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ILAR Journal V39(2/3) 1998
Comparative Gene Mapping
Jeffrey Rogers and John L. VandeBerg
| Jeffrey Rogers, Ph.D., is Associate Scientist in the Department of Genetics, and John L. VandeBerg, Ph.D., is Scientific Director, at Southwest Foundation for Biomedical Research, San Antonio, Texas. |
INTRODUCTION
Comparative gene mapping of mammals has progressed rapidly since the late 1980s. Much is known about the comparative structure and organization of the human, murine, feline, and bovine genomes, among others. A substantial amount of information has also been generated concerning the gene maps of primates. Nonhuman primates are, of course, the closest evolutionary relatives of humans; and as a result, an understanding of the genetics of these species is critical for addressing questions in both biomedical research and evolutionary biology. However, the available information concerning the comparative maps of nonhuman primates is narrowly focused, in the sense that only a few species have received significant attention. The data are also comparatively thin. Even in the most extensively analyzed species, relatively few functional genes have been assigned to specific chromosomal locations. In addition, the data are quite inconsistent, with different genes mapped in different primate species, making genome-wide comparisons difficult. Nevertheless, a significant amount of information is available, and the rate of progress is likely to increase.
REASONS FOR MAPPING THESE SPECIES
There are 4 basic reasons for constructing gene maps of nonhuman primates. The first is the importance of these species as animal models in biomedical research. Our understanding of many human diseases has been improved by the use of primates as model organisms (VandeBerg and Williams-Blangero 1996, 1997). These species are especially important in studies of cardiovascular disease (Hixson and others 1989: Rainwater and others 1992), bone diseases (Jerome and others 1994, 1997; Mahaney and others 1997), and other complex disorders influenced by both genetic and environmental factors (Blangero and others 1990). The development and use of detailed gene maps for common laboratory primates will provide opportunities for animal studies that identify new candidate genes possibly affecting individual variation among people in their risk of developing a particular disease (Palmour and others 1997; Rogers and Hixson 1997; VandeBerg and Williams-Blangero 1997). The mapping of genes that affect risk factors for disease can also identify genes that may be targets for therapeutic intervention, even if the specific gene does not influence a substantial proportion of variation in risk within human populations.
The second reason for constructing nonhuman primate gene maps is closely related to the first. In addition to facilitating the identification of genes that impact on specific diseases, linkage mapping studies provide opportunities to localize and identify functional genes that influence normal anatomical, physiological, or behavioral variation. For example, a study by Williams-Blangero and others (1994) demonstrated that specific measurements of clinical serum chemistries are heritable in chimpanzees. If a linkage map of the chimpanzee genome were available, it would be straightforward to design a study to map the specific loci that affect these traits (although the success of such a study is not guaranteed). Similarly, blood pressure is a heritable trait in baboons and vervet monkeys (Palmour and Ervin 1990). Traits that have no direct connection to disease, such as adult body weight (Jaquish and others 1997), age at first reproduction (Williams-Blangero and Blangero 1995), and relative organ weights (Mahaney and others 1993), are heritable in primates. Efforts to map these and other genes of evolutionary or other biological interest could also be undertaken.
Third, information regarding primate gene maps can also assist researchers in recognizing homology between particular genes of nonhuman primates and related genes in humans and/or mice. Multigene families are common in the mammalian genome; it may be that most mammalian genes are members of gene families. Identifying the homologue of a specific human or mouse gene in a nonhuman primate is not always easy, and specific criteria have been recommended (Andersson and others 1996). In most research circumstances, it is critical to establish that a particular locus is the orthologue, and not a paralogue, of a given human or mouse locus. Comparative chromosomal location is valuable information when such questions arise (Andersson and others 1996).
