TY - JOUR
T1 - Rate and directionality of mutations and effects of allele size constraints at anonymous, gene-associated, and disease-causing trinucleotide loci
AU - Deka, Ranjan
AU - Guangyun, Sun
AU - Smelser, Diane
AU - Zhong, Yixi
AU - Kimmel, Marek
AU - Chakraborty, Ranajit
PY - 1999/9
Y1 - 1999/9
N2 - We studied the patterns of within- and between-population variation at 29 trinucleotide loci in a random sample of 200 healthy individuals from four diverse populations: Germans, Nigerians, Chinese, and New Guinea highlanders. The loci were grouped as disease-causing (seven loci with CAG repeats), gene- associated (seven loci with CAG/CCG repeats and eight loci with AAT repeats), or anonymous (seven loci with AAT repeats). We used heterozygosity and variance of allele size (expressed in units of repeat counts) as measures of within-population variability and G(ST) (based on heterozygosity as well as on allele size variance) as the measure of genetic differentiation between populations. Our observations are: (1) locus type is the major significant factor for differences in within-population genetic variability; (2) the disease-causing CAG repeats (in the nondisease range of repeat counts) have the highest within-population variation, followed by the AAT-repeat anonymous loci, the AAT-repeat gene-associated loci, and the CAG/CTG-repeat gene- associated loci; (3) an imbalance index β, the ratio of the estimates of the product of effective population size and mutation rate based on allele size variance and heterozygosity, is the largest for disease-causing loci, followed by AAT- and CAG/CCG-repeat gene-associated loci and AAT-repeat anonymous loci; (4) mean allele size correlates positively with allele size variance for AAT- and CAG/CCG-repeat gene-associated loci and negatively for anonymous loci; and (5) G(ST) is highest for the disease-causing loci. These observations are explained by specific differences of rates and patterns of mutations in these four groups of trinucleotide loci, taking into consideration the effects of the past demographic history of the modern human population.
AB - We studied the patterns of within- and between-population variation at 29 trinucleotide loci in a random sample of 200 healthy individuals from four diverse populations: Germans, Nigerians, Chinese, and New Guinea highlanders. The loci were grouped as disease-causing (seven loci with CAG repeats), gene- associated (seven loci with CAG/CCG repeats and eight loci with AAT repeats), or anonymous (seven loci with AAT repeats). We used heterozygosity and variance of allele size (expressed in units of repeat counts) as measures of within-population variability and G(ST) (based on heterozygosity as well as on allele size variance) as the measure of genetic differentiation between populations. Our observations are: (1) locus type is the major significant factor for differences in within-population genetic variability; (2) the disease-causing CAG repeats (in the nondisease range of repeat counts) have the highest within-population variation, followed by the AAT-repeat anonymous loci, the AAT-repeat gene-associated loci, and the CAG/CTG-repeat gene- associated loci; (3) an imbalance index β, the ratio of the estimates of the product of effective population size and mutation rate based on allele size variance and heterozygosity, is the largest for disease-causing loci, followed by AAT- and CAG/CCG-repeat gene-associated loci and AAT-repeat anonymous loci; (4) mean allele size correlates positively with allele size variance for AAT- and CAG/CCG-repeat gene-associated loci and negatively for anonymous loci; and (5) G(ST) is highest for the disease-causing loci. These observations are explained by specific differences of rates and patterns of mutations in these four groups of trinucleotide loci, taking into consideration the effects of the past demographic history of the modern human population.
KW - Allele size constraint
KW - Coalescence
KW - Genome location
KW - Stepwise mutation
KW - Trinucleotide diseases
UR - http://www.scopus.com/inward/record.url?scp=0032840798&partnerID=8YFLogxK
U2 - 10.1093/oxfordjournals.molbev.a026207
DO - 10.1093/oxfordjournals.molbev.a026207
M3 - Article
C2 - 10486972
AN - SCOPUS:0032840798
SN - 0737-4038
VL - 16
SP - 1166
EP - 1177
JO - Molecular Biology and Evolution
JF - Molecular Biology and Evolution
IS - 9
ER -