Summary
Eight polymorphic restriction enzyme sites at the phenylalanine hydroxylase (PAH) locus were analyzed from the parental chromosomes in 33 Danish nuclear families with at least one phenylketonuric (PKU) child. Determination of haplotypes of 66 normal chromosomes and 66 chromosomes bearing mutant allele (S) demonstrated that there are at least two haplotypes which occur predominantly on PKU chromosomes and rarely otherwise. Overall, the relative frequencies of the various haplotypes are significantly different on PKU-and normal-allele bearing chromosomes, even though there is no predominantly occurring unique haplotype which can characterize the PKU chromosomes. In addition, no significant association (linkage disequilibrium) between any single polymorphic site and the mutant allele (s) was observed. The results suggest that either the phenylketonuric mutation was very ancient so that the polymorphic sites and the mutation have reached linkage equilibrium or the mutant allele (s) are the results of multiple mutations in the phenylalanine hydroxylase gene in man. Furthermore, a crude relationship between standardized linkage disequilibria and physical map distances of the polymorphic sites indicates that there is no apparent recombination hot-spot in the human phenylalanine hydroxylase gene, since the recombination rate within the locus apears to be uniform and likely to be occurring at a rate similar to that within the HLA gene cluster. The limitations of this later analysis are discussed in view of the sampling errors of disequilibrium measure used, and the potential untility of the PAH haplotypes for prenatal diagnosis and detection of PKU carriers is established.
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References
Barker D, Holm T, White R (1984) A locus on chromosome 11p with multiple restriction site polymorphisms. Am J Hum Genet 36:1159–1171
Brown AHD (1975) Sample size required to detect linkage disequilibrium between two or three loci. Theor Popul Biol 8:184–201
Chakraborty R (1986) Estimation of linkage disequilibrium from conditional haplotype data: application to β-globin gene cluster in American Blacks. Genet Epidemiol 3:323–333
Chakravarti A, Buetow KH (1985) A strategy for using multiple linked markers for genetic counselling. Am J Hum Genet 37:984–997
Chakravarti A, Nei M (1982) Utility and efficiency of linked marker genes for genetic counseling. II. Identification of linkage phase by offspring phenotypes. Am J Hum Genet 34:531–551
Chakravarti A, Buetow KH, Antonarakis SE, Waber PG, Boehm CD, Kazazian HH (1984a) Nonuniform recombination within the human β-globin gene cluster. Am J Hum Genet 36:1239–1258
Chakravarti A, Phillips JA, Mellits KH, Buetow KH, Seeburg PH (1984b) Patterns of polymorphism and linkage disequilibrium suggest independent origins of the human growth hormone gene cluster. Proc Natl Acad Sci USA 81:6085–6089
Chakravarti A, Elbein SC, Permutt MA (1986) Evidence for increased recombination near the human insulin gene: implication for disease association studies. Proc Natl Acad Sci USA 83:1045–1049
Daiger SP, Lidsky AS, Chakraborty R, Koch R, Güttler F, Woo SLC (1986) Polymorphic DNA haplotypes at the phenylalanine hydroxylase locus in prenatal diagnosis of phenylketonuria. Lancet I: 29–232
DiLella AG, Ledley FD, Rey F, Munnick A, Woo SLC (1985) Detection of phenylalanine hydroxylase messenger RNA in liver biopsy from patients with phenylketonuria. Lancet I:160–161
DiLella AG, Kwok SCM, Ledley FD, Marvet J, Woo SLC (1986a) Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene. Biochemistry 25:743–749
DiLella AG, Marvit J, Lidsky AS, Güttler F, Woo SLC (1986b) Tight linkage between a splicing mutation and a specific DNA haplotype in phenylketonuria. Nature 322:799–803
Fölling A (1934) Über Ausscheidung von Phenylbrenztraubensäure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillität. Z Physiol Chem 227:169–176
Golding GB (1984) The sampling distribution of linkage disequilibrium. Genetics 108:257–274
