Haplotype Structure and Population Genetic Inferences from Nucleotide-Sequence Variation in Human Lipoprotein Lipase
Open accessAbstract
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.
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A biochemical method that separately amplifies each chromosome allows direct determination of haplotype phase.
“Another way to resolve haplotype phase is to use a biochemical method that separately amplifies each chromosome, allowing direct determination of haplotype phase121.”
From Linkage disequilibrium--understanding the evolutionary past and mapping the medical future. (2008) · cites this paper as [121]
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“Thus, Clark et al. (1998) examined all base substitutions detected in a 9.”
BackgroundInfluentialLactase haplotype diversity in the Old World.
Hollox, E., Poulter, M., Zvarík, M., Ferák, V., Krause, A., Jenkins, T., Saha, N., Kozlov, A., & Swallow, D. (2001) · American Journal of Human Genetics · doi:10.1086/316924 · Cited by 188 · see citing works
“1999), but, recently, large regions containing autosomal genes usually associated with diseases have been analyzed in a variety of populations (Clark et al. 1998; Kidd et al. 1998; Tishkoff et al. 1998; Yip et al. 1999).”
BackgroundSpecific haplotypes of the P-selectin gene are associated with myocardial infarction
Trégouët, D. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.17.2015 · Cited by 177 · see citing works
Crawford, D. C., Carlson, C. S., Rieder, M. J., Carrington, D. P., Qian, Y., Smith, J. D., Eberle, M. A., Kruglyak, L., & Nickerson, D. A. (2004) · The American Journal of Human Genetics · doi:10.1086/382227 · Cited by 171 · see citing works
“Similar to our survey, other comprehensive sequence-based variation studies of single genes or regions such as LPL (Clark et al. 1998), bglobin (Harding et al.”
BackgroundResultInfluentialSelf-citationRecombinational and Mutational Hotspots within the Human Lipoprotein Lipase Gene
Templeton, A. R., Clark, A. G., Weiss, K. M., Nickerson, D. A., Boerwinkle, E., & Sing, C. F. (2000) · The American Journal of Human Genetics · doi:10.1086/302699 · Cited by 176 · see citing works
“Ignoring, in figure 5 of Clark et al. (1998), all cells for which the sample sizes were to small to yield a significant disequilibrium even if absolute disequilibrium existed, one finds that, within the 5′ end, 57 (49”
BackgroundMethodResultInfluentialSelf-citationPopulation genomics: linkage disequilibrium holds the key.
Goldstein, D., & Weale, M. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00348-7
“While we do not yet know which scenario is generally closer to reality, and whether it differs among populations, we have examples which appear closer to each [ 6 ,7].”
Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2–13.1
Zhang, B.-P., Henney, A., Eriksson, P., Hamsten, A., Watkins, H., & Ye, S. (1999) · Human Genetics · doi:10.1007/s004399900167 · Cited by 180
Inference of Haplotypes from Samples of Diploid Populations: Complexity and Algorithms
Gusfield, D. (2001) · Journal of Computational Biology · doi:10.1089/10665270152530863 · Cited by 157 · see citing works
“Clark (1990) before the current interest in SNPs, but has been extensively used in the rst large-scale study of haplotypes inferred from SNP data (Clark et al., 1998; Nickerson et al., 1998) and more recently in additional studies of haplotype variation (Fullerton et al.”
InfluentialPolymorphisms in toll-like receptor 4 are not associated with asthma or atopy-related phenotypes.
Raby, B., Klimecki, W., Laprise, C., Renaud, Y., Faith, J., Lemire, M., Greenwood, C., Weiland, K., Lange, C., Palmer, L., et al. (2002) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200207-634oc · Cited by 171 · see citing works
“Secondly, it has been recognized that the combination of several allelic variants within a gene, present together physically on the same chromosome, may act in concert as a ‘meta-allele’ to produce phenotypic effects distinct from those produced by the individual SNPs alone (52, 53).”
Assessing the performance of the haplotype block model of linkage disequilibrium.
Wall, J., & Pritchard, J. (2003) · American Journal of Human Genetics · doi:10.1086/378099 · Cited by 168 · see citing works
Haplotype inference by maximum parsimony
Wang, L., & Xu, Y. (2003) · Bioinformatics · doi:10.1093/bioinformatics/btg239 · Cited by 150 · see citing works
Oota, H., Pakstis, A., Bonné-Tamir, B., Goldman, D., Grigorenko, E., Kajuna, S. L. B., Karoma, N. J., Kungulilo, S., Lu, R., Odunsi, K., et al. (2004) · Annals of Human Genetics · doi:10.1046/j.1529-8817.2003.00060.x · Cited by 165 · see citing works
“However, both the idea of haplotype blocks and the tagging-SNPs approach to detect disease genes are still controversial (Clark et al. 1998; Templeton et al. 2000; Wang et al. 2002).”
BackgroundEvidence for balancing selection from nucleotide sequence analyses of human G6PD.
Verrelli, B., McDonald, J., Argyropoulos, G., Destro-Bisol, G., Froment, A., Drousiotou, A., Lefranc, G., Helal, A., Loiselet, J., & Tishkoff, S. (2002) · American Journal of Human Genetics · doi:10.1086/344345 · Cited by 160 · see citing works
“In accordance with other studies, we have revealed that selection for disease resistance can be associated with a complex pattern of nucleotide variability (Clark et al. 1998; Fullerton et al. 2000; Kidd et al. 2000; Nachman and Crowell 2000; Hamblin et al. 2002; Tishkoff and Williams 2002).”