The fourth reason to map the genomes of nonhuman primates is to investigate the evolution of genes, chromosomes, and complete genomes. Comparative gene mapping allows the direct analysis of changes through time in gene complement and chromosome organization within various primate evolutionary lineages. Comparative mapping also provides background data that facilitates inferences concerning the evolutionary history of noncoding sequences, such as telomeric or interspersed repeats. When more detailed gene maps are available for primates, it will be possible to perform more detailed analyses of the history of genomic rearrangements that produced the unique human genome. In addition, the data will lead to a better understanding of the mechanisms that have operated during mammalian and human genome evolution. Only by developing detailed maps of our closest relatives will it be possible to distinguish features of genome organization truly unique to humans from features recent in evolutionary terms but shared with other living primates (see for example McConkey 1997 and Nickerson and Nelson 1998).
CURRENT STATUS OF THE MAPS
The potential value of comparative gene maps of nonhuman primates is widely recognized (Andersson and others 1996; McConkey and Goodman 1997; Palmour and others 1997; Rogers and Hixson 1997; VandeBerg and Williams-Blangero 1996). However, relatively few loci and species have been thoroughly analyzed. One major reason for the incomplete and inconsistent nature of primate gene mapping data is that the research has been done by a variety of investigators with different research goals and perspectives. For example, a substantial amount of fluorescence in situ hybridization (FISH1) data is available (see below). Given the consensus that a basic list of conserved functional genes (anchor, or type 1, loci) should be mapped in many species (Lyons and others 1997; O'Brien and Graves 1991; O'Brien and others 1993), the field would be advanced most rapidly if FISH methods were used to map the recommended anchor loci (O'Brien and others 1993). However, of the 321 proposed anchor loci, only 80 have been localized in any nonhuman primate, and 36 of those have been mapped only in the platyrrhine genus Aotus. Yet many sequences not recognized as basic to comparative mapping have been localized in I or more primates. With a few notable exceptions, individual researchers have a strong interest in generating information about specific genes or species but little commitment to a systematic effort in comparative gene mapping. As a result, data are disjointed, incomplete, and not optimal for broad comparisons with nonprimate mammals or humans. However, one example of a systematic effort to generate valuable mapping data is the extensive work on the owl monkey (genus Aotus) by Dr. Nancy Ma (Ma and others 1991).
Primate gene mapping initiatives in most species have also been handicapped by the lack of necessary resources. Genetic linkage mapping has been limited because few multigeneration pedigrees suitable for these analyses are available. Physical mapping has been restricted by the lack of somatic cell hybrid or radiation hybrid panels for most species.
Graves and others (1995) reviewed the status of primate gene maps, finding that 189 genes or single-copy DNA segments had been mapped in 12 different genera. The number of loci per genus varied from 26 to 101, with the largest numbers of loci mapped in Aotus (n=101 ) and chimpanzees, genus Pan (n=88). All of these mapped genes or DNA segments have also been mapped in the human genome.
Progress has been made in several areas since the 1995 review by Graves and others. In Table 1 are listed the data published since that review. The majority of the new data has been produced through FISH mapping. At the time of this writing, 208 genes or single-copy DNA segments have been mapped in 16 genera, with 1 to 105 loci mapped per genus (Table 1). Most of the recent research effort has focused on mapping functional genes in the great apes (chimpanzee, gorilla, and orangutan). As a result, 17 new loci have been mapped in chimpanzees, bringing the total number of mapped loci (not including telomeric and other tandemly repeated sequences) to 105. Fifteen new loci have been mapped in gorillas, for a total of 69; and 14 new loci were added to the map for orangutans, for a total of 66.
Another area of rapid progress is the linkage mapping of the baboon (Papio hamadryas) genome. The first linkage analyses in baboons utilized protein polymorphisms (van Oorschot and VandeBerg 1991; VandeBerg and others 1991 ). More recently, a collaboration between the Southwest Foundation for Biomedical Research (San Antonio, Texas) and Axys Pharmaceuticals, Inc. (La Jolla, California) has generated a linkage map of the baboon genome that employs primarily microsatellite loci originally mapped in humans (Rogers and Hixson 1997). Published polymerase chain reaction (PCR1) primers for human microsatellite loci were screened to determine which would amplify polymorphisms in baboons. Results indicate that about half of human microsatellite primer pairs amplify baboon genomic DNA, and roughly one quarter of all primer pairs tested reveal useful baboon polymorphisms (Morin and others 1998; Rogers and others 1995). Analysis of genotypes in 694 pedigreed baboons has allowed construction of multipoint linkage maps for all the baboon autosomes and the X chromosome (unpublished data). A total of 330 loci are now incorporated into the map, and the average spacing between loci is less than 10 cM.
