Abstract
Geneticists have repeatedly turned to population isolates for mapping and cloning Mendelian disease genes. Population isolates possess many advantages in this regard. Foremost among these is the tendency for affected individuals to share ancestral haplotypes derived from a handful of founders. These haplotype signatures have guided scientists in the fine mapping of scores of rare disease genes. The past successes with Mendelian disorders using population isolates have prompted unprecedented interest among medical researchers in both the public and private sectors. Despite the obvious genetic and environmental complications, geneticists have targeted several population isolates for mapping genes for complex diseases.
Key Points
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Genetic isolates have proved very valuable for mapping and positionally cloning rare recessive diseases. Recently, however, the use of isolates in genetic studies of complex traits has been challenged.
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Isolates differ not only in their demographic histories and characteristic genetic diseases but also in their health-care standards and availability of geneological and patient records. Researchers should be mindful of these differences in designing genetic studies.
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Young population isolates are best for coarse haplotype mapping, and older isolates and outbred populations are best for fine haplotype mapping and final gene identification.
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Isolated populations have the advantage of reduced environmental (and diagnostic) heterogeneity, as well as of reduced genetic heterogeneity.
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Most successes in mapping complex trait loci in isolates have used genome-wide linkage analyses of large families with multiple affected individuals.
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Rare Mendelian variants of complex disease, potentially enriched in isolates, offer precious insights into the pathology of complex disease.
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The rapid development of SNP maps and SNP genotyping technologies is opening new avenues to the identification of shared haplotype signatures among affected individuals.
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References
Puffenberger, E. G. et al. Identity-by-descent and association mapping of a recessive gene for Hirschspring disease on human chromosome 13q22. Hum. Mol. Genet. 3, 1217–1225 ( 1994).
Puffenberger, E. G. et al. A missense mutation of the Endothelin-B receptor gene in multigenic Hirschsprung's disease. Cell 79, 1257– 1266 (1994).References 1 and 2 provide an early, beautiful example of how a complex disease can become a simple disease and how a population isolate can be used to dissect a phenotype.
Scott D. A. et al. Nonsyndromic autosomal recessive deafness is linked to the DFNBI locus in a large inbred Bedouin family from Israel. Am. J. Hum. Genet. 57, 965–968 (1995).
Bollobas, B. Littlewood's Miscellany (Cambridge Univ. Press, Cambridge, 1988).
Cavalli-Sforza, L. The DNA revolution in population genetics. Trends Genet. 14, 60–65 (1998).
Kidd, J. R. et al. Haplotypes and linkage disequilibrium at the phenylalanine hydroxylase locus, PAH, in a global, MH representation of populations. Am. J. Hum. Genet. 66, 1882–1899 (2000).
Sajantila, A. et al. Paternal and maternal linkages reveal a bottleneck in the founding of the Finnish population. Proc. Natl Acad. Sci. USA 93, 12035–12039 (1996).
Kittles, R. A. et al. Dual origins of Finns revealed by Y chromosome haplotype variation . Am. J. Hum. Genet. 62, 1171– 1179 (1998).
de la Chapelle, A & Wright F. A. Linkage disequilibrium mapping in isolate populations: The example of Finland revisited. Proc. Natl Acad. Sci. USA 95, 12416– 12423 (1998).
Jorde, L. B. et al. Gene mapping in isolated populations: New roles for old friends? Hum. Hered. 50, 57–65 (2000).
Varilo, T. et al. Linkage disequilibrium in isolated populations: Finland and a young sub–population of Kuusamo. Eur. J. Hum. Genet. (in the press).
Terwilliger, J. D., Zöllner, S., Laan, M. & Pääbo, S. Mapping in small populations with no demographic expansion. Hum. Hered. 48, 138–154 ( 1998).
Peltonen, L. Positional cloning of disease genes: Advantages of genetic isolates. Hum. Hered. 50, 66–75 ( 2000).
Peltonen, L., Jalanko, A. & Varilo, T. Molecular genetics of the Finnish disease heritage. Hum. Mol. Genet. 8, 1913–1923 (1999).
Wright, A. F., Carothers, A. D. & Pirastu, M. Population choice in mapping genes for complex diseases . Nature Genet. 23, 397– 404 (1999).Considers in some detail the advantages and disadvantages of various populations in mapping common disease genes.
Houwen, R. H. et al. Genome screening by searching for shared segments: Mapping a gene for benign recurrent intrahepatic cholestasis. Nature Genet. 8, 380–386 ( 1994).Shows the power of the founder effect and population isolation in the search for a disease gene. Scanning for a haplotype signature in affected individuals can be used to localize the gene.
