Haplotype Structure and Population Genetic Inferences from Nucleotide-Sequence Variation in Human Lipoprotein Lipase

Abstract

Allelic variation in 9.7 kb of genomic DNA sequence from the human lipoprotein lipase gene (LPL) was scored in 71 healthy individuals (142 chromosomes) from three populations: African Americans (24) from Jackson, MS; Finns (24) from North Karelia, Finland; and non-Hispanic Whites (23) from Rochester, MN. The sequences had a total of 88 variable sites, with a nucleotide diversity (site-specific heterozygosity) of .002+/-.001 across this 9.7-kb region. The frequency spectrum of nucleotide variation exhibited a slight excess of heterozygosity, but, in general, the data fit expectations of the infinite-sites model of mutation 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. Despite the strong evidence for recombination, extensive linkage disequilibrium was observed. The number of haplotypes generally is much greater than the number expected under the infinite-sites model, but there was sufficient multisite linkage disequilibrium to reveal two major clades, which appear to be very old. Variation in this region of LPL may depart from the variation expected under a simple, neutral model, owing to complex historical patterns of population founding, drift, selection, and recombination. These data suggest that the design and interpretation of disease-association studies may not be as straightforward as often is assumed.

Understanding the accuracy of statistical haplotype inference with sequence data of known phase

“…Experimental determination of ambiguous phase by allele-specific amplification can dramatically improve phasing, even when limited to a small number of SNP pairs and individuals [Clark et al, 1998]. Unfortunately, this method is not suitable for large-scale studies because experiments are individually designed along the phasing process, the technique is methodologically complex, and careful interpretation of agarose gels post-PCR is required.…”

Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection

“…More recently, studies have reported that the genome can be divided into blocks defined by LD between pairs of marker in a range from 5 to 100 kb with population differences in the extension. 42,54,55,57,67,68 Most of these studies report LD data for markers spanning large genomic regions, and used pre-ascertained SNPs from public databases with limited marker density. 56,[69][70][71] The identification of smaller blocks within candidate genes is probably beyond the resolution of these studies because of inadequate marker density for detection of LD patterns.…”

“…54 Overall, there were more estimated haplotypes in subjects of African ancestry. [55][56][57] In all, 31 haplotypes were population specific, with the highest number in AA (Table 3). The wild-type 'secretor haplotype' LYPA did not lie on a unique locus-wide haplotype.…”

Haplotype tagging efficiency in worldwide populations in CTLA4 gene

“…However, both the presence of blocks and the use of tagSNPs as markers for disease genes are controversial. 26,27 Moreover, tag-SNPs identified in one population may not be applicable to other populations 28 even if they seem to be quite general for Europeans. 29 Furthermore, Crawford et al, 30 after analyzing the sequence diversity in 100 human genes, concluded that the amount of LD and the haplotype structure should be empirically analyzed in order to assess which and how many SNPs must be typed in a specific gene to detect an association with a disease-causing SNP in a case-control study.…”