DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene


Lipoprotein lipase plays a central role in lipid metabolism and the gene that encodes this enzyme (LPL) is a candidate susceptibility gene for cardiovascular disease. Here we report the complete sequence of a fraction of the LPL gene for 71 individuals (142 chromosomes) from three populations that may have different histories affecting the organization of the sequence variation. Eighty-eight sites in this 9.7 kb vary among individuals from these three populations. Of these, 79 were single nucleotide substitutions and 9 sites involved insertion-deletion variations. The average nucleotide diversity across the region was 0.2% (or on average 1 variable site every 500 bp). At 34 of these sites, the variation was found in only one of the populations, reflecting the differing population and mutational histories. If LPL is a typical human gene, the pattern of sequence variation that exists in introns as well as exons, even for the small number of samples considered here, will present challenges for the identification of sites, or combinations of sites, that influence variation in risk of disease in the population at large.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: A schematic diagram of the human LPL gene.
Figure 2: Novel DNA variants identified in LPL using sequence analysis.
Figure 3: Comparison of observed and expected heterozygosities.
Figure 4: A plot of the heterozygosity for the 88 variant sites found in the LPL sequence.
Figure 5: Comparison of the 71 individuals to the reference LPL sequence for the 88 variant sites.


  1. 1

    Olson, M.V. A time to sequence . Science 270, 394–396 (1995).

  2. 2

    Rowen, L., Mahairas, G. & Hood, L. Sequencing the human genome. Science 278, 605–607 (1997).

  3. 3

    Collins, F.S., Guyer, M.S. & Chakravarti, A. Variations on a theme: cataloging human DNA sequence variation. Science 278, 1580– 1581 (1997).

  4. 4

    Cavalli-Sforza, L.L., Menozzi, P. & Piazza, A. The History and Geography of Human Genes. (Princeton University Press, Princeton, New Jersey, 1994).

  5. 5

    Cavalli-Sforza, L.L. Opinion: How can one study individual variation for 3 billion nucleotide of the human genome? Am. J. Hum. Genet. 46, 649– 651 (1990).

  6. 6

    Lander, E.S. The new genomics: global views of biology. Science 274, 536 –539 (1996).

  7. 7

    Lander, E.S. & Schork, N.J. Genetic dissection of complex traits . Science 265, 2037–2048 (1994).

  8. 8

    Weiss, K.M. Genetic Variation and Human Disease: Principles and Evolutionary Approaches(Cambridge University Press, Cambridge, England, 1997).

  9. 9

    Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).

  10. 10

    Murthy, V., Julien, P. & Gagne, C. Molecular pathobiology of the human lipoprotein lipase gene. Pharmacol. Ther. 70, 101–135 (1996).

  11. 11

    Kirchgessner, T.G., Svenson, K.L., Lusis, A.J. & Schotz, M.C. The sequence of the cDNA encoding lipoprotein lipase. A member of a lipase gene family. J. Biol. Chem. 262, 8463– 8466 (1987).

  12. 12

    Kirchgessner, T.G. et al. Organization of the human lipoprotein lipase gene and evolution of the lipase gene family. Proc. Natl Acad. Sci. USA 86, 9647–9651 (1989).

  13. 13

    Brunzell, J.D. Familial lipoprotein lipase deficiency and other causes of chylomicronemia syndrome. in The Metabolic and Molecular Basis of Inherited Diseases (eds Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.) 1913– 1932 (McGraw-Hill Inc., New York, 1995).

  14. 14

    Wiebusch, H. et al. Mutations in the lipoprotein lipase gene are not restricted to patients with type 1 hyperlipidemia. Circulation 86, 1 –609 (1992).

  15. 15

    Reymer, P.W. et al. A lipoprotein lipase mutation (Asn291Ser) is associated with reduced HDL cholesterol levels in premature atherosclerosis. Nature Genet. 10, 28–33 (1995).

  16. 16

    Clark, A.G. et al. Haplotype structure and population genetic inferences from the nucleotide sequence variation in human lipoprotein lipase. Am. J. Hum. Genet. submitted.

  17. 17

    Nickerson, D.A., Tobe, V.O. & Taylor, S.L. Polyphred: Automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res. 14, 2745–2751 (1997).

  18. 18

    Vogel, F. & Kopun, M. Higher frequencies of transitions among point mutations. J. Mol. Evol. 9, 159– 180 (1977).

  19. 19

    Kwok, P.-Y., Deng, Q., Zakeri, H., Taylor, S.L. & Nickerson, D.A. Increasing the information content of STS-based genome maps: Identifying polymorphisms in mapped STSs. Genomics 31, 123–126 (1996).

  20. 20

    Economou, E.P., Bergen, A.W., Warren, A.C. & Antonarakis, S.E. The polydeoxyadenylate tract of Alu repeat elements is polymorphic in the human genome. Proc. Natl Acad. Sci. USA 87, 2951–2954 (1990).

