Gene Mapping in Isolated Populations: New Roles for Old Friends?Jorde L.B.a,d · Watkins W.S.a · Kere J.b · Nyman D.c · Eriksson A.W.d
aDepartment of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA; bDepartment of Medical Genetics, University of Helsinki, cÅland Central Hospital, Mariehamn, and dFolkhälsans Institute of Genetics, Population Genetics Unit, Helsinki, Finland
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Population isolates are increasingly being used in attempts to map genes underlying complex diseases. To further explore the utility of isolates for this purpose, we explore linkage disequilibrium patterns in polymorphisms from two regions (VWF and NF1) in three isolated populations from Finland. At the NF1 locus, the Finnish populations have greater pairwise disequilibrium than populations from Africa, Asia, or northern Europe. However, populations from ‘New Finland’ and ‘Old Finland’ do not differ in their disequilibrium levels at either the NF1 or the VWF locus. In addition, disequilibrium patterns and haplotype diversity do not differ between a sample from the Åland Islands, Finland, and a collection of outbred Centre d’Etude du Polymorphisme Humain families. These results show that linkage disequilibrium patterns sometimes differ among populations with different histories and founding dates, but some putative isolated populations may not significantly differ from larger admixed populations. We discuss factors that should be considered when using isolated populations in gene-mapping studies.
- Morton NE: Population structure and historical genetics of isolates. Isr J Med Sci 1973;9:1299–1307.
- Roberts DF: Genetic effects of population size reduction. Nature 1968;220:1084–1088.
- Neel JV: The population structure of an Amerindian tribe, the Yanomama. Annu Rev Genet 1978;12:365–413.
Eriksson AW, Forsius H, Nevanlinna HR, Workman PL, Norio RK (eds): Population Structure and Genetic Disorders. New York, Academic Press, 1980.
- Morgan K, Holmes TM, Schlaut J, Marchuk L, Kovithavongs T, Pazderka F, Dossetor JB: Genetic variability of HLA in the Dariusleut Hutterites. A comparative genetic analysis of the Hutterites, the Amish, and other selected Caucasian populations. Am J Hum Genet 1980;32:246–257.
- Bonné B: Genes and phenotypes in the Samaritan isolate. Am J Phys Anthropol 1966;24:1–19.
- Jorde LB, Eriksson AW, Morgan K, Workman PL: The genetic structure of Iceland. Hum Hered 1982;32:1–7.
- Morton NE, Lew R, Hussels IE, Little GF: Pingelap and Mokil atolls: Historical genetics. Am J Hum Genet 1972;24:277–289.
McKusick VA (ed): Medical Genetic Studies of the Amish: Selected Papers. Baltimore, Johns Hopkins University Press, 1978.
- Carrasquillo MM, Zlotogora J, Barges S, Chakravarti A: Two different connexin 26 mutations in an inbred kindred segregating non-syndromic recessive deafness: Implications for genetic studies in isolated populations. Hum Mol Genet 1997;6:2163–2172.
- Klinger K, Horn GT, Stanislovitis P, Fujiwara TM, Morgan K: Cystic fibrosis mutations in the Hutterite brethren. Am J Hum Genet 1990;46:983–987.
- Cavalli-Sforza LL, Wilson AC, Cantor CR, Cook-Deegan RM, King M-C: Call for a worldwide survey of human genetic diversity: A vanishing opportunity for the Human Genome Project. Genomics 1991;11:490–491.
- Zamel N, McClean PA, Sandell PR, Siminovitch KA, Slutsky AS: Asthma on Tristan da Cunha: Looking for the genetic link. The University of Toronto Genetics of Asthma Research Group. Am J Respir Crit Care Med 1996;153:1902–1906.
- Ober C, Cox NJ, Abney M, Di Rienzo A, Lander ES, Changyaleket B, Gidley H, Kurtz B, Lee J, Nance M, et al: Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma. Hum Mol Genet 1998;7:1393–1398.
- Myles-Worsley M, Coon H, Tiobech J, Collier J, Dale P, Wender P, Reimherr F, Polloi A, Byerley W: Genetic epidemiological study of schizophrenia in Palau, Micronesia: Prevalence and familiality. Am J Med Genet 1999;88:4–10.
- Bonné-Tamir B, Nystuen A, Seroussi E, Kalinsky H, Kwitek-Black AE, Korostishevsky M, Adato A, Sheffield VC: Usher syndrome in the Samaritans: Strengths and limitations of using inbred isolated populations to identify genes causing recessive disorders. Am J Phys Anthropol 1997;104:193–200.
- Enserink M: Iceland OKs private health databank. Science 1999;283:13.
- Sheffield VC, Stone EM, Carmi R: Use of isolated inbred human populations for identification of disease genes. Trends Genet 1998;14:391–396.
- Schork NJ: Genetics of complex disease: Approaches, problems, and solutions. Am J Respir Crit Care Med 1997;156:S103–S109.
- Lander ES, Schork NJ: Genetic dissection of complex traits. Science 1994;265:2037–2048.
