Finding the molecular basis of quantitative traits: Successes and pitfalls

Nature Reviews Genetics

Volumn 2, Issue 6, 2001, Pages 437-445

  Flint, Jonathan ^a   Mott, Richard ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

HEXAPODA; RODENTIA;

ANIMAL; CHROMOSOME MAP; GENE EXPRESSION PROFILING; GENETIC LINKAGE; HUMAN; QUANTITATIVE TRAIT; REVIEW;

ANIMALS; CHROMOSOME MAPPING; GENE EXPRESSION PROFILING; HUMANS; LINKAGE (GENETICS); QUANTITATIVE TRAIT, HERITABLE;

EID: 0035380102     PISSN: 14710056     EISSN: None     Source Type: Journal    
DOI: 10.1038/35076585     Document Type: Review

References (68)

1. Barton, N. H. & Turell, M. Evolutionary quantitative genetics. Annu. Rev. Genet. 23, 337-370 (1989).
2. Thoday, J. M. in Quantitative Genetic Variation (eds Thompson, J. N. & Thoday, J. M.) 219-233 (Academic, New York, 1979).
3. Janksley, S. D. Mapping polygenes. Annu. Rev. Genet. 27, 205-233 (1993).
4. Lander, E. S. & Schork, N. J. Genetic dissection of complex traits. Science 265, 2037-2048 (1994).
5. Paterson, A. et al. Resolution of quantitative traits into Mendelian factors using a complete RFLP linkage map. Nature 335, 721-726 (1988).
6. Todd, J. A. et al. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature 351, 542-547 (1991).
7. Hilbert, P. et al. Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats. Nature 353, 521-529 (1991).
8. Jacob, H. et al. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell 67, 213-224 (1991). References 6-8 were the first studies to show QTL mapping using the genome-wide sets of polymorphic markers in crosses between inbred rodents.
9. Cardon, L. R. & Bell, J. I. Association study designs for complex diseases. Nature Rev. Genet. (2001).
10. Risch, N. J. Searching for genetic determinants in the new millennium. Nature 405, 847-856 (2000). References 9 and 10 are excellent reviews of the problems of mapping complex traits in humans.
11. Podolin, R. L. et al. Localization of two insulin-dependent diabetes (ldd) genes to the ldd10 region on mouse chromosome 3. Mamm. Genome 9, 283-286 (1998).
12. Legare, M. E., Bartlett, F. S. & Frankel, W. N. A major effect QTL determined by multiple genes in epileptic EL mice. Genome Res. 10, 42-48 (2000).
13. Darvasi, A. & Soller, M. A simple method to calculate resolving power and confidence interval of QTL map location. Behav. Genet. 27, 125-132 (1997).
14. Cohen, B. A., Mitra, R. D., Hughes, J. D. & Church, G. M. A computational analysis of whole-genome expression data reveals chromosomal domains of gene expression. Nature Genet. 26, 183-186 (2000).
15. Frankel, W. N. & Schork, N. J. Who's afraid of epistasis? Nature Genet. 14, 371-373 (1996).
16. Gurganus, M. C., Nuzhdin, S. V., Leips, J. W. & Mackay, T. F. High-resolution mapping of quantitative trait loci for sternopleural bristle number in Drosophila melanogaster. Genetics 152, 1585-1604 (1999).
17. Long, A. D. et al. High resolution mapping of genetic factors affecting abdominal bristle number in Drosophila melanogaster. Genetics 139, 1273-1291 (1995).
18. Lukens, L. N. & Doebley, J. Epistatic and environmental interactions for quantitative trait loci involved in maize evolution. Genet. Res. 74, 291-302 (1999).
19. Lark, K. G., Chase, K., Adler, F., Mansur, L. M. & Orf, J. H. Interactions between quantitative trait loci in soybean in which trait variation at one locus is conditional upon a specific allele at another. Proc. Natl Acad. Sci. USA 92, 4656-4660 (1995).
20. Fijneman, R. J., de Vries, S. S., Jansen, R. C. & Demant, P. Complex interactions of new quantitative trait loci, Sluc1, Sluc2, Sluc3, and Sluc4, that influence the susceptibility to lung cancer in the mouse. Nature Genet. 14, 465-467 (1996). An excellent demonstration of the Importance of epistasis and the need to design studies specifically to detect its effect.
21. Van Wezel, T. et al. Gene interaction and single gene effects in colon tumour susceptibility in mice. Nature Genet. 14, 468-470 (1996).