  21. 21

    Weber, J.L. & May, P.E. Abundant class of human DNA polymorphism which can be typed by the polymerase chain reaction. Am. J. Hum. Genet. 44, 388–396 ( 1989).

  22. 22

    Edwards, A., Civitello, A., Hammond, H.A. & Caskey, C.T. DNA typing and genetic mapping with trimeric and tetrameric tandem repeats. Am. J. Hum. Genet. 49, 746–756 (1991).

  23. 23

    Hata, A., Robertson, M., Emi, M. & Lalouel, J.M. Direct detection and automated sequencing of individual alleles after electrophoretic strand separation: identification of a common nonsense mutation in exon 9 of the human lipoprotein lipase gene. Nucleic Acids Res. 18 , 5407–5411 (1990).

  24. 24

    Eng, C. & Vijg, J. Genetic testing: The problems and the promise . Nature Biotechnol. 15, 422– 426 (1997).

  25. 25

    Fisher, K.L., Fitzgerald, G.A. & Lawn, R.M. Two polymorphisms in the human lipoprotein lipase (LPL) gene. Nucleic Acids Res. 15, 7657 ( 1987).

  26. 26

    Heinzmann, C. et al. RFLP for the human lipoprotein lipase (LPL) gene: HindIII. Nucleic Acids Res. 15, 6763 ( 1987).

  27. 27

    Roberts, R.J. & Macelis, D. REBASE-restriction enzymes and methylases . Nucleic Acids Res. 25, 248– 262 (1997).

  28. 28

    Davignon, J., Gregg, R.E. & Sing, C.F. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis 8, 1–21 (1988 ).

  29. 29

    Zhang, H. et al. Common sequence variants of lipoprotein lipase: standardized studies of in vitro expression and catalytic function. Biochim. Biophys. Acta 1302, 159–166 ( 1996).

  30. 30

    Li, W.-H. Molecular Evolution . 178–182 (Sinauer Associates, Inc., Sunderland, Massachusetts, 1997).

  31. 31

    Li, W.-H. & Sadler, L.A. Low nucleotide diversity in man . Genetics 129, 513–523 (1991).

  32. 32

    Cooper, D.N., Smith, B.A., Cooke, H.J., Niemann, S. & Schmidtke, J. An estimate of unique DNA sequence heterozygosity in the human genome. Hum. Genet. 69, 201– 205 (1985).

  33. 33

    Harding, R.M. et al. Archaic African and Asian lineages in the genetic ancestry of modern humans . Am. J. Hum. Genet. 60, 772– 789 (1997).

  34. 34

    Kruglyak, L. The use of a genetic map of biallelic markers in linkage studies. Nature Genet . 17, 21–24 ( 1997).

  35. 35

    Crandall, K.A. Identifying links between genotype and phenotype using marker loci and candidate genes . in The Impact of Plant Molecular Genetics (ed. Sobral, B.W.S.) 137–157 (Birkhauser Press, Basel, Switzerland, 1996).

  36. 36

    Templeton, A.R. Cladistic approaches to identifying determinants of variability in multifactorial phenotypes and the evolutionary significance of variation in the human genome. in Variation in the Human Genome (eds Chadwick, D.J. & Cardew, G.) 259–283 (John Wiley and Sons, Chichester, England, 1996).

  37. 37

    Rieder, M.J., Taylor, S.L., Tobe, V.O. & Nickerson, D.A. Automating the identification of DNA variations using quality-based fluorescence resequencing: analysis of the human mitochondrial genome. Nucleic Acids Res. 26, 967–973 ( 1998).

  38. 38

    Sing, C.F., Haviland, M.B. & Rielly, S.L. Genetic architecture of common multifactorial diseases . in Variation in the Human Genome (eds Chadwick, D.J. & Cardew, G.) 211–232 (John Wiley and Sons, Chichester, England, 1996).

  39. 39

    Ewing, B., Hillier, L., Wendl, M.C. & Green, P. Basecalling of automated sequencer traces using phred. I. Accuracy assessment. Genome Res . 8, 175–185 ( 1998).

  40. 40

    Ewing, B. & Green, P. Basecalling of automated sequencer traces using phred. II. Error probabilities. Genome Res. 8, 186–194 (1998).

  41. 41

    Gordon, D., Abajian, C. & Green, P. Consed: A graphical tool for sequence finishing. Genome Res. 8, 195–202 (1998).

Download references


We thank Q. Deng and V. Tobe for their assistance in obtaining the human LPL sequences, and M. Olson, D. Burke and P. Green for their advice and encouragement. This work was accomplished with support from the National Heart, Blood, and Lung Institute (HL58238, -39 & -40, HL39107) and the National Science Foundation (DIR 8809710).

Author information

Correspondence to Deborah A. Nickerson.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nickerson, D., Taylor, S., Weiss, K. et al. DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nat Genet 19, 233–240 (1998). https://doi.org/10.1038/907

Download citation

Further reading