Genomics 67, 237–247 (2000)doi:10.1006/geno.2000.6245, available online at http://www.idealibrary.com on

A Genetic Linkage Map of the Baboon (Papio hamadryas) GenomeBased on Human Microsatellite Polymorphisms

Jeffrey Rogers,*,† ,1 Michael C. Mahaney,*,† Shelly M. Witte,* Shalini Nair,*Deborah Newman,* Steven Wedel,‡ Lawrence A. Rodriguez,‡ Karen S. Rice,*Susan H. Slifer,* Andrey Perelygin,* Michael Slifer,* Paula Palladino-Negro,*

Timothy Newman,* Karen Chambers,* Geoff Joslyn,‡ Pauline Parry,‡ and Phillip A. Morin‡

*Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas 78245; †Southwest Regional PrimateResearch Center, San Antonio, Texas 78245; and ‡Axys Pharmaceuticals, Inc., La Jolla, California 92037

Received February 11, 2000; accepted May 3, 2000

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A first-generation genetic linkage map of the baboon(Papio hamadryas) genome was developed for use inbiomedical and evolutionary genetics. Pedigreed ba-boons (n 5 694) were selected from the breeding col-ony maintained by the Southwest Foundation for Bio-medical Research. To facilitate comparison with thehuman genome, the baboon linkage map consists pri-marily of human microsatellite loci amplified usingpublished human PCR primers. Genotypes for 325 hu-man microsatellites and 6 novel baboon microsatel-lites were used in linkage analyses performed with theMultiMap expert system. The resulting sex-averagedmeiotic recombination map covers all 20 baboon auto-somes, with average spacing among loci of 7.2 cM.Direct comparison among homologous (orthologous)loci reveals that, for 7 human autosomes, locus order isconserved between humans and baboons. For theother 15 autosomes, one or more rearrangements dis-tinguish the two genomes. The total centimorgan dis-tances among homologous markers are 28.0% longer inthe human genome than in the baboon, suggestingthat rates of recombination may be higher in humans.This baboon linkage map is the first reported for anynonhuman primate species and creates opportunitiesfor mapping quantitative trait loci in baboons, as wellas for comparative evolutionary analyses of genomestructure. © 2000 Academic Press

INTRODUCTION

Nonhuman primates occupy a unique place in bio-medical and evolutionary genetics. The close evolution-ary relationship between humans and nonhuman pri-mates makes these species particularly valuable asanimal models for studies of human diseases, as well

1 To whom correspondence should be addressed at Department ofGenetics, Southwest Foundation for Biomedical Research, P.O. Box760549, San Antonio, TX 78227. Telephone: (210) 258-9532. Fax:

(210) 670-3344. E-mail: jrogers@darwin.sfbr.org.

237

as for analysis of normal physiology and metabolism(VandeBerg and Williams-Blangero, 1997; Rogers andHixson, 1997). Reconstructions of the evolutionary his-tory of both individual human genes and the overallorganization of the human genome depend on compar-isons with other species, including nonhuman pri-mates. Baboons (Papio hamadryas) are members of the

rimate superfamily Cercopithecoidea, or Old Worldonkeys, which includes most of the commonly studied

aboratory primates, including macaques of the genusacaca. Only the other members of the superfamilyominoidea, the anthropoid apes, are more closely re-

ated to humans than are these Old World monkeys.Over the past decade, gene mapping has become aajor component of genetic research. However, current

nowledge of genetic maps for nonhuman primates,specially genetic linkage maps, is very limitedGraves et al., 1996; Rogers and VandeBerg, 1998). Innly two primate species, chimpanzees (Pan troglo-ytes) and owl monkeys (Aotus sp.), have more than 70

loci been mapped to specific chromosomes, and neitherof these species has received any significant attentionwith regard to genetic linkage mapping. Previous stud-ies by us and by other investigators from the South-west Foundation for Biomedical Research (SFBR) ini-tiated genetic linkage analyses in Papio baboons.

