TY - JOUR
T1 - DNA sequence variation in a 3.7-kb noncoding sequence 5′ of the CYP1A2 gene
T2 - Implications for human population history and natural selection
AU - Wooding, S. P.
AU - Watkins, W. S.
AU - Bamshad, M. J.
AU - Dunn, D. M.
AU - Weiss, R. B.
AU - Jorde, L. B.
N1 - Funding Information:
We would like to thank Ed Meenen, for technical assistance, and Chris Ricker, Henry Harpending, Alan Rogers, Jon Seger, Fred Adler, Bradley Demarest, and Thomas Hills, for helpful discussions on this manuscript. Justin Fay provided assistance with analyses. This research was supported by National Institutes of Health grants GM-59290, RR-00064, and ES-10058 and by NSF grants SBR-9514733 and SBR-9818215.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
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U2 - 10.1086/342260
DO - 10.1086/342260
M3 - Article
C2 - 12181774
AN - SCOPUS:0036724899
SN - 0002-9297
VL - 71
SP - 528
EP - 542
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
M1 - 60333
ER -