| Complex
Trait Mapping in the Hutterites
Carole Ober, Ph. D. |
| The Department of Human Genetics
University of Chicago 
in collaboration with the University of South Dakota |
Results
of ongoing research
The Hutterites of South DakotaThe Hutterites are a religious sect that originated in the Tyrolean Alps in the 1500's. Between the mid-1700's to mid-1800's, during their tenure in Russia, the population grew in size from approximately 120 to over 1,000 members (Hostetler 1974). In the 1870's approximately 900 of these members migrated to what is now South Dakota and roughly half settled on three communal farms. Due to a high natural fertility rate and the proscription of contraception among communal Hutterites (Sheps 1965), the population expanded dramatically since migrating to the United States. Today there are >35,000 Hutterites living on >350 communal farms (called colonies) in the northern United States and western Canada. Genealogical records, collected by Steinberg and his students in the 1950's and 1960's (Bleibtreu 1964; Mange 1964; Steinberg et al. 1967), trace all extant Hutterites to fewer than 90 ancestors who lived in the early 1700's to the early 1800's (Martin 1970). The relationships between these ancestors are unknown, but some of them may have been related. The three original South Dakota colonies have given rise to the three major subdivisions of Hutterite population structure, called the Schmiedeleut (S-leut), Dariusleut (D-leut), and Leherleut (L-leut) and members of each leut have remained reproductively isolated from each other since 1910 (Bleibtreu 1964).The subjects of our studies, the S-leut Hutterites of South Dakota, are descendants of 64 Hutterite ancestors. The average coefficient of inbreeding among the subjects in our study is 0.0327 (s.d. 0.016), slightly greater than that of 1? cousins. Thus, the small number of ancestral genomes present in the current population should result in a smaller number of asthma susceptibility alleles at any given locus, and possibly a smaller number of loci, than in outbred populations and facilitate the search for genes underlying this complex phenotype. The relatively recent origins of the population enhances the ability to detect linkage disequilibrium between asthma-susceptibility alleles and marker alleles over approximately 5-10 cM distances (Hall et al. 1997). Furthermore, the Hutterite communal lifestyle ensures that all members are exposed to a relatively uniform environment. In particular, the Hutterites prepare and eat meals in a communal kitchen and dining room, respectively, and smoking is prohibited (and rare) in the population. Thus, primary or secondary exposure to cigarette smoke does not complicate diagnoses of asthma or lung disease in the Hutterites as it does in other populations. Founder Populations are Useful for Mapping Complex TraitsThe advantages of inbred or founder populations for genetic studies were first noted over 30 years ago (McKusick et al. 1964; Neel 1970; Steinberg et al. 1967). Interest in these populations has recently been renewed as a result of the explosion of molecular biological techniques and the initiation of the Human Genome Project (Collins 1995; de la Chapelle 1993; Lander and Schork 1994). The relatively small number of founders and recent ancestries that are characteristic of these populations facilitate the search for human disease genes and make them particularly amenable to novel analytic strategies. Indeed, founder populations have proven useful for mapping genes that underlie Mendelian disorders (eg., (Hästbacka et al. 1992; Höglund et al. 1995; Houwen et al. 1994; Kestilä et al. 1994; Sulisalo et al. 1994) and multigenic disorders that segregate as Mendelian conditions in specific populations (Mahtani et al. 1996; Puffenberger et al. 1994). The same features of population history that advanced the search for Mendelian conditions in founder populations should also facilitate the search for genes that influence susceptibility to complex traits (Ober et al. 1998).
Bleibtreu HK (1964) Marriage and residence patterns in a genetic isolate Anthropology. Harvard, Cambridge Collins FS (1995) Positional cloning moves from perditional to traditional. Nature Genetics 9:347-350 de la Chapelle A (1993) Disease gene mapping in isolated human populations: the example of Finland. Am J Med Genet 30:857-865 Hall D, Cho J, Hill A, Spedini G, Ober C, Di Rienzo A (1997) Comparison of linkage disequilibrium within and between ethnic groups. Amer J Hum Genet 61:A200 Hästbacka J, de la Chapelle A, Kaitila I, Sistonen P, Weaver A, Lander E (1992) Linkage disequilbrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nature Genetics 2:204-211 Hostetler JA (1974) Hutterite Society. Johns Hopkins University Press, Baltimore Mange AP (1964) Growth and inbreeding of a human isolate. Human Biol 36:104-133 Martin AO (1970) The founder effect in a human isolate: Evolutionary implications. Am J Phys Anthropology 32:351-368 Ober C, Cox NJ (1998) Mapping genes for complex traits in founder populations. Clin Exp Allergy 28:101-105 Sheps MC (1965) An analysis of reproductive patterns in an American isolate. Popul Stud 19:65-80 Steinberg AG,
Bleibtreu HK, Kurczynski TW, Martin AO, Kurczynski EM (1967) Genetic studies
in an inbred human isolate. In: Crow Jh, Neel JV (eds) Proceedings of the
Third International Congress of Human Genetics. Johns Hopkins University
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Related Published Studies Donfack J, Tsalenko A, Hoki DM, Parry R, Solway J, Lester LA, Ober C (2000) HLA-DRB1*01 alleles and sensitization to cockroach allergies. JACI 105:960-966 Ober C, Cox N, Parry R, Abney M, DiRienzo A, Changyaleket B, Gidley H, Kurtz B, Lander ES, Lee J, Pettersson A, Prescott J, Richardson A, Schlenker E, Summerhill E, Willadsen S, CSGA (1998) Genome-wide search for asthma susceptibility loci in a founder population. Hum Molec Genet 7:1393-1398 Ober C, Cox NJ (1998) Mapping genes for complex traits in founder populations. Clin Exp Allergy (supp) 28:101-105 Ober C, Leavitt SA, Tsalenko A, Howard TD, Hoki DM, Daniel R, Newman DL, Wu X, R. P, Lester LA, Solway J, Blumenthal M, King RA, Xu J, Meyers DA, E.R. B, Cox NJ (2000) Variation in the interleukin 4 receptor a gene confers susceptibility to asthma and atopy in ethnically diverse populations. Am J Hum Genet 66:517-526 Ober C, Moffatt M (2000) Contributing factors to the pathobiology: The genetics of asthma. In: Wenzel S (ed) The Pathobiology of Asthma. Vol. 21. W.B. Saunders Company, Philadelphia, pp 245-261 Ober C, Tsalenko A, Parry R, Cox NJ (2000) A second generation genome-wide screen for asthma susceptibility alleles in a founder population. Am J Hum Genet 67:1154-1162 Ober C, Tsalenko A, Willadsen
SA, Newman D, Daniel R, Wu X, Andal J, Hoki D, Schneider D, True K, Schou
C, Parry R, Cox N (1999) Genome-wide screen for atopy susceptibility alleles
in the Hutterites. Clin Exp Allergy (supp) 4:11-15
Results of ongoing research
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