hese initial studies established four pairs of linkedoci (van Oorschot and VandeBerg, 1991; VandeBerg etl., 1991; Kammerer et al., 1992), one multipoint link-ge group of 5 loci (Rogers et al., 1995) and one multi-oint group of 8 markers (Perelygin et al., 1996). Allther available information concerning gene mappingn baboons is limited to comparisons of chromosomeanding patterns (Cambefort et al., 1976; Finaz et al.,978; Dutrillaux et al., 1979), somatic cell hybrid map-

ping of individual loci (e.g., Theisson and Lalley, 1986,1987; and references in Graves et al., 1996), and chro-mosome painting analyses (Best et al., 1998). These

studies collectively demonstrate homology between in-

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238 ROGERS ET AL.

dividual human and baboon chromosomes and haveassigned 62 single-copy loci to syntenic groups. How-ever, these results consist essentially of chromosomalassignments only, with little information about theorder or locations of loci within individual chromo-somes (Graves et al., 1996; Rogers and VandeBerg,1998). Current genetic linkage data for rhesus mon-keys (Macaca mulatta), a close evolutionary relative ofbaboons and a widely used research species, consist ofone pairwise linkage between two blood group markers(Hackleman et al., 1993). We know of no publishedrecombinational mapping data for any other nonhu-man primate.

The development of genetic linkage maps for nonhu-man primates will provide new opportunities for sev-eral diverse lines of research. Maps that consist ofhighly informative polymorphisms will make it possi-ble to use large pedigrees of nonhuman primates tolocate currently unknown genes that influence in-traspecies variability in any number of phenotypes,including normal variation in anatomical, physiologi-cal, metabolic, or behavioral traits, or risk factors forhuman diseases. Because environmental variation canbe controlled, mapping genes that influence some com-plex phenotypes may be more feasible in nonhumanprimate pedigrees than in similar studies of humanfamilies. If the same genetic markers are mapped innonhuman primates and humans, it will be possible to

TAB

Summary of Loci Included in t

Baboonchromosome

Humanchromosome

Total lociin baboon

map

Loci placed inunique

relative order

KosambcM

baboon,all loci

1 1 34 28 1722 3 16 14 1153 7/21 25 23 1644 6 24 24 1115 4 15 15 1006 5 16 15 1137 14/15 19 17 1168 8 19 17 939 10 11 8 91

10 20/22 15 14 8911 12 14 14 8812 2q 17 15 8813 2p 10 8 7614 11 27 21 12615 9 17 15 7716 17 9 9 7717 13 10 10 6918 18 12 11 6319 19 12 7 6320 16 8 8 84

Total 331 293 1975

FIG. 1. Comparative maps of baboon and human autosomes.ultimap system. The marker positions shown are in most cases 10ith asterisks and are shown in locations that are at least 100 time

sing the Unix program “draw2maps” (Zuazaga and Plaetke, 1996) mo

compare genome structure across species directly(O’Brien, 1991; Comparative Genome Organization;First International Workshop, 1996) and, therefore, toapply readily the results of gene and quantitative traitlocus mapping studies in primates to subsequent anal-yses of the human genome. Direct comparisons of orderand distances among the same loci studied in differentspecies (i.e., among orthologous loci) will facilitatenovel analyses of primate genome evolution and therelationship between physical and recombinationalmap distances in orthologous chromosomal segments.

In an effort to improve the value of baboons (P.hamadryas) as an animal model for studies of humanbiomedical genetics, and to create new opportunitiesfor evolutionary comparisons of human genome struc-ture with that of closely related species, we have de-veloped a genetic linkage map of the baboon genome(Table 1). This map consists of 325 microsatellite locioriginally cloned from and characterized in the humangenome and 6 novel microsatellite loci cloned from thebaboon genome. These markers are distributed over all20 pairs of baboon autosomes (Fig. 1).

MATERIALS AND METHODS

The genetic data used to construct the baboon linkage map wereobtained from 694 pedigreed animals bred and maintained at theSFBR in San Antonio, Texas. The majority of the animals are olive

1

Baboon Genetic Linkage Map

Kosambi cM,baboon,

homologousloci

Kosambi cM,human, all

loci

Kosambi cM,human,

homologous loci

Order conservedin human vs

baboon

172 253 224 No115 153 153 No146 185 185 No111 134 134 No100 156 156 No113 171 171 Yes116 160 160 No93 138 138 No91 119 119 No89 115 115 No88 152 152 No88 83 83 Yes76 88 88 Yes

126 135 135 No77 136 117 No64 56 56 No69 66 66 No63 81 81 No63 70 63 Yes84 93 93 Yes

1944 2544 2489

ese diagrams represent comprehensive maps produced using theimes more likely than any alternative order. Seven loci are markedore likely than any alternative location. Map figures were created

LE

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Th00 ts m

dified by P. A. Morin, W. Fugikawa, and D. Scott.

