, which are in disequilibrium in the human population, are suggestive of LD in the chimpanzee (p value <0.1) (Table 3 ).
LD on human chromosome 4 was positively related to small physical distance (11 ); the majority of pairwise associations in LD in the human involved loci within 76 centiRays (approximately 2 Mb) of each other. In the chimpanzee sample, only four of the 16 locus pairs in LD that were localized on the human radiation hybrid map used in Peterson et al. (11 ) were within 76 centiRays of each other on the human map. Of the 12 pairwise comparisons in LD that involve loci separated by more than 76 centiRays, nine were separated by more than 200 centiRays.
In this paper we present the first results from fine-scale genetic and sequence comparisons of the human and chimpanzee genomes over a single chromosomal region. These results confirm the prediction of prior studies (conducted at the chromosomal and sub-chromosomal levels) that these genomes are highly conserved with respect to each other. Several previous studies have indicated that in the majority of cases, human primers can be used to amplify (CA)n repeat arrays in the chimpanzee (5 -7 ,17 ). Our results extend these findings; as all 12 of the contiguous loci tested could be amplified in the chimpanzee using human primers, and displayed some degree of polymorphism in both species, it is likely that virtually all microsatellites in these genomes predate the divergence between humans and chimpanzees. Those specific instances noted in previous studies in which microsatellites cannot be amplified in chimpanzees using human primers (6 ) are probably due to changes in the primer sequence rather than due to the absence of a microsatellite sequence. In this respect it is interesting that we noted a high degree of interspecies sequence variation in the region flanking the repeat for one of the two loci that we sequenced (D4S885); this observation is consistent with previous suggestions that mutation rates for single copy sequences adjacent to microsatellites may be higher than for such sequences in other genome regions (1 ,7 ).
Our study differs from previous human-chimpanzee comparisons based on microsatellites in that the loci we tested were not selected from human genetic maps (which are biased in favor of markers that are highly polymorphic in humans) but rather included all previously identified markers (for a single defined region) that were available at the start of the study of Peterson et al. (11 ), and thus represented a wider range of heterozygosities. For example, we used three markers that were not considered sufficiently informative to be used in published human genetic maps (D4S551, D4S616 and D4S885). In contrast to previous studies (4 ,6 )we observed, for most markers, greater heterozygosity in the chimpanzee populations than in human populations (although this trend was not statistically significant with the sample sizes employed in this comparison). This is interesting in light of several studies (based on comparison of mtDNA sequences) that have consistently demonstrated greater genetic diversity in chimpanzees than in humans (18 ,19 ), suggesting that the size of ancestral chimpanzee populations is probably larger than the size of ancestral human populations. Our observations provide the first support from nuclear markers for this interpretation.
If the generally greater heterozygosity of microsatellites in chimpanzees, in comparison with humans, reflects the degree of genetic diversity in the two species, how does one explain the loci for which chimpanzees are substantially less heterozygous than humans? Our data suggest that these cases may not reflect a different evolutionary process in humans, but rather, reflect the ascertainment bias that occurs in choosing markers that are polymorphic in humans for such comparative studies. For two of the three markers which were substantially less heterozygous in the chimpanzee we sequenced several alleles in humans and chimpanzees. The decreased heterozygosity of these loci in chimpanzee is most likely due to interruptions of the repeat elements at these loci. This observation is in keeping with previous findings in human populations and experimental systems indicating that interruptions of perfect repeats are correlated with stability of microsatellites and that the microsatellite mutation rate (and degree of polymorphism) is increased in long uninterrupted repeats(20 -22 ). Notably, D4S885 is highly polymorphic in humans, where there is a long perfect repeat, and almost monomorphic in chimpanzees, where a base substitution interrupts the AC repeat. Similarly, for D4S404 low heterozygosity in both humans and chimpanzees is probably probably due to four imperfections in the repeat region, with the longest uninterrupted repeat being relatively short in both species, but longer in humans than in chimpanzees.