In Figure 1, the first multipoint linkage group in nonhuman primates (from Rogers and others 1995) is illustrated, revealing the sex-specific recombination fractions among 5 microsatellite loci located on chromosome I of humans and chromosome 1 of baboons. In Figure 2 is an elaboration of a baboon linkage map first published by Perelygin and others (1996). The baboon homologue of human chromosome 18 reveals the same order among microsatellite loci, except for an inversion that includes the centromere and most or all of the short arm (see also McConkey 1997). Karyotype comparisons with other species show that the inversion occurred in the evolutionary lineage leading to humans after the divergence from other living hominoids (Yunis and Prakash 1982).
APPROACHES USED TO DEVELOP THE MAPS
Until the early 1990s, the most widely used method for assigning primate loci to specific chromosomes (or regions within chromosomes) was the analysis of somatic cell hybrid panels. Panels of hybrid cell lines are created by fusing cells from a given primate species with rodent cells. During growth in culture, these cell lines lose individual primate chromosomes. Eventually each member of a panel of cell lines becomes stabilized with a random combination of chromosomes from the primate species under study. The panel members are then typed for presence or absence of particular genes or gene products, and chromosomal location is inferred from the concordances and discordances with the presence of each primate chromosome. This approach has been used to map genes to particular chromosomes in numerous primate species (for example, Ma and Gerhard 1988; Ma and Kurnit 1984; Thiessen and Lalley 1987).
Since the early 1990s, FISH has become the most commonly employed approach. Using clones of large human chromosomal segments (often yeast or bacterial artificial chromosome clones), investigators have used FISH methods to map single-copy DNA segments to particular regions within primate chromosomes. The FISH method is more informative than somatic cell hybrid mapping because it allows the sublocalization of a gene or other DNA segment to a smaller region within a chromosome. Unlike genetic linkage analysis (discussed below), F1SH mapping does not require polymorphism at the locus being mapped. In nonhuman primates, few polymorphisms have been identified within functional genes, and FISH is therefore applicable to a larger number of genes than is linkage analysis.
Genetic linkage mapping (also called recombinational or meiotic mapping) has been used in a small number of studies. Genetic linkage has been critical to the study of genome organization in humans, but few studies of linkage have been performed in nonhuman primates. Mapping by genetic linkage requires that the gene or DNA segment to be mapped exhibit intraspecific polymorphism. It also requires the analysis of genetic variability among several hundred pedigreed animals. Whenever a DNA or protein polymorphism is known in a given species, genetic linkage mapping can in principle be used to search for genetic linkage to previously mapped loci. If the goal of a researcher is simply to map a single locus in a nonhuman primate, this approach has major disadvantages in comparison to the methods above, since linkage mapping requires data from large numbers of pedigreed individuals as well as an initial framework linkage map.
Nevertheless, if the necessary pedigree material and framework map are available, genetic linkage mapping offers many research opportunities not provided by FISH or somatic cell hybrid analyses. In particular, the order among tightly linked loci can be readily established. Furthermore, genetic linkage maps make it possible to locate new, currently unknown genes that influence phenotypic traits (Palmour and others 1997; Rogers and Hixson 1997). The large number of important studies that have used genetic linkage methods to map disease genes in humans and mice illustrates the potential power of this approach. Linkage mapping in common laboratory primates such as macaques, baboons, vervets, and chimpanzees will open many new avenues for biomedical and comparative evolutionary research that are not practical at this time. Genetic variation related to specific human diseases, or genes that influence normal variation in anatomy or physiology, can be investigated in this way. Development of primate linkage maps will create opportunities for genetic epidemiology to be extended to our closest relatives, including comparisons of the genetic architecture of complex traits across closely related species.