239BABOON GENETIC LINKAGE MAP

240 ROGERS ET AL.

FIG. 1—Continued

241BABOON GENETIC LINKAGE MAP

FIG. 1—Continued

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242 ROGERS ET AL.

baboons (P. h. anubis) with a smaller proportion of yellow baboons(P. h. cynocephalus) and crosses between those two subspecies (seeJolly, 1993 for a discussion of baboon taxonomy and nomenclature).Given the pedigree data available, it is possible to construct a singleextended pedigree containing all 694 study baboons. However, forpurposes of the analyses reported here, we have divided that pedi-gree into 12 smaller, multigeneration families, which range in sizefrom 7 to 177, with a mean size of 83 animals. The 9 largest pedigreesare three generations deep, with two generations for the 3 smallest.This pedigree structure consists of 694 baboons with genotype dataand 297 additional animals without genotypes that serve to linkdifferent branches of the pedigrees. A total of 380 founder individu-als (i.e., individuals with no parents represented in the dataset), 497individuals in the first offspring generation, and 114 individuals inthe second offspring generation are used in the linkage analyses.There are 7161 relative pairs within the 12 pedigrees: 1222 parent–offspring pairs, 412 full sibling pairs, 262 grandparent–grandchildpairs, 84 avuncular pairs, 4327 half-sibling pairs, 400 half-avuncularpairs, 12 first-cousin pairs, 47 half-first-cousin pairs, and 4 half-sibhalf-avuncular pairs. Relative classes were tallied using routinesincorporated into the SOLAR genetic analysis package (Almasy andBlangero, 1998). All of the baboons are outbred progeny of unrelatedparents. Animal care and management were performed in accor-dance with accepted ethical guidelines, and all animal procedureswere approved by the Institutional Animal Care and Use Committeeof SFBR.

Published human PCR primers were used to amplify homologousmicrosatellite loci from baboon genomic DNA. To identify humanprimer pairs that would successfully amplify baboon polymorphisms,we screened more than 1300 primer pairs using panels of unrelatedbaboons. A range of PCR conditions was employed to increase theprobability of success for each locus. Initially, baboon genomic DNAwas amplified using a given human primer pair and annealing tem-peratures ranging from 46 to 62°C. Simultaneously, magnesiumchloride concentrations from 1.0 to 6.0 mM were tested. Early resultsindicated that the majority of primer pairs amplified well under anarrow range of conditions, especially when “touchdown” PCR pro-tocols were used (Don et al., 1991). Therefore, the screening protocolwas simplified to evaluate only two touchdown temperature proto-cols (one with the lowest annealing temperature set at 50°C and thesecond with 44°C as the lowest temperature) and three MgCl2 con-centrations (1.0, 1.5, and 2.0 mM). Additional details of the primerscreening procedure have been previously published (Rogers et al.,1995; Perelygin et al., 1996; Morin et al., 1998). We found that about25% of human primer pairs detect polymorphic microsatellites inbaboons. This success rate includes only those loci that amplifycleanly enough for reliable scoring of genotypes and that do not showevidence of null alleles. Through this screening process, we identified325 polymorphic markers in the SFBR baboons. In addition, 6 novelmicrosatellite loci were derived from a baboon genomic libraryscreened for AGAT tetranucleotide repeats (oligonucleotide primersavailable on request from P.A.M.).

Genotypes of the baboons were determined through standard gelelectrophoresis. The majority of genotypes were analyzed on ABI 373and ABI 377 Automated Sequencers using fluorescently labeledprimers and Perkin–Elmer Genescan and Genotyper software. Setsof 4 to 13 loci were run on each ABI gel. A small portion of the datasetwas generated by radiolabeling PCR primers, amplifying baboonDNA as described, running the products in standard sequencinggels, and scoring genotypes manually from autoradiographs (seeRogers et al., 1995). Baboon amplification products were not rou-inely sequenced to demonstrate homology to original human loci,or were the novel baboon tetranucleotide loci examined in theuman genome. Computerized management and preparation of ba-oon genotypes and pedigree data, including pedigree-based check-ng for violations of Mendelian inheritance, were accomplished by