.Results of linkage disequilibrium (LD) analysis of pairs of microsatellite loci in the chimpanzee and human samples
Locus pair
Chimp p value
Human p value
Locus pairs in LD only in the chimpanzee sample
D4S551-D4S419
0.0069
0.2492
D4S551-D4S616
0.0329
0.7375
D4S551-D4S404
0.0047
0.6072
D4S551-D4S190
0.0002
0.4199
D4S419-D4S616
0.0229
0.3162
D4S419-D4S404
0.0102
0.9354
D4S419-D4S190
0.0011
0.6537
D4S616-D4S404
0.0008
0.6277
D4S616-D4S405
0.0033
0.8500
D4S616-D4S190
0.0081
0.3327
D4S404-D4S391
0.0136
0.5550
D4S404-D4S230
0.0030
0.5723
D4S404-D4S418
0.0250
0.4198
D4S404-D4S174
0.0011
0.2779
D4S404-D4S405
0.0014
0.1586
D4S404-D4S190
0.0016
0.5033
D4S391-D4S190
0.0265
0.6781
D4S230-D4S190
0.0053
0.0634
D4S418-D4S190
0.0241
0.9294
D4S174-D4S190
0.0043
0.1981
Locus pairs in LD only in the human sample
D4S425-D4S616
0.0837
0.0088
D4S391-D4S230
0.8079
0.0055
D4S230-D4S418
0.0950
0.0210
Locus pairs in LD in both samples
D4S418-D4S885
0.0194
0.0014
D4S551-D4S405
0.0384
0.0207
D4S405-D4S190
0.0069
0.0020
LD was analysed using a Monte Carlo approximation to Fisher's exact test and the P value from this approach is presented for both chimpanzee and human samples.
Possible differences in microsatellite allele length between humans and other primates have recently received considerable attention(23 ,24 ). It has been suggested that such differences reflect important biological differences between primates, indicating directional evolution of human microsatellites (23 ). In response it has been argued that such apparent length differences are artifactual: virtually all of the loci that have been evaluated in primate species have been developed for genetic mapping purposes in humans and identified through hybridization with oligonucleotide probes consisting of long uninterrupted repeats (which are generally highly polymorphic and thus useful for mapping studies); therefore a selection bias exists for loci that have such repeats in humans. This argument has been supported by results from species comparisons using markers developed in each system (24 ). Our observation (for contiguous microsatellites) that chimpanzees displayed greater heterozygosity and variance in repeat length but shorter alleles than humans indicates that the evolutionary history of microsatellites in humans and closely related species should not be inferred from interspecies differences in mean allele length. As our current sequence data, (in conjunction with previous data from our laboratories for other microsatellites (7 ,25 ), Grimaldi, M.-C., Avoustin, P., Crouau-Roy, B., unpublished results) indicate that differences in microsatellite structure between humans and chimpanzees are more complex than is evident from comparisons of the overall length of the alleles, it is likely that elucidating the evolutionary history of these repeat sequences will require sequence analysis of a large number of loci (26 ).
Because we had extensive pedigree information on the chimpanzee sample we were able to use linkage analysis to address the degree of conservation of the region compared between humans and chimpanzees. The observation that all informative loci that are linked in humans are also linked in chimpanzees suggests that, in this particular region, there is likely to be nearly complete conservation at the locus level between the two species. The observed recombinations permit placement of the loci within groups; the relative order of these groups on the chromosome further supports conservation at this level of analysis. Similar conclusions have recently been suggested by linkage analysis of a smaller number of human microsatellites in a baboon sample (27 ).
It was previously shown using microsatellites in the Finnish population that LD is abundantly distributed on chromosome 4 and is positively associated with small physical distance between markers (11 ). Based on population genetics theory (13 ) we predicted that more LD would be seen in chimpanzees than in the Finnish sample, given the supposition that the chimpanzee population is old and has either remained stable or decreased in size and that the Finnish population was founded recently by a small number of individuals and has rapidly expanded. Additionally, as the theory predicts that selection and drift are more important in producing and maintaining LD in old, stable populations than in rapidly expanding ones, we anticipated that the relationship between LD and intermarker distance would be less marked in the chimpanzees than in the Finns. Both of these theoretical predictions were supported in our comparison of LD in humans and chimpanzees. We observed more LD in the chimpanzees (23 pairs of loci showing allelic associations) than in the Finns (six pairs of loci showing associations) and the majority of locus pairs in LD [that could be localized on the human radiation hybrid map used by Peterson et al. (11 )] were separated by more than 76 centiRays. The associations observed in the human population were largely conserved in the chimpanzee; of the six pairwise associations detected in the Finns, three were also detected in the chimpanzee with almost identical P values. For two others, there is a suggestion of LD (P<0.1). Given the separation of the human and chimpanzee populations at least several million years ago, these associations most likely reflect conserved genome structure between the populations or selection (at one or both loci). The latter possibility is suggested by the observation of LD in both species between two loci that are separated (in the human) by more than 30 cM (D4S551 and D4S405). In accord with our expectations, several additional associations were observed in the chimpanzee sample but not in the Finnish one. It is noteworthy that these associations involve loci that are relatively non-polymorphic in the chimpanzee. For example, eight of nine comparisons involving loci in LD that were separated by more than 200 centiRays involved one of the loci found to have very low heterozygosity in the chimpanzee (D4S404 or D4S190), and were likely in LD because of haplotype sharing of rare alleles. In general, one expects that such loci are uninformative for detecting LD, however, in this case LD appears to be caused at least in part by the sharing of rare haplotypes including these loci by a small number of individuals. Although these individuals are apparently unrelated it is also possible that these haplotypes reflect unrecognized population substructure within the chimpanzee sample, in particular the possiblility that this sample includes members of more than one subspecies cannot be discounted (16 ), as the origin of many of the wild-caught chimpanzees at Yerkes Primate Center is unknown.
