Nature Genetics
22, 239 - 247 (1999)
doi:10.1038/10297
Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure
homeostasisMarc K. Halushka1, Jian-Bing Fan2, Kimberly Bentley1, Linda Hsie2, Naiping Shen2, Alan Weder3, Richard Cooper4, Robert Lipshutz2
& Aravinda Chakravarti11
Department of Genetics and Center for Human Genetics,
Case Western Reserve University School of Medicine and University Hospitals
of Cleveland, Cleveland, Ohio 44106,
USA. 2
Affymetrix, Inc., 3380 Central Expressway
, Santa Clara, California 95051,
USA. 3
Department of Medicine, University of Michigan,
Ann Arbor, Michigan 48109, USA. 4
Department of Epidemiology, Loyola University Medical
Center,, Maywood, Illinois 60153,
USA.
Correspondence should be addressed to Aravinda Chakravarti axc39@po.cwru.eduSequence variation in human genes is largely confined to single-nucleotide
polymorphisms (SNPs) and is valuable in tests of association with common diseases
and pharmacogenetic traits. We performed a systematic and comprehensive survey
of molecular variation to assess the nature, pattern and frequency of SNPs
in 75 candidate human genes for blood-pressure homeostasis and hypertension.
We assayed 28 Mb (190 kb in 148 alleles) of genomic sequence, comprising the 5´
and 3´ untranslated regions (UTRs), introns and coding sequence of these
genes, for sequence differences in individuals of African and Northern European
descent using high-density variant detection arrays (VDAs). We identified
874 candidate human SNPs, of which 22% were confirmed by DNA sequencing to
reveal a discordancy rate of 21% for VDA detection. The SNPs detected have
an average minor allele frequency of 11%, and 387 are within the coding sequence
(cSNPs). Of all cSNPs, 54% lead to a predicted change in the protein sequence,
implying a high level of human protein diversity. These protein-altering SNPs
are 38% of the total number of such SNPs expected, are more likely to be population-specific
and are rarer in the human population, directly demonstrating the effects
of natural selection on human genes. Overall, the degree of nucleotide polymorphism
across these human genes, and orthologous great ape sequences, is highly variable
and is correlated with the effects of functional conservation on gene sequences.
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