BackgroundInfluentialAn utter refutation of the ‘Fundamental Theorem of the HapMap’
Terwilliger, J. D., & Hiekkalinna, T. (2006) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5201583 · Cited by 173 · see citing works
Association testing by DNA pooling: An effective initial screen
Bansal, A. T., van den Boom, D., Kammerer, S., Honisch, C., Adam, G., Cantor, C. R., Kleyn, P. W., & Braun, A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.262671399 · Cited by 154 · see citing works
Doney, A., Fischer, B., Frew, D., Cumming, A., Flavell, D. M., World, M., Montgomery, H., Boyle, D., Morris, A., & Palmer, C. (2002) · BMC Genetics · doi:10.1186/1471-2156-3-21 · Cited by 149 · see citing works
“It is also clear that the extent of allelic disequilibrium may be different in geographically/ethnically distinct populations [41], and as such, the relationship between the Pro12Ala and C1431T polymorphism may be different in different ethnic groups and thus provide discordant associations when studied in isolation.”
BackgroundWorldwide distribution of NAT2 diversity: Implications for NAT2 evolutionary history
Sabbagh, A., Langaney, A., Darlu, P., Gérard, N., Krishnamoorthy, R., & Poloni, E. S. (2008) · BMC Genetics · doi:10.1186/1471-2156-9-21 · Cited by 147 · see citing works
“The inferred levels of sequence diversity (Table 2) were found to be consistent with values reported at other highly variable human autosomal loci, such as LPL [18], GYPA [19], and CCR5 [20].”
Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)
Pauli-Magnus, C., & Kroetz, D. (2004) · Pharmaceutical Research · doi:10.1023/b:pham.0000029276.21063.0b · Cited by 144 · see citing works
Characterizing Linkage Disequilibrium in Pig Populations
Du, F., Clutter, A., & Lohuis, M. (2007) · International Journal on Biological Sciences · doi:10.7150/ijbs.3.166 · Cited by 141 · see citing works
“While a few earlier studies work with microsatellite marker genotype data (e.g., [27, 28]), most focus on single nucleotide polymorphism (SNP) genotype data, especially on extremely tightly linked SNPs (e.g., [ 29 -31 ]) in European populations.”
BackgroundGenotyping:The predictive power of haplotypes in clinical response
Judson, R., Stephens, J. C., & Windemuth, A. (2000) · Pharmacogenomics · doi:10.1517/14622416.1.1.15 · Cited by 130 · see citing works
“(We should note that Clark and co-workers have sequenced about a third of the LPL gene locus in a cohort of 71 individuals [11,12].”
BackgroundThe Evolution of Drug Metabolism
Nebert, D., & Dieter, M. Z. (2000) · Pharmacology · doi:10.1159/000028393 · Cited by 138 · see citing works
Haplotype‐Association Analysis
Liu, N., Zhang, K., & Zhao, H. (2008) · Advances in genetics · doi:10.1016/s0065-2660(07)00414-2 · Cited by 141 · see citing works
“Examples include lipoprotein lipase-responsible gene in humans (Clark et al., 1998) and a gene influencing initial lactase activity in humans (Hollox et al.”
BackgroundTHE PATTERNS OF NATURAL VARIATION IN HUMAN GENES
Crawford, D. C., Akey, D. T., & Nickerson, D. A. (2005) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.6.080604.162309 · Cited by 129 · see citing works
“As expected, for the SeattleSNPs PGA data set, the African-American population has a greater overall number of variants (17, 701) compared with the European-American sample (11,009).”
ResultSelf-citation
- Authors
- Clark, A. G., Weiss, K. M., Nickerson, D. A., Taylor, S. L., Buchanan, A., Stengård, J., Salomaa, V., Vartiainen, E., Perola, M., Boerwinkle, E., & Sing, C. F.
- Affiliations
- Pennsylvania State University (US)
- University of Washington (US)
- The University of Texas Health Science Center at Houston (US)
- University of Michigan (US)
- Corresponding author
- Clark, Andrew G.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 1998-08
- Volume
- 63
- Issue
- 2
- Pages
- 595-612
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1377318
- OpenAlex
- W2022005040
- Cited by
- 435
- References
- 0
- Citations by year
- 2025: 1 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 2 · 2015: 2 · 2014: 2 · 2013: 3 · 2012: 2
- FWCI
- 33.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL58238, R01HL058238, HL 58239, R01HL058239, HL-39107, R01HL039107)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic diversity and population structure
- Keywords
- lipoprotein lipase gene, lipoprotein lipase, haplotype structure, linkage disequilibrium, recombination, nucleotide diversity, African Americans, Finns, non-Hispanic whites, population structure, disease association studies, selection, genetic drift, allele-specific PCR
- MeSH terms
- Animals, Black or African American, Pan troglodytes, Finland, Genetics, Population, Genotype, Haplotypes, Heterozygote, Humans, Lipoprotein Lipase, Minnesota, Mississippi, Models, Genetic, Recombination, Genetic, Reference Values, Genetic Variation, Linkage Disequilibrium, Polymerase Chain Reaction, Black People, White People
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