Nikali, K. et al. Random search for shared chromosomal regions: the assignment of a new hereditary ataxia locus. Am. J. Hum. Genet. 56, 1088–1095 (1995).
Peltomaki, P. et al. Genetic mapping of a locus predisposing to human colorectal cancer. Science 260, 810– 812 (1993).
Pajukanta, P. et al. Linkage of familial combined hyperlipidaemia to chromosome 1q21–q23. Nature Genet. 18, 369– 373 (1998).
Hanson, R. L. et al. An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am. J. Hum. Genet. 63, 1130–1138 ( 1998).
Collins, F. S., Guyer, M. S. & Charkravarti, A. Variations on a theme: cataloguing human DNA sequence variation. Science 278, 1580– 1581 (1997).Lays out the rationale for the discovery and application of single nucleotide polymorphisms.
Kruglyak, L. Prospect for whole-genome linkage disequilibrium mapping of common disease genes. Nature Genet. 22, 139– 144 (1999).
Zwick, M. E. et al. Characterizing human genomic variation and linkage disequililibrium in multiple 100kb genomic segments using large-scale, microarray–based SNP detection. Am. J. Hum. Genet. 67, S22 (2000).
Nickerson, D. A. et al. DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nature Genet. 19, 233– 240 (1998).Explores one human gene intensely for polymorphisms and linkage disequilibrium. This type of study is a forerunner of what will be done on a genome-wide basis.
Eaves, I. A. et al. The genetically isolated populations of Finland and Sardinia may not be a panacea for linkage disequilibrium mapping of common disease genes. Nature Genet. 25, 320– 323 (2000).
Taillon-Miller, P. et al. Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28. Nature Genet. 25, 324–328 (2000).
Moehlke, K. L. et al. Marker–marker linkage disequilibrium extends beyond 1 cM on chromosome 20 in Finns. Am. J. Human Genet. 67, S25 (2000).
Greenberg, D. A., Abreu, P. & Hodge, S. E. The power to detect linkage in complex disease by means of simple LOD-score analyses. Am. J. Hum. Genet. 63 , 870–879 (1998).
Clerget-Darpoux, F., Bonaiti-Pellie, C. & Hochez, J. Effects of misspecifying genetic parameters in lod score analysis. Biometrics 42, 393– 399 (1986).
Kruglyak, L., Daly, M. J., Reeve-Daly, M. P. & Lander, E. S. Parametric and nonparametric linkage analysis: A unified multipoint approach . Am. J. Hum. Genet. 58, 1347– 1363 (1996).
Sobel, E. & Lange, K. Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker sharing statistics . Am. J. Hum. Genet. 58, 1323– 1337 (1996).
Abreu, P. C., Greenberg, D. A. & Hodge, S. E. Direct power comparisons between simple lod scores and NPL scores for linkage analysis in complex diseases. Am. J. Hum. Genet. 65, 847–857 (1999).
Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996). Argues the case for association studies over linkage studies.
Terwilliger, J. D. & Ott, J. A haplotype-based 'haplotype relative risk' approach to detecting allelic associations. Hum. Hered. 42, 337–346 (1992).
Spielman, R. S., McGinnis, R. E. & Ewens, W. J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52, 506–516 (1993).
Allison, D. B., Heo, M., Kaplan, N. & Martin, E. R. Sibling–based tests of linkage and association for quantitative traits. Am. J. Hum. Genet. 64, 1754–1763 (1999).
Boehnke, M. & Langefeld, C. D. Genetic association mapping based on discordant sib pairs: the discordant-alleles test. Am. J. Hum. Genet. 62, 950–961 (1998).
Spielman, R. S. & Ewens, W. J. A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am. J. Hum. Genet. 62, 450– 458 (1998).
Schaid, D. J. & Rowland, C. Use of parents, sibs, and unrelated controls for detection of associations between genetic markers and disease . Am. J. Hum. Genet. 63, 1492– 1506 (1998).
Teng, J. & Risch, N. The relative power of family-based and case-control designs for linkage disequilibrium studies of complex human diseases. II. Individual genotyping. Genome Res. 9, 234–241 (1999).
Sinsheimer, J. S., Blangero, J. & Lange, K. Gamete competition models. Am. J. Hum. Genet. 66, 1168–1172 ( 2000).
Collins, A. & Morton, N. E. Mapping a disease locus by allelic association. Proc. Natl Acad. Sci. USA 95, 1741–1745 (1998).
Devlin, B., Risch, N. & Roeder, K. Disequilibrium mapping: composite likelihood for pairwise disequilibrium. Genomics 36, 1– 16 (1996).
Kaplan, N. L. Hill, W. G. & Weir, B. S. Likelihood methods for locating disease genes in non-equilibrium populations. Am. J. Hum. Genet. 56, 18– 32 (1995).
