Blocks of Limited Haplotype Diversity Revealed by High-Resolution Scanning of Human Chromosome 21

Global patterns of human DNA sequence variation (haplotypes) defined by common single nucleotide polymorphisms (SNPs) have important implications for identifying disease associations and human traits. We have used high-density oligonucleotide arrays, in combination with somatic cell genetics, to identify a large fraction of all common human chromosome 21 SNPs and to directly observe the haplotype structure defined by these SNPs. This structure reveals blocks of limited haplotype diversity in which more than 80% of a global human sample can typically be characterized by only three common haplotypes.

[1]  B. Bainbridge,et al.  Genetics , 1981, Experientia.

[2]  D. Hartl,et al.  Principles of population genetics , 1981 .

[3]  AC Tose.  Cell , 1993, Cell.

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

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

[6]  S. Tishkoff,et al.  Molecular haplotyping of genetic markers 10 kb apart by allele-specific long-range PCR. , 1996, Nucleic acids research.

[7]  E. Lander.  The New Genomics: Global Views of Biology , 1996, Science.

[8]  James L. Winkler,et al.  Accessing Genetic Information with High-Density DNA Arrays , 1996, Science.

[9]  N Risch,et al.  The Future of Genetic Studies of Complex Human Diseases , 1996, Science.

[10]  C. Nusbaum,et al.  Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. , 1998, Science.

[11]  L. Eguiarte.  Principles of population genetics: by D. L. Hard and A. G. Clark, Sinauer Associates Inc. Publishers, Sunderland, MA, 1997. $58.95 (casebound), xiii + 542 pp. ISBN 0-87893-306-9 , 1998 .

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

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

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

[15]  M. Boehnke,et al.  Loss of information due to ambiguous haplotyping of SNPs , 1999, Nature Genetics.

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

[17]  Eric S. Lander,et al.  An SNP map of the human genome generated by reduced representation shotgun sequencing , 2000, Nature.

[18]  E. Danforth.  Failure of adipocyte differentiation causes type II diabetes mellitus? , 2000, Nature Genetics.

[19]  E. Boerwinkle,et al.  Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism. , 2000, American journal of human genetics.

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

[21]  M. Boehnke,et al.  Experimentally-derived haplotypes substantially increase the efficiency of linkage disequilibrium studies , 2001, Nature Genetics.

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

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

[24]  Pui-Yan Kwok,et al.  Single-nucleotide polymorphisms in the public domain: how useful are they? , 2001, Nature Genetics.

[25]  N. Hollenberg,et al.  A genomic-systems biology map for cardiovascular function. , 2002, Current hypertension reports.