In practical terms, substantial effort is required to initiate a linkage mapping study in primates. Complete pedigree information must be available for hundreds of individuals, and multiple genetic polymorphisms must be genotyped. In our experience, genotype data for 250 offspring of known parentage is sufficient to generate initial multipoint linkage maps. Human microsatellite polymorphisms can be used in Old World monkeys, wherein about one fourth of such markers are polymorphic. A larger proportion of human micro-satellites will be useful in apes, and a smaller proportion in New World primates or prosimians (Witte and Rogers 1998).
Various methods are commonly used to identify and assay DNA sequence polymorphisms in type I anchor loci and other functional genes. Given the DNA sequence similarity between humans and nonhuman primates, particularly in coding regions of genes, it is often possible to use human sequence data to design PCR primers and amplify short segments of genes in nonhuman samples. When primers are designed to bind to adjacent exons and to amplify the intervening intron, a substantial amount of noncoding DNA can be assayed while using conserved primer sequences. The PCR products can then be surveyed for restriction site polymorphisms or for variation detectable by single-strand conformation polymorphisms. Microsatellite polymorphisms are more informative for genetic linkage due to their higher heterozygosity; however, as mentioned above, it will be important to incorporate appropriate type I loci into primate maps as well.
Finally, it is important to mention radiation hybrid mapping (McCarthy 1996; Walter and others 1994). This approach has not yet been extensively used for primates, although it has been exploited very effectively for studies of the human genome, and those of several other taxa. To construct a radiation hybrid panel for human gene mapping, human fibroblasts are irradiated at a dose lethal to the cells, which induces frequent breaks in all the chromosomes. These fibroblasts are fused with a series of rodent cell lines and grown in culture. Fragments of human chromosomes are retained in the various cell lines, either as independent chromosome elements or as pieces integrated into the recipient rodent chromosomes. To map specific genes or DNA segments, each member of the panel of radiation hybrid cell lines is scored for the presence or absence of the DNA segment of interest. Two loci that occur close together on a single human chromosome will show greater concordance across the panel than is expected by chance. Computer programs are available to perform rapid analysis of the presence/ absence data and to assist in combining many loci into a multipoint radiation hybrid map (Boehnke and others 1991 ). A radiation hybrid panel is available for baboons from Research Genetics, Inc. (Huntsville, Alabama) and can be used to map both functional genes and noncoding DNA segments.
Like somatic cell hybrids and FISH, radiation hybrid mapping is not dependent on known polymorphisms within the DNA segment to be mapped. If a sufficiently detailed framework map is available, new loci can be mapped into the established multipoint locus order very quickly. This method may be valuable in the future for baboons and for any other primate species for which radiation hybrid panels are produced. However, a substantial effort will be required to generate a high-density framework map before the mapping of any given new segment can be accomplished easily.
SCIENTIFIC CONTRIBUTIONS OF THE MAPS
As of 1998, the major contribution of comparative primate gene maps is an improved understanding of the evolutionary history of primate genome organization. Direct comparisons of the human genome with those of other primates have provided insight into the origin of human chromosome structure. The general outline of the phylogeny of primates is reasonably well understood, and this background allows inferences concerning the broader history of genomic change. For example, karyotype comparisons of humans with other hominoids have shown that several chromosome rearrangements (such as an inversion on chromosome 18 and a fusion that produced human chromosome 2) are unique to our species. Other changes are shared with chimpanzees and gorillas, but not with other primates. Analyses have also shown that some clades of primates (such as baboons and macaques) have experienced a slower rate of chromosome evolution than other clades (such as gibbons). These conclusions are based on karyotype studies, chromosome painting, and gene mapping. However, as more detailed gene maps are produced, more detailed analyses that depend primarily on comparative gene maps will be possible.