Lazzeroni, L. C. & Lange, K. A conditional inference framework for extending the transmission/disequilibrium test. Hum. Hered. 48, 67–81 ( 1998).
McPeek, M. S. & Strahs, A. Assessment of linkage disequilibrium by the decay of haplotype sharing, with application to fine scale genetic mapping. Am. J. Hum. Genet. 65, 858– 875 (1999).
Rannala, B. & Slatkin, M. Likelihood analysis of disequilibrium mapping, and related problems. Am. J. Hum. Genet. 62 , 459–473 (1998).
Terwilliger, J. D. A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic marker loci. Am. J. Hum. Genet. 56, 777–787 ( 1995).
Xiong, M. & Guo, S. W. Fine-scale genetic mapping based on linkage disequilibrium: theory and applications. Am. J. Hum. Genet. 60, 1513–1531 ( 1997).
Göring, H. H. H. & Terwilliger, J. D. Linkage analysis in the presence of errors IV: Joint pseudomarker analysis of linkage and/or linkage disequilibrium on a mixture of pedigrees and singletons when the mode of inheritance cannot be accurately specified. Am. J. Hum. Genet. 66, 1310–1327 (2000).
Leach, F. S. et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75, 1215– 1225 (1993).
Bronner, C. E. et al. Mutation in the DNA mismatch pair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 368, 258–261 (1994).
Sheffield, V. C., Stone, E. M. & Carmi, R. Use of isolated inbred human populations for identification of disease genes. Trends Genet. 14, 391– 396 (1998).
Kuokkanen, S. et al. Genome wide scan of multiple sclerosis in Finnish multiplex families. Am. J. Hum. Genet. 61, 1379– 1387 (1997).
Chataway, J. et al. The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic genome screen. Brain 121, 1869–1887 ( 1998).
Castellani, L. W. et al. Mapping a gene for combined hyperlipidemia in a mutant mouse strain. Nature Genet. 18, 374– 377 (1998).
Pei, W. et al. Support for linkage of familial combined hyperlipidemia to chromosome 1q21–q23 in Chinese and German families. Clin. Genet. 57, 29–34 (2000).
Pajukanta, P. et al. Genomewide scan for familial combined hyperlipidemia genes in Finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol, and apolipoprotein B levels. Am. J. Hum. Genet. 64, 1453–1463 (1999).
Almasy, L. & Blangero, J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am. J. Hum. Genet. 62 , 1198–1211 (1998).
Amos, C. I. Robust variance-components approach for assessing genetic linkage in pedigrees . Am. J. Hum. Genet. 54, 535– 543 (1994).
Blangero, J. & Almasy, L. Multipoint oligenic linkage analysis of quantitative traits. Genet. Epidemiol. 14, 959–964 (1997).
Goldar, D. E. Multipoint analysis of human quantitative genetic variation. Am. J. Hum. Genet. 47, 957–967 (1990).
Hoppers, J. L. & Mathews, J. D. Extensions to multivariate normal models for pedigree analysis. Ann. Hum. Genet. 46, 373–383 ( 1982).
Schork, N. J. Extended multipoint identity-by-descent analysis of human quantitative traits: efficiency, power, and modeling considerations. Am. J. Hum. Genet. 53, 1306–1319 ( 1993).
Frary, A. et al. fw2.2: A quantitative trait locus key to the evolution of tomato fruit size. Science 289, 85– 88 (2000).A landmark publication reporting the isolation of a quantitative trait locus gene by positional cloning.
Varilo, T. et al. Linkage disequilibrium in isolated populations: Finland and a young subpopulation of Kuusamo. Eur. J. Hum. Genet. (in the press).
Helgason, A. et al. Estimating Scandinavian and Gaelic ancestry in the male settlers of Iceland. Am. J. Hum. Genet. 67, 697– 717 (2000).
Ginns, E. I. et al. A genome-wide search for chromosomal loci linked to bipolar affective disorder in the Old Order Amish. Nature Genet. 12, 431–435 (1996).
Detera-Wadleigh, S. et al. A high-density genome scan detects evidence for a biopolar–disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2 . Proc. Natl Acad. Sci. USA 96, 5604– 5609 (1999).
Ober, C. et al. Collaborative study on the genetics of asthma. Genome-wide search for asthma susceptibility loci in a founder population. Hum. Mol. Genet. 7, 1393–1398 ( 1998).
Ober, C., Tsalenko, A., Parry, R. & Cox, N. J. A second-generation genomewide screen for asthma-suspectibility alleles in a founder population Am. J. Hum. Genet. 67, 1154– 1162 (2000).