eans of PEDSYS routines (Dyke, 1993).Published baboon–human karyotype and chromosome painting

omparisons (Graves et al., 1996; Best et al., 1998) provided strong apriori hypotheses concerning sets of human microsatellites that

would form linkage groups in baboons. Automated two-point linkage

analysis and construction of multipoint linkage maps for each ba-boon chromosome were facilitated by the expert system programMultimap (Matise et al., 1994), which implements routines of thecomputer program CRIMAP (Green, 1990). To begin, pairwise link-age analysis was performed to test hypotheses regarding syntenyamong baboon loci. Once linkage groups were established, Multimapwas used to construct framework maps in which the order of loci is1000 times more likely than any alternative order. The Multimapsystem constructs framework maps for each chromosome by select-ing the two loci with the highest levels of linkage information, basedon heterozygosity and pairwise distances. The system then adds loci,one at a time in decreasing order of informativeness, until no moreloci can be placed in unique positions relative to markers already inthe map. Only loci that can be placed in a unique position with aparticular user-selected level of statistical support are added. Whenthis is completed, locus order is checked and validated using theFLIPS function of CRI-MAP, which tests the relative likelihood ofother orders produced by inverting groups of n loci, where n $ 2. Thelocus order with the highest likelihood is retained. Finally, to pro-duce the comprehensive maps, the remaining loci that cannot begiven unique locations are added by assigning them to broaderlocations spanning two or more intervals in the previous, uniquelyordered map. Figure 1 presents the comprehensive maps producedby the Multimap system, in which the position of each of the 331 lociis, in general, 1000 times more likely than any alternative location.The only exceptions are 7 loci that are shown in positions that are atleast 100 times more likely than all alternatives. Apparent double-recombinants were inferred using the CHROMPIC program withinCRI-MAP and traced to specific individuals. Genotypes for thoseindividuals were deleted, and the pairwise and multipoint linkageanalyses (framework and comprehensive) were conducted again togenerate the maps in Fig. 1. Order among loci was once againevaluated using the FLIPS routine. Human genetic map positions forall loci were inferred from public genetic and physical maps usingLocation Database software (Morton et al., 1992) when data wereavailable. Nomenclature for baboon chromosomes follows Cambefortet al. (1976). Interested readers should see Best et al. (1998) and

oore et al. (1999) for further discussion of baboon chromosomenomenclature.

RESULTS

Of the 331 total markers reported here, 293 havebeen placed into the comprehensive maps with aunique location relative to other marker loci. The av-erage spacing between markers in this ordered map of293 microsatellites is 7.2 Kosambi cM. There are 11gaps larger than 20 cM, with the largest gap being 28.8cM. The remaining 38 loci could not be placed in uniquelocations, but are assigned to chromosomal regionsspanning two or more intervals within the map of 293ordered loci. Of the 293 loci placed in a unique order,286 are mapped with likelihood ratios of at least1000:1. Seven loci (1 from PHA18, 2 from PHA9, and 4from PHA10) are mapped with at least 100:1 statisticalsupport and are marked with asterisks in Fig. 1. Thehuman microsatellite loci used in this map exhibit ahigh degree of variability in the pedigreed baboons.Figure 2 presents the distribution of mean heterozy-gosity. Over the 331 loci, the mean heterozygosity is0.71 and the mean number of alleles per locus is 8.8.The following discussion of mapping results for eachbaboon chromosome is organized according to humanchromosome numbers to facilitate comparison with

previously published human gene mapping data.

1

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243BABOON GENETIC LINKAGE MAP

Table 2 presents a summary of the comparative map-ping results organized by chromosome. Overall, thereare seven cases in which the baboon–human homo-logues differ by multiple rearrangements. In eightcases, a human chromosome shows one simple inver-sion or translocation relative to its baboon equivalent.There are seven human autosomes for which the ba-boon homologues show the same order among loci.However, one of these autosomes (HSA2) exists as twoindependent chromosomes in baboons (PHA12 andPHA13). Human chromosome 2 is the result of anevolutionarily recent fusion event unique to the humanlineage (Ijdo et al., 1991). The 27 loci we investigatedfrom HSA2 are separated into two linkage groups inbaboons at an interval that is consistent with the pre-viously published comparative cytogenetic data (Ijdo etal., 1991; Graves et al., 1996).