22. Van Wezel, T., Ruivenkamp, C. A., Stassen, A. P., Moen, C. J. & Demant, P. Four new colon cancer susceptibility loci, Scc6 to Scc9 in the mouse. Cancer Res. 59, 4216-4218 (1999).
23. Rikke, B. A. & Johnson, T. E. Towards the cloning of genes underlying murine QTLs. Mamm. Genome 9, 963-968 (1998).
24. Darvasi, A. Experimental strategies for the genetic dissection of complex traits in animal models. Nature Genet. 18, 19-24 (1998). An outstanding review of QTL mapping in animals.
25. Alpert, K. B. & Tanksley, S. D. High-resolution mapping and isolation of a yeast artificial chromosome contig containing fw2.2: a major fruit weight quantitative trait locus in tomato. Proc. Natl Acad. Sci. USA 93, 15503-15507 (1996).
26. Fridman, E., Pleban, T. & Zamir, D. A recombination hotspot delimits a wild-species quantitative trait locus for tomato sugar content to 484 bp within an invertase gene. Proc. Natl Acad. Sci. USA 97, 4718-4723 (2000).
27. Denny, P. et al. Mapping of the IDDM locus ldd3 to a 0.35-cM interval containing the interleukin-2 gene. Diabetes 46, 695-700 (1997).
28. Hanson, W. D. Theoretical distribution of the initial linkage block lengths intact in the gametes of a population intermarried for n generations. Genetics 44, 839-846 (1959).
29. Hanson, W. D. The breakup of initial linkage blocks under selected mating systems. Genetics 44, 857-868 (1959).
30. Darvasi, A. & Soller, M. Advanced intercross lines, an experimental population for fine genetic mapping. Genetics 141, 1199-1207 (1995).
31. Xiong, M. I. & Guo, S. W. Fine-scale mapping of quantitative trait loci using historical recombinations. Genetics 145, 1201-1218 (1997).
32. Haley, C. S. Livestock QTLs - bringing home the bacon? Trends Genet. 11, 488-492 (1995).
33. Riquet, J. et al. Fine-mapping of quantitative trait loci by identity by descent in outbred populations: application to milk production in dairy cattle. Proc. Natl Acad Sci. USA 96, 9252-9257 (1999).
34. Coppieters, W. et al. A QTL with major effect on milk yield and composition maps to bovine chromosome 14. Mamm. Genome 9, 540-544 (1998).
35. Iraqi, F. et al. Fine mapping of trypanosomiasis resistance loci in murine advanced intercross lines. Mamm. Genome 11, 645-648 (2000).
36. Talbot, C. J. et al. High-resolution mapping of quantitative trait loci in outbred mice. Nature Genet. 21, 305-308 (1999).
37. Mott, R., Talbot, C., Turri, M., Collins, A. C. & Flint, J. A new method for fine mapping quantitative trait loci in outbred animal stocks. Proc. Natl Acad. Sci. USA 97, 12649-12654 (2000). References 36 and 37 introduced QTL mapping in outbred animals to mouse genetics.
38. Lyman, R. F., Lai, C. & Mackay, T. F. Linkage disequilibrium mapping of molecular polymorphisms at the scabrous locus associated with naturally occurring variation in bristle number in Drosophila melanogaster. Genet. Res. 74, 303-311 (1999).
39. Wang, R. L., Stec, A., Hey, J., Lukens, L. & Doebley, J. The limits of selection during maize domestication. Nature 398, 236-239 (1999).
40. Higgs, D. R. et al. A major positive regulatory region located far upstream of the human α-globin gene locus. Genes Dev. 4, 1588-1601 (1990).
41. Symula, D. J. et al. Functional screening of an asthma QTL in YAC transgenic mice. Nature Genet. 23, 241-244 (1999). The first attempt to use large insert YAC clones to identify QTL The method relies on the addition of exogenous DNA and is thus a departure from tests in which the animal Is diploid at the QTL.
42. Cormier, R. T. et al. Secretory phospholipase P1a2g2a confers resistance to intestinal tumorigenesis. Nature Genet. 17, 88-91 (1997). One of the first attempts to use functional complementation to identify a QTL in mice.
43. Aitman, T. J. et al. Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nature Genet. 21, 76-63 (1999). The first use of combined mapping and expression profiling to identify a QTL in animals.
44. Frary, A. et al. fw2.2: a quantitative trait locus key to the evolution of tomato fruit size. Science 289, 85-88 (2000). The first QTL to be cloned by positional information and complementation.