ANTICIPATED FUTURE CONTRIBUTIONS OF THE MAPS
Further refinement of the gene maps of nonhuman primates will contribute to biomedical and evolutionary research in several ways. Continued progress in FISH mapping and eventual use of radiation hybrid mapping will lead to more detailed descriptions of genomic differences among primate species, including humans. This information will certainly lead to new insights into genome evolution (see for example Kingsley and others 1997). Linkage maps will contribute to many areas of research by facilitating the localization and identification of genes that influence risk factors for disease, as well as genes that affect normal variation. Rodent and other nonprimate models can often provide important insights into human physiology, but many complexities of human physiological processes and pathways are shared only with other primate species. Several aspects of the central nervous system are prime examples. As a result, genetic linkage mapping in primates will provide unique opportunities to identify and investigate genes that influence primate central nervous system function, with direct and unique implications for our understanding of human neurobiology.
Construction of linkage maps that include type I, type II or both types of loci (O'Brien and Graves 1991) will require large pedigrees of nonhuman primates. Multigeneration pedigrees of chimpanzees, baboons, macaques, vervet monkeys, and other species are available for only a small number of research colonies. Additional primate research colonies could generate multigeneration pedigrees suitable for linkage analyses if the breeding groups were maintained as single-male groups or if genetic markers were used to identify true sires within multimale breeding units. Management of such colonies to create appropriate 2- and 3-generation fully documented pedigrees would greatly improve research opportunities for primate gene mapping in the future, since methods for identifying and rapidly genotyping new DNA polymorphisms in primates are constantly improving. Advances such as DNA chip technologies may have an impact on both the analysis of polymorphisms and the rapid production of large-scale sequence data for nonhuman primates (Hacia and others 1998).
A number of investigators have recently suggested that the time is right for expanding efforts in physical mapping and sequence comparisons across primate species. Much of this discussion has focused on direct comparisons of genes and gene function among humans, chimpanzees, and gorillas (Gibbons 1998; McConkey and Goodman 1997). We certainly agree that remarkable new insights will be gained by increased research effort in this area and that new concepts and methods developed through the Human Genome Project have immediate application to comparative primate genetics. Given that Old World monkeys comprise the group of primates most commonly used in biomedical research and that they are more appropriate for large-scale, intensive studies of comparative gene expression and function, it will be important to include analyses of these species as well.
USES OF THE MAPS AND ACCESSIBLITY
The most comprehensive sources of primate gene mapping data are the reports published by the Committee on Comparative Gene Mapping, part of the Human Gene Mapping consortium (Graves and others 1995). Primate mapping data are also available on-line at the Mouse Genome Database (http://www.informatics.jax.org). This database is maintained by the Jackson Laboratory (Bangor, Maine) and has comparative mapping information for a wide range of primate and other taxa, in addition to its focus on the mouse genome. A search of this database generated comparative mapping data for 64 loci in chimpanzees, 34 in gorillas, and 29 in baboons. Several other primate species are also represented.
CONCLUSION
We summarize the state of nonhuman primate gene mapping with 3 conclusions. First, a significant amount of comparative mapping data is available for a few primate species, and a lesser amount for several more. Most of these data were derived from somatic cell hybrid or FISH analyses. Our second conclusion is that the total extent of the data, and especially the consistency of the data across taxa, are limited. Given the importance of primates in biomedical research and evolutionary biology, we argue that detailed and systematic study of primate genomes should be undertaken. The results will have a significant impact on many areas of biomedical research, and other biological sciences. Our third conclusion is that recent advances in genomic methods, especially improvements in FISH mapping and the initiation of primate genetic linkage mapping, make it likely that progress in nonhuman primate gene mapping will accelerate. Given the examples provided by other mammalian taxa and the potential rewards in evolutionary and biomedical insights, we expect this to be an active and valuable field of research in the coming years.
1Abbreviations used in this paper: FISH, fluorescence in situ hybridization; PCR, polymerase chain reaction.
ACKNOWLEDGMENTS
We thank Dr. Michael Mahaney and Debbie Newman, who performed much of the linkage analysis in the baboons of Southwest Foundation and contributed to the results presented in Figure 2.