Marsh, D. G. et al. A genome-wide search for asthma susceptibility loci in ethnically diverse populations. Nature Genet. 15, 389 –392 (1997).
Hanson, R. L. et al. An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am. J. Hum. Genet. 63, 1130–1138 ( 1998).Shows the power of the quantitative trait locus strategy and the quantitation of phenotypes for the identification of disease susceptibility loci.
Elbein, S., Hoffman, M., Teng, K., Leppert, M. & Hasstect, S. A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians. Diabetes 48, 1175 –1182 (1999).
Ghosh, S. et al. The Finland–United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. I. An autosomal genome scan for genes that predispose to Type 2 diabetes. Am. J. Hum. Genet. 67, 1174–1185 (2000).
Guilford, P. et al. A non–syndromic form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q. Nature Genet. 6, 24–28 (1994 ).
Scott, D. A. et al. Nonsyndromic autosomal recessive deafness is linked to the DFNBI locus in a large inbred Bedouin family from Israel. Am. J. Hum. Genet. 57, 965–968 (1995).
Kelsell, D.P. et al. Connexin 26 mutations in hereditary nonsyndromic sensorineural deafness. Nature 387, 80– 83 (1997).
Hovatta, I. et al. A genomewide screen for schizophrenia genes in an isolated Finnish subpopulation suggesting multiple susceptibility loci. Am. J. Hum. Genet. 65, 1114–1124 (1999).
Brzustowicz, L. M., Hodgkinson, K. A., Chow, E. W. C., Honer, W. G. & Bassett A. S. Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21–q22 . Science 288, 678–682 (2000).
Kuokkanen, S. et al. A putative vulnerability locus to multiple sclerosis maps to 5p14–p12 in a region syntenic to the murine locus Eae2. Nature Genet. 13, 477–480 (1996).
Sawcer, S. et al. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nature Genet. 13 , 444–468 (1996).
Castellani, L. W. et al. Mapping a gene for combined hyperlipidemia in a mutant mouse strain. Nature Genet. 18, 374– 377 (1998).
Pei, W. et al. Support for linkage of familial combined hyperlipidemia to chromosome 1q21–q23 in Chinese and German families. Clin. Genet. 57, 29–34 (2000).
Moises, H. W. et al. An international two-stage genome-wide search for schizophrenia susceptibility genes. Nature Genet. 11, 321–324 (1995).
Straub, R. E. et al. A potential vulnerability locus for schizophrenia on chromosome 6p24–22: evidence for genetic heterogeneity. Nature Genet. 11, 287–293 ( 1995).
Levinson, D. F. et al. Genome scan of schizophrenia. Am. J. Psychiatry 155, 741–750 ( 1998).
Smith, J. R. et al. Major suscpetibility locus for prostate cancer on chromosome 1 suggested by a genome wide search. Science 274, 1371–1374 (1996).
Berthon, P. Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2–43. Am. J. Hum. Genet. 62, 1416–1424 (1998).
Xu, J. et al. Combined analysis of hereditary prostate cancer linkage to 1q24–25. Results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics. Am. J. Hum. Genet. 66, 945–957 (2000).
Acknowledgements
Our research has been supported by grants from the National Institutes of Health and an award to the Centre of Excellence in Disease Genetics by the Academy of Finland.
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Glossary
- MENDELIAN VARIANT
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An individual phenotype that is due to a single gene.
- POPULATION BOTTLENECK
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A marked reduction in population size followed by the survival and expansion of a small random sample of the original population.
- GENETIC DRIFT
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The random fluctuation in allele frequencies as genes are transmitted from one generation to the next.
- HAPLOTYPE SIGNATURE
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The haplotype surrounding a particular disease susceptibility allele. The haplotype signature can be identified among the affected individuals of an isolated population.
- TRANSMISSION DISTORTION
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Over or under transmission of certain alleles to affected individuals.
- ASSOCIATION TESTING
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A statistical approach that tests for association between marker or candidate gene alleles and diseases.
- POPULATION STRATIFICATION
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Subdivision of a population into different ethnic groups with potentially different marker allele frequencies and different disease prevalences.
- CONTINGENCY TABLE
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A table or matrix to count the numbers of observations falling into various categories. Each category is classified on the basis of several factors.
- GAMETE COMPETITION MODEL
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A statistical model that views transmission of marker alleles to affected children as a contest between the alleles. Each allele is ranked much as competing teams are ranked in a sports league.
- UNASCERTAINED SAMPLE
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A sample selected without regard to disease status.
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Peltonen, L., Palotie, A. & Lange, K. Use of population isolates for mapping complex traits. Nat Rev Genet 1, 182–190 (2000). https://doi.org/10.1038/35042049
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DOI: https://doi.org/10.1038/35042049
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