Abstract
To better understand the forces affecting individual alleles, we introduce a method for finding the joint distribution of the frequency of a neutral allele and the extent of variability at closely linked marker loci (the intraallelic variability). We model three types of intraallelic variability: (a) the number of nonrecombinants at a linked biallelic marker locus, (b) the length of a conserved haplotype, and (c) the number of mutations at a linked marker locus. If the population growth rate is known, the joint distribution provides the basis for a test of neutrality by testing whether the observed level of intraallelic variability is consistent with the observed allele frequency. If the population growth rate is unknown but neutrality can be assumed, the joint distribution provides the likelihood of the growth rate and leads to a maximum-likelihood estimate. We apply the method to data from published data sets for four loci in humans. We conclude that the Delta32 allele at CCR5 and a disease-associated allele at MLH1 arose recently and have been subject to strong selection. Alleles at PAH appear to be neutral and we estimate the recent growth rate of the European population to be approximately 0.027 per generation with a support interval of (0.017-0.037). Four of the relatively common alleles at CFTR also appear to be neutral but DeltaF508 appears to be significantly advantageous to heterozygous carriers.
Full Text
The Full Text of this article is available as a PDF (239.6 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Aaltonen L. A., Salovaara R., Kristo P., Canzian F., Hemminki A., Peltomäki P., Chadwick R. B., Käriäinen H., Eskelinen M., Järvinen H. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med. 1998 May 21;338(21):1481–1487. doi: 10.1056/NEJM199805213382101. [DOI] [PubMed] [Google Scholar]
- Chakraborty R., Kimmel M., Stivers D. N., Davison L. J., Deka R. Relative mutation rates at di-, tri-, and tetranucleotide microsatellite loci. Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):1041–1046. doi: 10.1073/pnas.94.3.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Felsenstein J. Inbreeding and variance effective numbers in populations with overlapping generations. Genetics. 1971 Aug;68(4):581–597. doi: 10.1093/genetics/68.4.581. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Griffiths R. C., Tavaré S. Sampling theory for neutral alleles in a varying environment. Philos Trans R Soc Lond B Biol Sci. 1994 Jun 29;344(1310):403–410. doi: 10.1098/rstb.1994.0079. [DOI] [PubMed] [Google Scholar]
- Kaplan N. L., Lewis P. O., Weir B. S. Age of the delta F508 cystic fibrosis mutation. Nat Genet. 1994 Nov;8(3):216–218. doi: 10.1038/ng1194-216a. [DOI] [PubMed] [Google Scholar]
- McPeek M. S., Strahs A. Assessment of linkage disequilibrium by the decay of haplotype sharing, with application to fine-scale genetic mapping. Am J Hum Genet. 1999 Sep;65(3):858–875. doi: 10.1086/302537. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moisio A. L., Sistonen P., Weissenbach J., de la Chapelle A., Peltomäki P. Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer. Am J Hum Genet. 1996 Dec;59(6):1243–1251. [PMC free article] [PubMed] [Google Scholar]
- Morral N., Bertranpetit J., Estivill X., Nunes V., Casals T., Giménez J., Reis A., Varon-Mateeva R., Macek M., Jr, Kalaydjieva L. The origin of the major cystic fibrosis mutation (delta F508) in European populations. Nat Genet. 1994 Jun;7(2):169–175. doi: 10.1038/ng0694-169. [DOI] [PubMed] [Google Scholar]
- Peltonen L., Pekkarinen P., Aaltonen J. Messages from an isolate: lessons from the Finnish gene pool. Biol Chem Hoppe Seyler. 1995 Dec;376(12):697–704. doi: 10.1515/bchm3.1995.376.12.697. [DOI] [PubMed] [Google Scholar]
- Richman A. D., Uyenoyama M. K., Kohn J. R. Allelic diversity and gene genealogy at the self-incompatibility locus in the Solanaceae. Science. 1996 Aug 30;273(5279):1212–1216. doi: 10.1126/science.273.5279.1212. [DOI] [PubMed] [Google Scholar]
- Rommens J. M., Iannuzzi M. C., Kerem B., Drumm M. L., Melmer G., Dean M., Rozmahel R., Cole J. L., Kennedy D., Hidaka N. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989 Sep 8;245(4922):1059–1065. doi: 10.1126/science.2772657. [DOI] [PubMed] [Google Scholar]
- Slatkin M. Allele age and a test for selection on rare alleles. Philos Trans R Soc Lond B Biol Sci. 2000 Nov 29;355(1403):1663–1668. doi: 10.1098/rstb.2000.0729. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Slatkin M., Rannala B. Estimating allele age. Annu Rev Genomics Hum Genet. 2000;1:225–249. doi: 10.1146/annurev.genom.1.1.225. [DOI] [PubMed] [Google Scholar]
- Stephens J. C., Reich D. E., Goldstein D. B., Shin H. D., Smith M. W., Carrington M., Winkler C., Huttley G. A., Allikmets R., Schriml L. Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes. Am J Hum Genet. 1998 Jun;62(6):1507–1515. doi: 10.1086/301867. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weber J. L., Wong C. Mutation of human short tandem repeats. Hum Mol Genet. 1993 Aug;2(8):1123–1128. doi: 10.1093/hmg/2.8.1123. [DOI] [PubMed] [Google Scholar]
- Wiuf C. On the genealogy of a sample of neutral rare alleles. Theor Popul Biol. 2000 Aug;58(1):61–75. doi: 10.1006/tpbi.2000.1469. [DOI] [PubMed] [Google Scholar]
- Wright S. W., Morton N. E. Genetic studies on cystic fibrosis in Hawaii. Am J Hum Genet. 1968 Mar;20(2):157–169. [PMC free article] [PubMed] [Google Scholar]
- Xiong M., Guo S. W. Fine-scale genetic mapping based on linkage disequilibrium: theory and applications. Am J Hum Genet. 1997 Jun;60(6):1513–1531. doi: 10.1086/515475. [DOI] [PMC free article] [PubMed] [Google Scholar]