FIG. 2. Average heterozygosity of 331 microsatellite polymor-hisms in baboons.

TAB

Comparisons of Locus Ord

Human chromosome Differences in locus

HSA1 Multiple complex rearrangementsHSA2p Order conservedHSA2q Order conservedHSA3 Multiple complex rearrangementsHSA4 One simple inversionHSA5 Order conservedHSA6 One simple inversionHSA7 Two inversions, one other rearrangemHSA8 One simple inversionHSA9 Multiple complex rearrangements

HSA10 One inversion, one other translocatioHSA11 Multiple complex rearrangementsHSA12 One translocationHSA13 One simple inversionHSA14 One simple inversion (fused to HSA1HSA15 Order conserved (fused to HSA14 in bHSA16 Order conservedHSA17 One simple inversion and one other tHSA18 One simple inversionHSA19 Order conservedHSA20 One simple inversion (fused to HSA2HSA21 Order conserved (fused to HSA7 in ba

HSA22 Order conserved (fused to HSA20 in bab

In three cases, baboon chromosomes consist of thefusion of two human chromosomes. The baboon ortho-logue of HSA7 is fused with the orthologue of HSA21 toform PHA3 (Best et al., 1998). We have mapped 17 locifrom HSA7, and the observed order among these loci isdifferent in the two species. At least three rearrange-ments are required to account for the differences, butthere is no apparent intermixing at the boundary be-tween HSA7 and HSA21. Papio chromosome 7 is ho-mologous to both HSA14 and HSA15 (Best et al., 1998;van Oorshot and VandeBerg, 1991). The fusion is asimple end-to-end fusion with no intermixing of locifrom the two human chromosomes. The homologues ofHSA20 and HSA22 are combined into a single baboonchromosome, PHA10. The order among the 7 loci fromHSA20 is different on PHA10, suggesting that a seg-ment containing 3 mapped loci has been inverted. Forthe 8 loci from HSA22, we see no differences in relativemap order between PHA10 and its human equivalent.Also, as in the other cases, there is no mixing of locifrom the two human chromosomes at the boundary.

DISCUSSION

A number of studies have shown that microsatellitepolymorphisms originally identified in humans can beinformative in genetic analyses of nonhuman primates,using the published human PCR primers (Morin et al.,1994, 1997, 1998; Rogers et al., 1995; Altmann et al.,996; Coote and Bruford, 1996; St. George et al., 1998;

Witte and Rogers, 1999). We have used this approach,and the large multigeneration pedigrees of baboonsmaintained at the Southwest Foundation, to generate

2

in Humans and Baboons

er in baboonsMinimum number of loci

involved in rearrangement

6007507

t (fused to HSA21 in baboons) 8263

1612

baboons) 2oons) 0

0slocation 3

20

baboons) 4ons) 0

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244 ROGERS ET AL.

a first-generation genetic linkage map for this species.The mapping results confirm and extend many of thepreviously published conclusions regarding compara-tive chromosome structure in the two species. As pre-dicted by previous studies of chromosome banding pat-terns (Cambefort et al., 1976; Finaz et al., 1978;Dutrillaux et al., 1979) and chromosome painting (Bestet al., 1998), several chromosomes are largely con-served, while others have undergone substantial rear-rangement. For example, the baboon orthologues ofhuman chromosomes 5, 16, and 19 exhibit the sameorder among markers as is found in the human genome(Table 2). Other chromosomes show conserved orderinternally but have undergone fission or fusion (HSA2,HSA15, HSA21, and HSA22). On the other hand, themaps we obtained for the baboon orthologues of sevenhuman chromosomes suggest that multiple inversionsand/or translocations have occurred in one or both evo-lutionary lineages since the ancestors of humans di-verged from the ancestors of baboons about 25 millionyears ago.

Given the established homologies between baboonand human chromosomes, it was possible to predictwhich sets of human microsatellite polymorphismsshould fall into specific syntenic groups in the baboongenome. However, it was also anticipated that someloci would not fall into the predicted groups, whichwould indicate that interchromosomal translocationshad occurred in the evolutionary past that were notdetected by previous analyses. On the contrary, wefound no examples of human microsatellite markersthat exhibit definitive linkage to an anomalous syn-tenic group in baboons. Other than the fissions andfusions predicted by chromosome painting studies, wefind no interchromosomal rearrangements, only intra-chromosomal changes. The order among loci withingroups does, however, exhibit several unanticipatedpatterns. In several cases, these results suggest thepresence of chromosomal differences between baboonsand humans, the details of which were not previouslyappreciated, such as the complex changes involvingHSA9/PHA15 and HSA11/PHA14.

