DNA sequence variation in a 3.7-kb noncoding sequence 5' of the CYP1A2 gene: implications for human population history and natural selection.

CYP1A2 is a cytochrome P450 gene that is involved in human physiological responses to a variety of drugs and toxins. To investigate the role of population history and natural selection in shaping genetic diversity in CYP1A2, we sequenced a 3.7-kb region 5' from CYP1A2 in a diverse collection of 113 individuals from three major continental regions of the Old World (Africa, Asia, and Europe). We also examined sequences in the 90-member National Institutes of Health DNA Polymorphism Discovery Resource (PDR). Eighteen single-nucleotide polymorphisms (SNPs) were found. Most of the high-frequency SNPs found in the Old World sample were also found in the PDR sample. However, six SNPs were detected in the Old World sample but not in the PDR sample, and two SNPs found in the PDR sample were not found in the Old World sample. Most pairs of SNPs were in complete linkage disequilibrium with one another, and there was no indication of a decline of disequilibrium with physical distance in this region. The average +/- SD nucleotide diversity in the Old World sample was 0.00043+/-0.00026. The African population had the highest level of nucleotide diversity and the lowest level of linkage disequilibrium. Two distinct haplotype clusters with broadly overlapping geographical distributions were present. Of the 17 haplotypes found in the Old World sample, 12 were found in the African sample, 8 were found in Indians, 5 were found in non-Indian Asians, and 5 were found in Europeans. Haplotypes found outside Africa were mostly a subset of those found within Africa. These patterns are all consistent with an African origin of modern humans. Seven SNPs were singletons, and the site-frequency spectrum showed a significant departure from neutral expectations, suggesting population expansion and/or natural selection. Comparison with outgroup species showed that four derived SNPs have achieved high (>0.90) frequencies in human populations, a trend consistent with the action of positive natural selection. These patterns have a number of implications for disease-association studies in CYP1A2 and other genes.

[1]  L. Jin,et al.  Worldwide Dna Sequence Variation in a 10-kilobase Noncoding Region on Human Chromosome 22 Materials and Methods Dna Samples. Sixty-four Individuals Were Collected Worldwide from 16 Populations in Four Major Geographic Areas, including 20 , 2022 .

[2]  Yun-Xin Fu,et al.  New statistical tests of neutrality for DNA samples from a population. , 1996, Genetics.

[3]  M. King,et al.  Genomic views of human history. , 1999, Science.

[4]  M. Nachman,et al.  Single nucleotide polymorphisms and recombination rate in humans. , 2001, Trends in genetics : TIG.

[5]  S. Pääbo.  Human evolution. , 1999, Trends in cell biology.

[6]  S. Pääbo,et al.  Mitochondrial genome variation and the origin of modern humans , 2000, Nature.

[7]  Wen-Hsiung Li,et al.  Low nucleotide diversity in man. , 1991, Genetics.

[8]  M. Rieder,et al.  Sequence variation in the human angiotensin converting enzyme , 1999, Nature Genetics.

[9]  N. Shen,et al.  Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis , 1999, Nature Genetics.

[10]  Justin C. Fay,et al.  Hitchhiking under positive Darwinian selection. , 2000, Genetics.

[11]  E. Boerwinkle,et al.  Sequence diversity and large-scale typing of SNPs in the human apolipoprotein E gene. , 2000, Genome research.

[12]  M. Nachman,et al.  DNA variability and recombination rates at X-linked loci in humans. , 1998, Genetics.

[13]  H. Harpending,et al.  Population growth makes waves in the distribution of pairwise genetic differences. , 1992, Molecular biology and evolution.

[14]  I. Evett,et al.  Interpreting DNA Evidence: Statistical Genetics for Forensic Scientists , 1998 .

[15]  M. Nei,et al.  Extent of protein polymosphism and the neutral mutation theory , 1984 .

[16]  Microsatellite evolution in modern humans: a comparison of two data sets from the same populations. , 2000, Annals of human genetics.

[17]  W Stephan,et al.  The hitchhiking effect on the site frequency spectrum of DNA polymorphisms. , 1995, Genetics.

[18]  D. Nickerson,et al.  PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. , 1997, Nucleic acids research.

[19]  M Masellis,et al.  A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia , 2000, Molecular Psychiatry.