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TABLE 1 Loci mapped in nonhuman primates
| Locus symbol | Location | Pan | Gorilla | Pongo | Other | Reference |
| p58 | 1p36 | 1p36 | 1p36 | 1p36 | Samonte and others 1996b | |
| V kappa immunoglobulin | 1q31-q32 | 1q | 1q | 1q | Arnold and others 1995 | |
| V kappa immunoglobulin | 2p11-p12 | 12q | 12q | 12q | Arnold and others 1995 | |
| YCN | 2p24.3 | 12q24 | 12q24 | 12q24 | Ramesh and others 1996 | |
| V kappa immunoglobulin | 2q | 12p | 12q | 12q | Arnold and others 1995 | |
| CSN2 | 4q13-q21 | 3p13-p12 | McConkey and others 1996 | |||
| WHS | 4p16.3 | 3p | 3p | 3p | Tarzami and others 1996 | |
| ESR | 6q25.1 | 5q25 | 5q25 | 5q25 | Samonte and others 1997 | |
| MYC | 8q24.12-q24.13 | 7q24 | 7q16 | 7q24 | Samonte and others 1996b | |
| IGHEP2 | op24.1-p24.s | Tanabe and others 1996 | ||||
| ZNF75B | 12q13 | 10q13 | Villa and others 1996 | |||
| TCF1 | 12q24 | Ateles paniscus 2p | Moreira and others 1997 | |||
| RB1 | 13q14 | Pithecia, M. sylvanus C. aethiops | Tihy and others 1996 | |||
| RB1 | 13q14 | 14q14 | 14q14 | 14q14 | Verma and others 1996 | |
| TGM1 | 14q11 | A. paniscus 2q | Moreira and others 1997 | |||
| CALM1 | 14q32 | A. paniscus 2q | Moreira and others 1997 | |||
| CKB | 14q32 | A. paniscus 11 or 12 | Moreira and others 1997 | |||
| IGHE | 14q32.33 | Tanabe and others 1995 | ||||
| KGF | 15q13-q22 | 16q14-q21 | 15q15-q21 | 16q15-q21 | Zimonjic and others 1997 | |
| THBS1 | 15q15 | A. paniscus 2q | Moreira and others 1997 | |||
| FES | 15q26 | A. paniscus 3 | Moreira and others 1997 | |||
| B2M | 15q | A. paniscus 2q | Moreira and others 1997 | |||
| RNU2 | 17q21 | 19p | 4p | 19q | Papio 17q | Pavelitz and others 1995 |
| ZNF91 | 19p12 | anthropoids | Bellefroid and others 1995 | |||
| V kappa immunoglobulin | 22q11 | 23q | 23q | 23q | Arnold and others 1995 | |
| M-BCR | 22q11 | 23q11 | 23q11 | 23q11 | Samonte and others 1996a | |
| KAL | Xp22.32 | Xp22 | Xp22 | Xp22 | Samonte and others 1997 | |
| ZNF75 | Xq26 | Xq26 | Villa and others 1996 | |||
| STS | Xp22.32 | Xp | Nasalis Xp Callicebus moloch Xp Lemur 8 Eulemur autosomal | Toder and others 1995 | ||
| ANT3 | Xp22.32 Yp11.3 | Pan paniscus Xp Nasalis Xp, Yp Callicebus moloch Xp, Yp Lemur 8 Eulemur autosomal | Toder and others 1995 | |||
| 5S rRNA | M. fascicularis | Lomholt and others 1996 | ||||
| NF1 related | 11 sites | M. sylvanus M. fuscata Hylobates concolor | Regnier and others 1997 | |||
| KGF-like | 2q, 9p, 9q, 18p, 18q, 21q | 11q, 13p, 17q, 22q | 11p, 16q, 22q | 22q | Hylobates 15q | Zimonjic and others 1997 |
FIGURE 1 First multipoint linkage group published for a nonhuman primate. This map of a small region of baboon chromosome 1 is from Rogers and others (1995).
FIGURE 2 Comparative maps of 11 microsatellite loci. Comparison of locus order in humans and baboons reveals an inversion that was first recognized in humans through karyotype studies. This map of baboon chromosome 18 is based on linkage analyses and is expanded from the work of Perelygin and others (1996).
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