The comprehensive baboon linkage map of 293 or-dered loci has an average spacing between markers ofless than 8 cM. As a result, these study animals andtheir microsatellite genotypes are useful for genomescanning analyses designed to locate currently uniden-tified genes that influence various types of phenotypicvariation. Baboons are used as animal models in stud-ies of cardiovascular disease risk factors such as cho-lesterol and lipoprotein metabolism, bone biology, en-docrinology, immunology and infectious diseaseresearch, aging, obesity, and various other risk factorsfor human disease. In addition, these pedigrees will beuseful for studies of normal variation in traits such asgrowth, anatomical features, neurobiology, and behav-ior.

The total intermarker distances for all ordered loci

sum to 1975 cM. If we use a conservative estimate that c

genetic coverage by these loci extends out from theterminal markers toward each telomere a distance of10 cM, then the total genetic length covered by thisfirst-generation map is 1975 cM 1 (10 cM 3 20 auto-omes 3 2 ends) 5 2375 cM.Nadeau and Taylor (1984) developed a method for

sing comparative linkage mapping data to estimatehe average lengths of chromosomal segments that areonserved between any two genomes. Using their ap-roach, we find that the average segment length con-erved between baboons and humans is 36.7 cM. Thisalculation uses the Kosambi centimorgan distanceseported for the human genome as the basis of thestimate, rather than distances estimated for baboons.he inferred total number of chromosomal disruptionsistinguishing baboons and humans is 73.4. The exist-ng baboon data identify 52 segments (defined by ateast two loci) that are conserved in humans, suggest-ng that as additional markers are added to the baboon

ap, additional rearrangements will be identified. Weote that, like humans and baboons, the ancestors ofhe laboratory rat and laboratory mouse have beeneparate evolutionary lineages for about 25 millionears. The number of segments conserved between hu-an and baboon is roughly equivalent to the number

onserved for rats and mice (Levan et al., 1998). How-ver, we should take these estimates of average con-erved segment length and total number of disruptionss preliminary, because there are several small inver-ions or translocations noted in the baboon genomeelative to the published human map order that mayeserve additional analysis and study. For example,mall inversions of 3 cM or less occur on PHA8 andHA15. These are supported by likelihood ratios of at

east 1000:1 and are considered to be reliable. How-ver, experience from other genomes indicates thatrder among tightly linked loci can be difficult to es-ablish definitively, and additional baboon data mayead to revisions of locus order in some cases. Thisould tend to increase the average conserved segment

ize slightly and reduce the inferred total number ofisruptions.The most significant unexpected finding in this study

s that the recombinational (Kosambi) distances be-ween pairs of homologous loci are, on average, shortern the baboon genome than is reported for humans. Forxample, the total length of our map of baboon chro-osome 6 is substantially less than the distance cov-

red by the same loci on HSA5 (113 cM versus 171 cMor the loci we analyzed). Similarly, HSA12 is 1.73imes as long as its homologue, PHA11 (152 cM versus8 cM for the loci included in this study). This patternolds for all but four linkage groups (PHA12, PHA16,HA17, and PHA19) in which the baboon length isqual to or slightly greater than the equivalent humanength. Table 1 presents the total centimorgan lengthf this first-generation baboon map and the total re-

ombinational length covered by the homologous loci in

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245BABOON GENETIC LINKAGE MAP

humans. Overall, the human centimorgan distance is28.0% longer than the equivalent map in baboons.

There are several possible explanations for this ob-served difference in apparent rates of recombination. Asimple but unpersuasive explanation is that the num-ber of genotyping errors in the baboon dataset is lowerthan in the data used to calculate recombination ratesin humans. This seems unlikely to be a major factorunderlying this observation. Second, the density ofmarkers differs in the two maps, with the human mapcontaining many more loci than this initial baboonlinkage map. Placing additional loci within internalintervals of this baboon map will probably increase theapparent lengths of some intervals, thus reducing thedifference between human and baboon recombina-tional distances. However, it seems unlikely to us thatthis could account for all of the difference we observed(e.g., HSA4 vs PHA5, HSA5 vs PHA6, and HSA12 vsPHA11). Additional studies using data that have beengenerated and checked using identical methods in bothspecies may be warranted to test the hypothesis thatrates of recombination (centimorgans per megabase)are higher in humans than in baboons.