Güttler F (1980) Hyperphenylalaninemia: diagnosis and classification of the various types of phenylalanine hydroxylase deficiency in childhood. Acta Paediatr Scand [Suppl] 280:7–80
Hill WG, Robertson A (1968) Linkage disequilibrium in finite populations. Theor Appl Genet 38:226–231
Hudson RR (1985) The sampling distribution of linkage disequilibrium under infinite allele model without selection. Genetics 109:611–631
Kendall MG (1948) The advanced theory of statistics, vol I. Griffin, London
Kwok S, Ledley FD, DiLella AG, Robson KJH, Woo SLC (1985) Nucleotide sequence of a full-length cDNA clone of human phenylalanine hydroxylase. Biochemistry 24:556–561
Ledley FD, Grenett HE, DiDella AG, Kwok SCM, Woo SLC (1985) Gene transfer and expression of human phenylhydroxylase. Science 228:77–79
Lidsky A, Robson K, Chandra T, Barker P, Ruddle F, Woo SLC (1984) The PKU locus in man is on chromoosme 12. Am J Hum Genet 36:527–534
Lidsky AS, Güttler F, Woo SLC (1985a) Prenatal diagnosis of phenylketonuria by DNA analyses. Lancet I:549–551
Lidsky AS, Law ML, Morse HG, Kao FT, Rabin MR, Ruddle F, Woo SLC (1985b) Regional mapping of the phenylalanine hydroxylase gene and the phenylketonuria locus in the human genome. Proc Natl Acad Sci USA 82:6221–6225
Lidsky AS, Ledley FD, DiLella AG, Kwok SCM, Daiger SP, Robson KJH, Woo SLC (1985c) Extensive restriction site polymorphism at the human phenylalanine hydroxylase locus and application in prenatal diagnosis of phenylketonuria. Am J Hum Genet 37:619–634
Mantel NA (1967) The detection of disease clustering and a generalized regression approach. Cancer Res 27:209–220
Nei M, Roychoudhury AK (1982) Genetic relationship and evolution of human races. Evol Biol 14:1–59
Orkin SH, Kazazian HH (1984) The mutation and polymorphism of the human β-globin gene and its surrounding DNA. Annu Rev Genet 18:131–172
Pagnier J, Labie D, Lachman HM, Dunda-Belkhodja O, Kaptue-Noche L, Zohoun I, Nagel RL, Mears JG (1983) Distribution and evolution of hemoglobin and globin loci. Elsevier, New York Amsterdam, pp 145–158
Pagnier J, Mears JG, Dunda-Belkhodja O, Schaeffer-Rego KE, Beldjord C, Nagel RL, Labie D (1984) Evidence for the multicentric origin of the sickle cell hemoglobin gene in Africa. Proc Natl Acad Sci USA 81:1771–1773
Rao CR (1965) Linear statistical inference and its applications. Wiley, New York
Smouse PE, Long JC, Sokal RR (1986) Extensions of Mantel's permutation test to multiple regressions involving several variables. Syst Zool 35:627–635
Spritz RA (1981) Duplication/deletion polymorphism 5′-to the human β globin gene. Nucleic Acids Res 9:5037–5047
Sved JA (1971) Linkage disequilibrium and homozygosity of chromosomal segments in finite populations. Theor Popul Biol 2:125–141
Terasaki PI (1980) Histocompatibility testing. UCLA Tissue Typing Laboratory, Los Angeles
Treco D, Thomas B, Arheim N (1985) Analysis of a recombinational hotspot in the human β-globin gene cluster: meiotic recombination of human DNA fragments in S. crevisiae. Mol Cell Biol 5:2029–2038
Vogel F, Motulsky AG (1979) Human genetics: problems and approaches. Springer, Berlin Heidelberg New York
Weir BS, Hill WG (1986) Non-uniform recombination within the human β-globin gene cluster. Am J Hum Genet 38:776–778
Weitkamp LR, Lamm L (1982) Report of the committee on the gene constitution of chromosome 6. Cytogenet Cell Genet 32:130–142
Woo SLC, Lidsky AS, Güttler F, Chandra T, Robson KJH (1983) Cloned human phenylalanine hydroxylase gene allows prenatal diagnosis and carrier detection of classical phenylketonuria. Nature 306:151–155
Woolf LI (1976) A study of the cause of the high incidence of phenylketonuria in Ireland and west Scotland. J Ir Med Assoc 69:398–401
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Chakraborty, R., Lidsky, A.S., Daiger, S.P. et al. Polymorphic DNA haplotypes at the human phenylalanine hydroxylase locus and their relationship with phenylketonuria. Hum Genet 76, 40–46 (1987). https://doi.org/10.1007/BF00283048
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DOI: https://doi.org/10.1007/BF00283048