In summary, we have described the first detailed comparison of the human and chimpanzee genomes over a single extended region and have not only confirmed the high degree of conservation between these species but have also supported predictions of population genetics theory. Our results indicate the utility of such inter-species comparisons using population samples. The approaches used in our study should become more informative as more extensive human genomic sequences are identified.
Fifty-four chimpanzee DNA samples were obtained from the Yerkes Primate Center (YPC) at Emory University, Atlanta, GA. Complete pedigree information (for the past several generations) was available except for six wild-born chimpanzees, who were not known to be closely related to each other or to the chimpanzees born at YPC. These are the same chimpanzee samples used in previous studies in our laboratory (7 ,25 ). The chimpanzees from YPC that were used for the population-level analyses were separated from each other by at least four meioses [the same criterion was used to select Finnish samples for similar analyses (11 )]. In total there were 56 unrelated chromosomes.
All individuals were genotyped for 12 human dinucleotide repeat loci extending over a single region of 30 cM on chromosome 4. These loci were chosen from the most densely clustered subset of the 32 microsatellites studied by Peterson et al. (11 ), and included all loci with heterozygosity (in humans) > 0.6 over this region. PCR was performed according to a previously described protocol (28 ) on 24 ng of DNA in a final volume of 10 [mu]l using the original primers obtained from human sequences. Chimpanzee alleles of D4S404 and D4S885 were sequenced using the 32-P cycle sequencing protocol in the Promega fmol DNA sequencing kit. Before sequencing, PCR products of the different samples were amplified, purified and cloned in Jm109. Sequencing reactions were visualized by autoradiography, on 8% acrylamide gels. The human sequence data for D4S885 and D4S404 were obtained from Genbank (accession numbers L09766 and Z16706, respectively).
Linkage analyses using LINKAGE (29 -31 ) and FASTLINK (32 ,33 ) were performed to assess the inter-marker recombination fractions in a subset of the extended chimpanzee pedigree. The extensive consanguinity observed in the entire pedigree would have made calculation times unacceptably long, as many individuals involved in the inbreeding loops were not available for typing at the 12 marker loci. We therefore used a subset of the known chimpanzee pedigree for the linkage analyses; this sub-pedigree consisted of 76 individuals, 48 of whom were typed for the 12 marker loci.
Haplotypes for the 12 microsatellites examined were constructed using genotypes of parents and children of the chimpanzees, if available. In some cases phase could not be established. We generated a gametic dataset, which included the unambiguous haplotypes and in which all phase-ambiguous haplotypes were resolved randomly. For this randomly generated data set we evaluated LD between marker loci in the chimpanzee sample using a Monte Carlo approximation to Fisher's exact test (11 ,34 ). All pairwise comparisons of the 12 microsatellite loci were examined, and in this way we obtained an estimated P value for each pair of loci in the randomly resolved data set. We then repeated this procedure 99 times and obtained an average (and standard deviation) of the P values for each pair of loci over the set of haplotypes that were randomly resolved through these 100 repetitions. Marker pairs were considered in disequilibrium if the P value for the Fisher's exact test was <0.05. The P values are used as indicators of the extent of pairwise LD and not as the outcomes of statistical tests (which would obviously not be independent of each other).
L. Bull, S. Blower and V. Carlton provided helpful comments on the manuscript. This work was supported by grants from the NIH to NBF and MS and by a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression (to NBF). BC-R was supported by the CNRS. We thank the Yerkes Primate Center for providing the chimpanzee samples, and Carlos Garza for helpful discussions.
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*To whom correspondence should be addressed at: Box F-0984, University of California, San Francisco, CA 94143, USA
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