We note that the autosomal genomes of mice, cattle,sheep, and pigs are all about 3000 cM in length or less,while the human autosomal genome is about 3500 cMlong (Table 3). Like these domestic mammals, baboonsexhibit a genetic linkage map that seems to be shorteroverall than the human map. This variation in genomelength occurs despite the fact that the total cellularDNA content of humans is approximately equal to thatof other mammals (Sober, 1968).

The baboon data suggest that the differences notedabove between humans and domestic mammals are notdue to differences between primates and other nonpri-mate mammals. Rather, the data indicate that thehuman genome may be unusual among mammals inhaving a relatively high rate of recombination. Thiswould have implications for various aspects of humancytogenetics, as well as for the long-term evolutionary

TABLE 3

Approximate Autosomal Lengthsof Mammalian Genomes

Species Autosomal length (cM) Reference

Mice 1350 Dietrich et al. (1994)Cattle 2850 Kappes et al. (1997)Sheep 3060 De Gotari et al. (1998)Pigs 2200 Rohrer et al. (1996)Cats 2900a Menotti-Raymond et al. (1999)Humans 3500 Gyapay et al. (1994)

a The size of the feline genome was observed to be about 2900 cM,ut with extensions for singleton loci and telomeres, it is estimatedo total 3300 cM, nearest to the size of the human genome, butevertheless smaller.

dynamics of the human genome. For example, this

observation predicts a reduction relative to other mam-mals in the significance of “genetic hitchhiking” when asingle human locus is under positive directional selection.It also predicts a more rapid decay of linkage disequilib-rium along a human chromosome than along the samephysical length of chromosome in other mammals.

This series of 331 microsatellite loci will also beuseful in genetic analyses of other nonhuman pri-mates, especially macaques (e.g., rhesus macaques, M.mulatta) and other papionin monkeys. In a prelimi-nary study of 21 microsatellites demonstrated here tobe polymorphic in baboons, 19 were also polymorphicin pigtail macaques, Macaca nemestrina (Nair et al., in

ress). A recent analysis of metaphase banding andhromosome painting demonstrates that the karyotypef rhesus macaques (M. mulatta) is essentially identi-al to that of baboons (Moore et al., 1999). For a num-er of years, summaries of primate gene mapping dataave used different nomenclatures for the karyotypesf rhesus macaques and baboons (e.g., Graves et al.,996), which has indicated real chromosome differ-nces between these closely related species. However,he reported differences are due to differing nomencla-ure rather than true karyotypic differences (Moore etl., 1999). Therefore, the linkage map reported here foraboons can serve as a basis for developing equivalentaps for rhesus macaques, as well as other closely

elated primate species. The polymorphic loci analyzedere will also be valuable for studies of the geneticariability and population genetic structure of naturalopulations of baboons and macaques (Altmann et al.,996). Five of the loci used for linkage analyses haveeen used in a comparison of allele frequencies be-ween two natural populations of baboons (St. Georget al., 1998).In summary, microsatellite loci originally cloned

rom and mapped in the human genome have beensed to develop a first-generation genetic linkage mapor a species of Old World monkey, P. hamadryas. Thispproach should also be useful for genomic analysis ofther nonhuman primates. Development of completeinkage maps for various primates will create new re-earch opportunities in biomedical and evolutionaryenetics, including genome scanning for single-locusraits, quantitative trait locus mapping, and compara-ive genomics. Nonhuman primates already play a crit-cal role in biomedical and evolutionary research. Ex-anding this role to include modern genomic andenetic linkage analyses will significantly increase theange of studies possible, as well as provide new in-ights into the human genome itself.

ACKNOWLEDGMENTS

This work was supported by Boehringer Mannheim Inc., AxysPharmaceuticals, Inc., and NIH Grants HL28972 and RR08781. Wethank J. L. VandeBerg, J. E. Hixson, C. M. Kammerer, B. Dyke, K. D.

Carey, and J. Lichter for assistance and advice.

246 ROGERS ET AL.

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