- Nickerson DA, Taylor SL, Weiss KM, Clark AG, Hutchinson RG, Stengard J, Salomaa V, Vartiainen E, Boerwinkle E, Sing CF: DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nat Genet 1998;19:233–240.
- Risch N, Merikangas K: The future of genetic studies of complex human diseases. Science 1996;273:1516–1517.
- Wang DG, Fan J-B, Siao C-J, Berno A, Young P, Sapolsky R, Ghandour G, Perkins N, Winchester E, Spencer J, et al: Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science 1998;280:1077–1082.
- Lonjou C, Collins A, Morton NE: Allelic association between marker loci. Proc Natl Acad Sci USA 1999;96:1621–1626.
- Puffenberger EG, Hosoda K, Washington SS, Nakao K, deWit D, Yanagisawa M, Chakravarti A: A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung’s disease. Cell 1994;79:1257–1266.
- de la Chapelle A, Wright FA: Linkage disequilibrium mapping in isolated populations: The example of Finland revisited. Proc Natl Acad Sci USA 1998;95:12416–12423.
von Willebrand EA: Über hereditäre Pseudohämophilie. Acta Med Scand 1931;76:521–550.
Lehmann W, Forsius HR, Eriksson AW: Von Willebrand-Jürgens syndrome on Åland; in Eriksson AW, Forsius H, Nevanlinna HR (eds): Population Structure and Genetic Disorders. New York, Academic Press, 1980, pp 537–545.
- Watkins WS, Zenger R, O’Brien E, Nyman D, Eriksson E, Renlund M, Jorde LB: Linkage disequilibrium patterns vary with chromosomal location: A case study from the von Willebrand factor region. Am J Hum Genet 1994;55:348–355.
- Purandare SM, Cawthon R, Nelson LM, Sawada S, Watkins WS, Ward K, Jorde LB, Viskochil DH: Genotyping of PCR-based polymorphisms and linkage disequilibrium analysis at the NF1 locus. Am J Hum Genet 1996;59:159–166.
Weir BS, Cockerham CC: Complete characterization of disequilibrium at two loci; in Feldman MW (ed): Mathematical Evolutionary Theory. Princeton, Princeton University Press, 1989, pp 86–109.
Schneider S, Kueffer J-M, Roesslie D, Excoffier L: Arlequin ver. 1.1: A software for population genetic data analysis. Geneva, Genetics and Biometry Laboratory, University of Geneva, 1997.
- Excoffier L, Slatkin M: Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 1995;12:921–927.
Weir BS, Cockerham CC: Testing hypotheses about linkage disequilibrium with multiple alleles. Genetics 1978;88:633–642.
- Jorde LB: Linkage disequilibrium as a gene mapping tool. Am J Hum Genet 1995;56:11–14.
- Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui L: Identification of the cystic fibrosis gene: Genetic analysis. Science 1989;245:1073–1080.
- MacDonald ME, Novelletto A, Lin C, Tagle D, Barnes G, Bates G, Taylor S, Allitto B, Altherr M, Myers R, et al: The Huntington’s disease candidate region exhibits many different haplotypes. Nat Genet 1992;1:99–103.
- Bowcock AM, Tomfohrde J, Weisenbach J, Bonné-Tamir B, St. George-Hyslop P, Giagheddu M, Cavalli-Sforza LL, Farrer LA: Refining the position of Wilson disease by linkage disequilibrium with polymorphic microsatellites. Am J Hum Genet 1994;54:79–87.
- Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R, Ellis MC, Fullan A, et al: A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996;13:399–408.
- Devlin B, Risch N, Roeder K: Disequilibrium mapping: Composite likelihood for pairwise disequilibrium. Genomics 1996;36:1–16.
- Terwilliger JD: A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic marker loci. Am J Hum Genet 1995;56:777–787.
- Terwilliger JD, Zöllner S, Laan M, Pääbo S: Mapping genes through the use of linkage disequilibrium generated by genetic drift: ‘Drift mapping’ in small populations with no demographic expansion. Hum Hered 1998;48:138–154.
- Durham LK, Feingold E: Genome scanning for segments shared identical by descent among distant relatives in isolated populations. Am J Hum Genet 1997;61:830–842.
- Kaplan NL, Hill WG, Weir BS: Likelihood methods for locating disease genes in nonequilibrium populations. Am J Hum Genet 1995;56:18–32.
- Xiong M, Guo S-W: Fine-scale genetic mapping based on linkage disequilibrium: Theory and applications. Am J Hum Genet 1997;60:1513–1531.
- Spielman RS, Ewens WJ: The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet 1996;59:983–989.
- Collins A, Morton NE: Mapping a disease locus by allelic association. Proc Natl Acad Sci USA 1998;95:1741–1745.
- Lazzaroni LC: Linkage disequilibrium and gene mapping: An empirical least-squares approach. Am J Hum Genet 1998;62:159–170.