[20]  J. Klein,et al.  Divergence time and population size in the lineage leading to modern humans. , 1995, Theoretical population biology.

[21]  W. Gilbert,et al.  Absence of polymorphism at the ZFY locus on the human Y chromosome. , 1995, Science.

[22]  S T Sherry,et al.  Genetic traces of ancient demography. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[23]  F. Tajima.  Evolutionary relationship of DNA sequences in finite populations. , 1983, Genetics.

[24]  E. Boerwinkle,et al.  DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene , 1998, Nature Genetics.

[25]  R J Mitchell,et al.  The geographic distribution of human Y chromosome variation. , 1997, Genetics.

[26]  L. Jin,et al.  Microsatellite data support an early population expansion in Africa. , 1997, Genome research.

[27]  M. Nachman,et al.  Estimate of the mutation rate per nucleotide in humans. , 2000, Genetics.

[28]  S. Sherry,et al.  Alu evolution in human populations: using the coalescent to estimate effective population size. , 1997, Genetics.

[29]  L. Zhivotovsky,et al.  Human population expansion and microsatellite variation. , 2000, Molecular biology and evolution.

[30]  S. P. Fodor,et al.  Determination of ancestral alleles for human single-nucleotide polymorphisms using high-density oligonucleotide arrays , 1999, Nature Genetics.

[31]  K. Kidd,et al.  Evolution of a HOXB6 intergenic region within the great apes and humans. , 1999, Journal of human evolution.

[32]  S. Shyue,et al.  Larger genetic differences within africans than between Africans and Eurasians. , 2002, Genetics.

[33]  E. Lander,et al.  Characterization of single-nucleotide polymorphisms in coding regions of human genes , 1999 .

[34]  M Kimmel,et al.  Signatures of population expansion in microsatellite repeat data. , 1998, Genetics.

[35]  M. Rietschel,et al.  Lack of association between a functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene and tardive dyskinesia in schizophrenia. , 2001, American journal of medical genetics.

[36]  S. Easteal,et al.  Departure from neutrality at the mitochondrial NADH dehydrogenase subunit 2 gene in humans, but not in chimpanzees. , 1998, Genetics.

[37]  S. Fullerton,et al.  Molecular and population genetic analysis of allelic sequence diversity at the human beta-globin locus. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Michael F. Hammer,et al.  A recent common ancestry for human Y chromosomes , 1995, Nature.

[39]  A. Pérez-Lezaun,et al.  Microsatellite variation and the differentiation of modern humans , 1996, Human Genetics.

[40]  Henrik Kaessmann,et al.  DNA sequence variation in a non-coding region of low recombination on the human X chromosome , 1999, Nature Genetics.

[41]  W S Watkins,et al.  Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region. , 1994, American journal of human genetics.

[42]  C. Aquadro,et al.  Genome-wide variation in the human and fruitfly: a comparison. , 2001, Current opinion in genetics & development.

[43]  M W Feldman,et al.  Recent common ancestry of human Y chromosomes: evidence from DNA sequence data. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[44]  S. Kitareewan,et al.  Expression of CYP1A1 and CYP1A2 genes in human liver. , 1993, Pharmacogenetics.

[45]  K K Kidd,et al.  A global haplotype analysis of the myotonic dystrophy locus: implications for the evolution of modern humans and for the origin of myotonic dystrophy mutations. , 1998, American journal of human genetics.

[46]  N E Morton,et al.  Genetic epidemiology of single-nucleotide polymorphisms. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[47]  R. Lewontin,et al.  A molecular approach to the study of genic heterozygosity in natural populations. II. Amount of variation and degree of heterozygosity in natural populations of Drosophila pseudoobscura. , 1966, Genetics.

[48]  L. Jorde,et al.  Genetic evidence on modern human origins. , 1995, Human biology.

[49]  D. Labuda,et al.  Archaic lineages in the history of modern humans. , 2000, Genetics.

[50]  Simon Tavaré,et al.  Linkage disequilibrium: what history has to tell us. , 2002, Trends in genetics : TIG.

[51]  K K Kidd,et al.  The accuracy of statistical methods for estimation of haplotype frequencies: an example from the CD4 locus. , 2000, American journal of human genetics.

[52]  M. Feldman,et al.  Population growth of human Y chromosomes: a study of Y chromosome microsatellites. , 1999, Molecular biology and evolution.

