HAPLOTYPE STRUCTURE AND POPULATION GENETIC INFERENCES FROM NUCLEOTIDE-SEQUENCE VARIATION IN HUMAN LIPOPROTEIN-LIPASE

Allelic variation in 3.7 kb of genomic DNA sequence from the human lip oprotein lipase gene (LPL) was scored in 71 healthy individuals (142 c hromosomes) from three populations: African Americans (24) from Jackso n, MS; Finns (24) from North Karelia, Finland; and non-Hispanic Whites (23) from Rochester, MN. The sequences had a total of 88 variable sit es, with a nucleotide diversity (site-specific heterozygosity) of .002 +/- .001 across this 9.7-kb region. The frequency spectrum of nucleot ide variation exhibited a slight excess of heterozygosity, but, in gen eral, the data fit expectations of the infinite-sites model of mutatio n and genetic drift. Allele-specific PCR helped resolve linkage phases , and a total of 88 distinct haplotypes were identified. For 1,410 (64 %) of the 2,211 site pairs, all four possible gametes were present in these haplotypes, reflecting a rich history of past recombination. Des pite the strong evidence for recombination, extensive linkage disequil ibrium was observed. The number of haplotypes generally is much greate r than the number expected under the infinite-sites model, but there w as sufficient multisite linkage disequilibrium to reveal two major cla des, which appear to be very old. Variation in this region of LPL may depart from the variation expected under a simple, neutral model, owin g to complex historical patterns of population founding, drift, select ion, and recombination. These data suggest that the design and interpr etation of disease-association studies may not be as straightforward a s often is assumed.