- Rannala B, Slatkin M: Likelihood analysis of disequilibrium mapping, and related problems. Am J Hum Genet 1998;62:459–473.
- Spielman RS, Ewens WJ: A sibship test for linkage in the presence of association: The sib transmission/disequilibrium test. Am J Hum Genet 1998;62:450–458.
Peltonen L, Pekkarinen P, Aaltonen J: Messages from an isolate: Lessons from the Finnish gene pool. Biol Chem Hoppe-Seyler 1995;376:697–704.
- de la Chapelle A: Disease gene mapping in isolated human populations: The example of Finland. J Med Genet 1993;30:857–865.
- Risch N, de Leon D, Ozelius L, Kramer P, Almasy L, Singer B, Fahn S, Breakfield X, Bressman S: Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population. Nat Genet 1995;9:152–159.
- Jorde LB, Watkins WS, Viskochil D, O’Connell P, Ward K: Linkage disequilibrium in the neurofibromatosis 1 region: Implications for gene mapping. Am J Hum Genet 1993;53:1038–1050.
- Tishkoff SA, Dietzsch E, Speed W, Pakstis AJ, Kidd JR, Cheung K, Bonné-Tamir B, Santachiara-Benerecetti AS, Moral P, Krings M: Global patterns of linkage disequilibrium at the CD4 locus and modern human origins. Science 1996;271:1380–1387.
- Kunst CG, Zerylnick C, Karickhoff L, Eichler E, Bullard J, Chalifoux M, Holden JJA, Torroni A, Nelson DL, Warren ST: FMR1 in global populations. Am J Hum Genet 1996;58:513–522.
- Tishkoff SA, Goldman A, Calafell F, Speed WC, Deinard AS, Bonné-Tamir B, Kidd JR, Pakstis AJ, Jenkins T, Kidd KK: A global haplotype analysis of the myotonic dystrophy locus: Implications for the evolution of modern humans and for the origin of myotonic dystrophy mutations. Am J Hum Genet 1998;62:1389–1402.
- Kidd KK, Morar B, Castigione CM, Zhao H, Pakstis AJ, Speed WC, Bonné-Tamir B, Lu RB, Goldman D, Lee C, Nam YS, Grandy DK, Jenkins T, Kidd JR: A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus. Hum Genet 1998;103:211–227.
- Jorde LB, Bamshad M, Rogers AR: Using mitochondrial and nuclear DNA markers to reconstruct human evolution. Bioessays 1998;20:126–136.
- Kittles RA, Perola M, Peltonen L, Bergen AW, Aragon RA, Virkkunen M, Linnoila M, Goldman D, Long JC: Dual origins of Finns revealed by Y chromosome haplotype variation. Am J Hum Genet 1998;62:1171–1179.
Jorde LB, Pitkänen KJ, O’Brien E, Eriksson AW: Consanguinity and genetic disease in Finland’s Swedish-speaking minority; in Bittles AH, Roberts DF (eds): Minority Populations: Genetics, Demography, and Health. London, Macmillan, 1992, pp 14–34.
- Peterson AC, Di Rienzo A, Lehesjoki A-E, de la Chapelle A, Slatkin M, Freimer NB: The distribution of linkage disequilibrium over anonymous genome regions. Hum Mol Genet 1995;4:887–894.
- Eriksson AW, Eskola MR, Workman PL, Morton NE: Population studies on the Åland Islands. II. Historical population structure: Inference from bioassay of kinship and migration. Hum Hered 1973;23:511–534.
Jorde LB, Eriksson AW, Workman PL: Genetic microevolution in the Åland Islands, Finland; in Crawford MH, Mielke JH (eds): Current Developments in Anthropological Genetics. New York, Plenum Press, 1982, pp 333–365, vol 2.
- O’Brien E, Jorde LB, Rönnlöf B, Fellman JO, Eriksson AW: Founder effect and genetic disease in Sottunga, Finland. Am J Phys Anthropol 1988;77:335–346.
- O’Brien E, Kerber RA, Jorde LB, Rogers AR: Founder effect: An assessment of variation in genetic contribution among founders. Hum Biol 1994;66:185–204.
- Kruglyak L: Genetic isolates: Separate but equal? Proc Natl Acad Sci USA 1999;96:1170–1172.
- Lonjou C, Collins A, Ajioka RS, Jorde LB, Kushner JP, Morton NE: Allelic association under map error and recombinational heterogeneity: A tale of two sites. Proc Natl Acad Sci USA 1998;95:11366–11370.
- Lander ES, Botstein D: Homozygosity mapping: A way to map human recessive traits with the DNA of inbred children. Science 1987;236:1567–1570.
- Morton NE, Collins A: Tests and estimates of allelic association in complex inheritance. Proc Natl Acad Sci USA 1998;95:11389–11393.
- Laan M, Pääbo S: Demographic history and linkage disequilibrium in human populations. Nat Genet 1997;17:435–438.
- Slatkin M: Linkage disequilibrium in growing and stable populations. Genetics 1994;137:331–336.
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