[53]  D. Collier,et al.  Identification of novel polymorphisms in the 5' flanking region of CYP1A2, characterization of interethnic variability, and investigation of their functional significance. , 2000, Pharmacogenetics.

[54]  M. Daly,et al.  A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms , 2001, Nature.

[55]  J. Kere,et al.  Microsatellite diversity and the demographic history of modern humans. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[56]  R. Lewontin.  The Interaction of Selection and Linkage. I. General Considerations; Heterotic Models. , 1964, Genetics.

[57]  R. W. Davis,et al.  Population genetic implications from sequence variation in four Y chromosome genes. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[58]  F. Tajima.  Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. , 1989, Genetics.

[59]  P Donnelly,et al.  Heterogeneity of microsatellite mutations within and between loci, and implications for human demographic histories. , 1998, Genetics.

[60]  Joanna L. Mountain,et al.  Molecular evolution and modern human origins , 1998 .

[61]  Charles F. Sing,et al.  Genetics of cellular, individual, family, and population variability , 1993 .

[62]  J. Wall,et al.  When did the human population size start increasing? , 2000, Genetics.

[63]  S. Fullerton,et al.  Molecular andpopulation genetic analysis ofallelic sequence diversity atthehuman,B-globin locus , 1994 .

[64]  L. Excoffier,et al.  Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. , 1995, Molecular biology and evolution.

[65]  Pardis C Sabeti,et al.  Linkage disequilibrium in the human genome , 2001, Nature.

[66]  M. Batzer,et al.  Patterns of ancestral human diversity: an analysis of Alu-insertion and restriction-site polymorphisms. , 2001, American journal of human genetics.

[67]  M. Hammer,et al.  Out of Africa and back again: nested cladistic analysis of human Y chromosome variation. , 1998, Molecular biology and evolution.

[68]  J. Relethford,et al.  Genetic evidence for larger African population size during recent human evolution. , 1999, American journal of physical anthropology.

[69]  Hongyu Zhao,et al.  A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus , 1998, Human Genetics.

[70]  J. Swanson,et al.  Evidence of positive selection acting at the human dopamine receptor D4 gene locus , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[71]  M. Bamshad,et al.  Using mitochondrial and nuclear DNA markers to reconstruct human evolution , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[72]  L. Cavalli-Sforza,et al.  High resolution of human evolutionary trees with polymorphic microsatellites , 1994, Nature.

[73]  M. Shriver,et al.  Intra‐ and inter‐population diversity at short tandem repeat loci in diverse populations of the world , 1995, Electrophoresis.

[74]  J. Brockmöller,et al.  Functional significance of a C-->A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. , 1999, British journal of clinical pharmacology.

[75]  P. Green,et al.  Base-calling of automated sequencer traces using phred. I. Accuracy assessment. , 1998, Genome research.

[76]  R. Griffiths,et al.  Archaic African and Asian lineages in the genetic ancestry of modern humans. , 1997, American journal of human genetics.

[77]  Alberto Piazza,et al.  The History and Geography of Human Genes: Abridged paperback Edition , 1996 .

[78]  E. Ford,et al.  Genetic polymorphism , 2020, Proceedings of the Royal Society of London. Series B. Biological Sciences.

[79]  K K Kidd,et al.  Drift, admixture, and selection in human evolution: a study with DNA polymorphisms. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[80]  S. Tishkoff,et al.  Global Patterns of Linkage Disequilibrium at the CD4 Locus and Modern Human Origins , 1996, Science.

[81]  M. Nachman,et al.  Contrasting evolutionary histories of two introns of the duchenne muscular dystrophy gene, Dmd, in humans. , 2000, Genetics.

[82]  S. Liu-Cordero.  Patterns of linkage disequilibrium in the human genome , 2002 .

[83]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[84]  J. Pritchard,et al.  Linkage disequilibrium in humans: models and data. , 2001, American journal of human genetics.

[85]  W. Speed,et al.  Short tandem repeat polymorphism evolution in humans , 1998, European Journal of Human Genetics.

[86]  W. Li,et al.  Statistical tests of neutrality of mutations. , 1993, Genetics.

[87]  Peter D. Keightley,et al.  High genomic deleterious mutation rates in hominids , 1999, Nature.

[88]  B Brinkmann,et al.  A short tandem repeat-based phylogeny for the human Y chromosome. , 2000, American journal of human genetics.