45. Monforte, A. J. & Tanksley, S. D. Development of a set of near isogenic and backcross recombinant inbred lines containing most of the Lycopersicon hirsutum genome in a L. esculentum genetic background: a tool for gene mapping and gene discovery. Genome 43, 803-813 (2000).
46. Mackay, T. F. Quantitative trait loci in Drosophila. Nature Rev. Genet. 2, 11-20 (2001). An excellent review of the approaches available to Drosophila geneticists for cloning QTL.
47. Zheng, B. et al. Engineering a mouse balancer chromosome. Nature Genet. 22, 375-378 (1999).
48. Su, H., Wang, X. & Bradley, A. Nested chromosomal deletions induced with retroviral vectors in mice. Nature Genet. 24, 92-95 (2000).
49. Ramirez-Solis, R., Liu, P. & Bradley, A. Chromosome engineering in mice. Nature 378, 720-724 (1995). References 47-49 show that the genetic reagents available to fly geneticists can also be generated for use in mice.
50. Wakayama, T., Tateno, H., Mombaerts, P. & Yanagimachi, R. Nuclear transfer into mouse zygotes. Nature Genet. 24, 108-109 (2000).
51. Rideout, W. M. et al. Generation of mice from wild-type and targeted ES cells by nuclear cloning. Nature Genet. 24, 109-110 (2000).
52. Loots, G. G. et al. Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science 288, 136-140 (2000).
53. Karp, C. L. et al. Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nature Immunol. 1, 221-226 (2000).
54. Iyer, V. R. et al. The transcriptional program in the response of human fibroblasts to serum. Science 283, 83-87 (1999).
55. Castensson, A., Emilsson, L., Preece, P. & Jazin, E. E. High-resolution quantification of specific mRNA levels in human brain autopsies and biopsies. Genome Res. 10, 1219-1229 (2000).
56. Horikawa, Y. et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nature Genet. 26, 163-175 (2000).
57. Mackay, T. F. & Langley, C. H. Molecular and phenotypic variation in the achaete-scute region of Drosophila melanogaster. Nature 348, 64-66 (1990).
58. Lai, C., Lyman, R. F., Long, A. D., Langley, C. H. & Mackay, T. F. Naturally occurring variation in bristle number and DNA polymorphisms at the scabrous locus of Drosophila melanogaster. Science 266, 1697-1702 (1994).
59. Long, A. D., Mullaney, S. L., Mackay, T. F. C. & Langley, C. H. Genetic interactions between naturally occurring alleles at quantitative trait loci and mutant alleles at candidate loci affecting bristle number in Drosophila melanogaster. Genetics 144, 1497-1510 (1996).
60. Long, A. D., Lyman, R. F., Morgan, A. H., Langley, C. H. & Mackay, T. F. Both naturally occurring insertions of transposable elements and intermediate frequency polymorphisms at the achaete-scute complex are associated with variation in bristle number in Drosophila melanogaster. Genetics 154, 1255-1269 (2000).
61. Lynch, M. & Walsh, B. Genetics and Analysis of Quantitative Traits (Sinauer Associates, Sunderland, Massachusetts, 1998). All you could wish to know about the statistical analysis of QTL mapping. A classic textbook on quantitative genetics.
62. Falconer, D. S. & Mackay, T. F. C. Quantitative Genetics (Longman, Harlow, UK, 1996). A classic textbook on quantitative genetics.
63. Brown, S. D. & Nolan, P. M. Mouse mutagenesis -systematic studies of mammalian gene function. Hum. Mol. Genet. 7, 1627-1633 (1998).
64. Hunter, A. J., Nolan, P. M. & Brown, S. D. Towards new models of disease and physiology in the neurosciences: the role of induced and naturally occurring mutations. Hum. Mol. Genet. 9, 893-900 (2000).
65. Nadeau, J. H. & Frankel, W. N. The roads from phenotypic variation to gene discovery: mutagenesis versus QTLs. Nature Genet. 25, 381-384 (2000). This article argues that mutagenesis is the way ahead for the genetic dissection of complex traits.
66. Comuzzie, A. G. & Allison, D. B. The search for human obesity genes. Science 280, 1374-1377 (1998).
67. Hager, J. et al. A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10. Nature Genet. 20, 304-308 (1998).
68. Jackson, R. S. et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nature Genet. 16, 303-306 (1997).