Sequence variation within the fragile X locus.

The human genome provides a reference sequence, which is a template for resequencing studies that aim to discover and interpret the record of common ancestry that exists in extant genomes. To understand the nature and pattern of variation and linkage disequilibrium comprising this history, we present a study of approximately 31 kb spanning an approximately 70 kb region of FMR1, sequenced in a sample of 20 humans (worldwide sample) and four great apes (chimp, bonobo, and gorilla). Twenty-five polymorphic sites and two insertion/deletions, distributed in 11 unique haplotypes, were identified among humans. Africans are the only geographic group that do not share any haplotypes with other groups. Parsimony analysis reveals two main clades and suggests that the four major human geographic groups are distributed throughout the phylogenetic tree and within each major clade. An African sample appears to be most closely related to the common ancestor shared with the three other geographic groups. Nucleotide diversity, pi, for this sample is 2.63 +/- 6.28 x 10(-4). The mutation rate, mu is 6.48 x 10(-10) per base pair per year, giving an ancestral population size of approximately 6200 and a time to the most recent common ancestor of approximately 320,000 +/- 72,000 per base pair per year. Linkage disequilibrium (LD) at the FMR1 locus, evaluated by conventional LD analysis and by the length of segment shared between any two chromosomes, is extensive across the region.

[1]  Delina Lyon,et al.  Caloramator viterbensis sp. nov., a novel thermophilic, glycerol-fermenting bacterium isolated from a hot spring in Italy. , 2002, International journal of systematic and evolutionary microbiology.

[2]  Elizabeth M. Smigielski,et al.  dbSNP: the NCBI database of genetic variation , 2001, Nucleic Acids Res..

[3]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.

[4]  J. Wall,et al.  Detecting ancient admixture in humans using sequence polymorphism data. , 2000, Genetics.

[5]  M. P. Cummings,et al.  PAUP* Phylogenetic analysis using parsimony (*and other methods) Version 4 , 2000 .

[6]  K. Katz,et al.  Introducing RefSeq and LocusLink: curated human genome resources at the NCBI. , 2000, Trends in genetics : TIG.

[7]  L. Kruglyak.  Prospects for whole-genome linkage disequilibrium mapping of common disease genes , 1999, Nature Genetics.

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

[9]  Thomas L. Madden,et al.  BLAST 2 Sequences, a new tool for comparing protein and nucleotide sequences. , 1999, FEMS microbiology letters.

[10]  D. Hewett‐Emmett,et al.  High polymorphism at the human melanocortin 1 receptor locus. , 1999, Genetics.

[11]  Jody Hey,et al.  The limits of selection during maize domestication , 1999, Nature.

[12]  J. Hey,et al.  X chromosome evidence for ancient human histories. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[13]  A. Chakravarti.  Population genetics—making sense out of sequence , 1999, Nature Genetics.

[14]  C. Gunter,et al.  Re-examination of factors associated with expansion of CGG repeats using a single nucleotide polymorphism in FMR1. , 1998, Human molecular genetics.

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

[16]  E. Boerwinkle,et al.  Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase. , 1998, American journal of human genetics.

[17]  R. Foley.  The context of human genetic evolution. , 1998, Genome research.

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

[19]  P. Green,et al.  Consed: a graphical tool for sequence finishing. , 1998, Genome research.

[20]  P Green,et al.  Base-calling of automated sequencer traces using phred. II. Error probabilities. , 1998, Genome research.

[21]  X. Gu,et al.  Sequence variation in ZFX introns in human populations. , 1998, Molecular biology and evolution.

[22]  S. Karlin,et al.  Prediction of complete gene structures in human genomic DNA. , 1997, Journal of molecular biology.

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

[24]  G. Neri,et al.  Significance of linkage disequilibrium between the fragile X locus and its flanking markers. , 1996, American journal of medical genetics.

[25]  P. Jacobs,et al.  Population screening at the FRAXA and FRAXE loci: molecular analyses of boys with learning difficulties and their mothers. , 1996, Human molecular genetics.

[26]  E. Eichler,et al.  Haplotype and interspersion analysis of the FMR1 CGG repeat identifies two different mutational pathways for the origin of the fragile X syndrome. , 1996, Human molecular genetics.

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

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

[29]  P Donnelly,et al.  Coalescents and genealogical structure under neutrality. , 1995, Annual review of genetics.

[30]  S. Warren,et al.  Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles , 1994, Cell.

[31]  P. Jacobs,et al.  Insert size and flanking haplotype in fragile X and normal populations: possible multiple origins for the fragile X mutation. , 1994, Human molecular genetics.

[32]  D. Labie,et al.  Molecular Evolution , 1991, Nature.

[33]  M. Kreitman,et al.  Adaptive protein evolution at the Adh locus in Drosophila , 1991, Nature.

[34]  R. Richards,et al.  Fragile X syndrome: diagnosis using highly polymorphic microsatellite markers. , 1991, American journal of human genetics.

[35]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[36]  Bruce S. Weir,et al.  Genetic Data Analysis: Methods for Discrete Population Genetic Data. , 1991 .

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

[38]  M. Corey,et al.  DNA marker haplotype association with pancreatic sufficiency in cystic fibrosis. , 1989, American journal of human genetics.

[39]  R. Lewontin,et al.  On measures of gametic disequilibrium. , 1988, Genetics.

[40]  N. Saitou,et al.  The neighbor-joining method: a new method for reconstructing phylogenetic trees. , 1987, Molecular biology and evolution.

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

[42]  M. Nei.  Molecular Evolutionary Genetics , 1987 .

[43]  D. Mccormick.  Sequence the Human Genome , 1986, Bio/Technology.

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

[45]  D. Penny,et al.  Branch and bound algorithms to determine minimal evolutionary trees , 1982 .

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

[47]  L. Pauling,et al.  Evolutionary Divergence and Convergence in Proteins , 1965 .

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