[89]  H. Harpending,et al.  Genetic perspectives on human origins and differentiation. , 2000, Annual review of genomics and human genetics.

[90]  D. F. Roberts,et al.  The History and Geography of Human Genes , 1996 .

[91]  W S Watkins,et al.  Population genomics: a bridge from evolutionary history to genetic medicine. , 2001, Human molecular genetics.

[92]  Li Jin,et al.  Y chromosome sequence variation and the history of human populations , 2000, Nature Genetics.

[93]  Wen-Hsiung Li,et al.  Global patterns of human DNA sequence variation in a 10-kb region on chromosome 1. , 2001, Molecular biology and evolution.

[94]  W S Watkins,et al.  The distribution of human genetic diversity: a comparison of mitochondrial, autosomal, and Y-chromosome data. , 2000, American journal of human genetics.

[95]  M. Seielstad,et al.  A view of modern human origins from Y chromosome microsatellite variation. , 1999, Genome research.

[96]  S. Tishkoff,et al.  Genetic Structure of the Ancestral Population of Modern Humans , 1998, Journal of Molecular Evolution.

[97]  Feng-Chi Chen,et al.  Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. , 2001, American journal of human genetics.

[98]  J. Stephens,et al.  Haplotype Variation and Linkage Disequilibrium in 313 Human Genes , 2001, Science.

[99]  R. Hudson,et al.  A test of neutral molecular evolution based on nucleotide data. , 1987, Genetics.

[100]  J. Witte,et al.  Linkage disequilibrium and allele-frequency distributions for 114 single-nucleotide polymorphisms in five populations. , 2000, American journal of human genetics.

[101]  D. Goldstein,et al.  Genetic evidence for a Paleolithic human population expansion in Africa. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[102]  M. Stoneking.  Recent African origin of human mitochondrial DNA: Review of the evidence and current status of the hypothesis , 1997 .

[103]  J. Armour,et al.  A highly variable segment of human subterminal 16p reveals a history of population growth for modern humans outstide Africa. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[104]  G. A. Watterson.  On the number of segregating sites in genetical models without recombination. , 1975, Theoretical population biology.

[105]  M. Feldman,et al.  Statistical properties of the variation at linked microsatellite loci: implications for the history of human Y chromosomes. , 1996, Molecular biology and evolution.

[106]  D. Nebert,et al.  Human CYP1A2: sequence, gene structure, comparison with the mouse and rat orthologous gene, and differences in liver 1A2 mRNA expression. , 1989, Molecular endocrinology.

[107]  K. Hawkes,et al.  African populations and the evolution of human mitochondrial DNA. , 1991, Science.

[108]  L. Brooks,et al.  A DNA polymorphism discovery resource for research on human genetic variation. , 1998, Genome research.

[109]  H. Bandelt,et al.  Mitochondrial footprints of human expansions in Africa. , 1997, American journal of human genetics.

[110]  A. Di Rienzo,et al.  Branching pattern in the evolutionary tree for human mitochondrial DNA. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[111]  Justin C. Fay,et al.  Positive and negative selection on the human genome. , 2001, Genetics.

[112]  Jonathan Scott Friedlaender,et al.  Haplotypes and linkage disequilibrium at the phenylalanine hydroxylase locus, PAH, in a global representation of populations. , 2000, American journal of human genetics.

[113]  Hongyu Zhao,et al.  Global patterns of linkage disequilibrium in Homo sapiens , 2001 .

[114]  T. Kamataki,et al.  Genetic polymorphism in the 5'-flanking region of human CYP1A2 gene: effect on the CYP1A2 inducibility in humans. , 1999, Journal of biochemistry.

[115]  M. Slatkin,et al.  Pairwise comparisons of mitochondrial DNA sequences in stable and exponentially growing populations. , 1991, Genetics.

[116]  P Donnelly,et al.  Microsatellite mutations and inferences about human demography. , 2000, Genetics.

[117]  J. Ott,et al.  The effect of marker heterozygosity on the power to detect linkage disequilibrium. , 1997, Genetics.

[118]  N. Takahata,et al.  Allelic genealogy and human evolution. , 1993, Molecular biology and evolution.

[119]  L. Jorde,et al.  Linkage disequilibrium and the search for complex disease genes. , 2000, Genome research.