Haplotype Evolution and Linkage Disequilibrium: A Simulation Study

We simulated the evolution of a three-site haplotype system, two restriction fragment length polymorphisms flanking one short tandem repeat polymorphism, under five different demographic scenarios, three with constant population size and two with population growth. The simulation was designed to observe the effects of population history, recombination fraction, and mutation rate on allele and haplotype frequencies, haplotype diversity, frequency of ancestral alleles, and linkage disequilibrium. The known ancestral haplotypes were often found at low frequencies and even became extinct after 5,000 generations, especially with small effective population sizes. The original linkage disequilibrium was eroded and even reversed.

[1]  H. Jennings.  The Numerical Results of Diverse Systems of Breeding, with Respect to Two Pairs of Characters, Linked or Independent, with Special Relation to the Effects of Linkage. , 1917, Genetics.

[2]  E. Allott,et al.  The rhesus factor; a summary based on 200 cases. , 1949, Lancet.

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

[4]  M. Feldman,et al.  Evolution of the Rh polymorphism: a model for the interaction of incompatibility, reproductive compensation, and heterozygote advantage. , 1969, American journal of human genetics.

[5]  J. Bodmer,et al.  The HL-A System as a Model for Studying the Interaction between Selection, Migration, and Linkage , 1976 .

[6]  G. A. Watterson,et al.  Is the most frequent allele the oldest? , 1977, Theoretical population biology.

[7]  S Karlin,et al.  Statistical methods for assessing linkage disequilibrium at the HLA‐A, B, C loci , 1981, Annals of human genetics.

[8]  A. Piazza,et al.  Genetic analysis of eight linked polymorphisms within the human immunoglobulin heavy-chain region. , 1985, American journal of human genetics.

[9]  J. Neel,et al.  The rate with which spontaneous mutation alters the electrophoretic mobility of polypeptides. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Weber,et al.  Mutation of human short tandem repeats. , 1993, Human molecular genetics.

[11]  Cécile Fizames,et al.  The 1993–94 Généthon human genetic linkage map , 1994, Nature Genetics.

[12]  X. Estivill,et al.  The origin of the major cystic fibrosis mutation (ΔF508) in European populations , 1994, Nature Genetics.

[13]  N. Freimer,et al.  Mutational processes of simple-sequence repeat loci in human populations. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[14]  M. Slatkin.  Linkage disequilibrium in growing and stable populations. , 1994, Genetics.

[15]  A. Torroni,et al.  mtDNA and the origin of Caucasians: identification of ancient Caucasian-specific haplogroups, one of which is prone to a recurrent somatic duplication in the D-loop region. , 1994, American journal of human genetics.

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

[17]  N. Risch,et al.  A comparison of linkage disequilibrium measures for fine-scale mapping. , 1995, Genomics.

[18]  L. Jorde.  Linkage disequilibrium as a gene-mapping tool. , 1995, American journal of human genetics.

[19]  M Slatkin,et al.  A measure of population subdivision based on microsatellite allele frequencies. , 1995, Genetics.

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

[21]  N. Freimer,et al.  The distribution of linkage disequilibrium over anonymous genome regions. , 1995, Human molecular genetics.

[22]  A J Pakstis,et al.  Evolution of haplotypes at the DRD2 locus. , 1995, American journal of human genetics.

[23]  A. Torroni,et al.  MtDNA haplogroups in Native Americans. , 1995, American journal of human genetics.

[24]  J. Cornuet,et al.  Size homoplasy and mutational processes of interrupted microsatellites in two bee species, Apis mellifera and Bombus terrestris (Apidae). , 1995, Molecular biology and evolution.

[25]  L. Excoffier,et al.  Analysis of mtDNA variation in African populations reveals the most ancient of all human continent-specific haplogroups. , 1995, American journal of human genetics.

[26]  L. Jin,et al.  Dispersion of human Y chromosome haplotypes based on five microsatellites in global populations. , 1996, Genome research.

[27]  K. Kidd,et al.  Minisatellite diversity supports a recent African origin for modern humans , 1996, Nature Genetics.

[28]  A. Langaney,et al.  DNA analysis of the immunoglobulin IGHG loci in a Mandenka population from eastern Senegal: correlation with Gm haplotypes and hypotheses for the evolution of the Ig CH region , 1996, Human Genetics.

[29]  F. Weissing,et al.  Constraints on allele size at microsatellite loci: implications for genetic differentiation. , 1996, Genetics.

[30]  R. J. Mitchell,et al.  Human evolution and the Y chromosome. , 1996, Current opinion in genetics & development.

[31]  K. K. Kidd,et al.  Molecular biology and human diversity: A nuclear perspective on human evolution , 1996 .

[32]  K. Kidd,et al.  DRD2 haplotypes containing the TaqI A1 allele: implications for alcoholism research. , 1996, Alcoholism, clinical and experimental research.

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

[34]  D N Stivers,et al.  Relative mutation rates at di-, tri-, and tetranucleotide microsatellite loci. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Grimaldi,et al.  Microsatellite Allelic Homoplasy Due to Variable Flanking Sequences , 1997, Journal of Molecular Evolution.

[36]  M. Xiong,et al.  Fine-scale genetic mapping based on linkage disequilibrium: theory and applications. , 1997, American journal of human genetics.

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

[38]  E. Thompson,et al.  Allelic disequilibrium and allele frequency distribution as a function of social and demographic history. , 1997, American journal of human genetics.

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

[40]  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.

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

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

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

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