Worldwide DNA sequence variation in a 10-kilobase noncoding region on human chromosome 22

Abstract

Human DNA sequence variation data are useful for studying the origin, evolution, and demographic history of modern humans and the mechanisms of maintenance of genetic variability in human populations, and for detecting linkage association of disease. Here, we report worldwide variation data from a Ϸ10-kilobase noncoding autosomal region. We identified 75 variant sites in 64 humans (128 sequences) and 463 variant sites among the human, chimpanzee, and orangutan sequences. Statistical tests suggested that the region is selectively neutral. The average nucleotide diversity () across the region was 0.088% among all of the human sequences obtained, 0.085% among African sequences, and 0.082% among non-African sequences, supporting the view of a low nucleotide diversity (Ϸ0.1%) in humans. The comparable value in nonAfricans to that in Africans indicates no severe bottleneck during the evolution of modern non-Africans; however, the possibility of a mild bottleneck cannot be excluded because non-Africans showed considerably fewer variants than Africans. The present and two previous large data sets all show a strong excess of low frequency variants in comparison to that expected from an equilibrium population, indicating a relatively recent population expansion. The mutation rate was estimated to be 1.15 ؋ 10 ؊9 per nucleotide per year. Estimates of the long-term effective population size Ne by various statistical methods were similar to those in other studies. The age of the most recent common ancestor was estimated to be Ϸ1.29 million years ago among all of the sequences obtained and Ϸ634,000 years ago among the non-African sequences, providing the first evidence from a noncoding autosomal region for ancient human histories, even among non-Africans.human origins ͉ nucleotide diversity ͉ rare variants ͉ population expansion

GC Content Evolution of the Human and Mouse Genomes: Insights from the Study of Processed Pseudogenes in Regions of Different Recombination Rates

“…To explain this and given the values of c, we can only assume that c, Ne, or both are higher in the mouse genome. Ne was estimated to be approximately 10,000 in the human lineage (Takahata et al 1995;Zhao et al 2000;Yu et al 2003;Keightley et al 2005) and between 450,000 and 810,000 in the mouse lineage (Keightley et al 2005). These values are in agreement with our results.…”

Neutral Substitutions Occur at a Faster Rate in Exons Than in Noncoding DNA in Primate Genomes

“…For instance, we find that the analyses of pseudogenes (Li and Tanimura 1987;Nachman and Crowell 2000;Martinez-Arias et al 2001) and introns (Bergstrom et al 1999;Chen et al 2001) have produced much lower estimates of evolutionary divergence than those observed in synonymous sites in protein coding genes (Li and Tanimura 1987;Wolfe et al 1989;Easteal 1991;Keightley and Eyre-Walker 2000;Duret et al 2002;Kumar and Subramanian 2002). Also, intergenic DNA (excluding regulatory sites), which is expected to mutate at a rate similar to that for the coding DNA, also consistently shows much smaller evolutionary divergences than those obtained from coding sequences (Bohossian et al 2000;Zhao et al 2000;Chen et al 2001;Mathews et al 2001;Yu et al 2001). This observation is not a random chance occurrence due to paucity of data, because these studies have involved direct comparisons of long intergenic regions (Bohossian et al 2000;Zhao et al 2000;Chen et al 2001) and relatively large numbers of coding genes (Wolfe et al 1989;Keightley and Eyre-Walker 2000;Duret et al 2002;Kumar and Subramanian 2002).…”

“…Also, intergenic DNA (excluding regulatory sites), which is expected to mutate at a rate similar to that for the coding DNA, also consistently shows much smaller evolutionary divergences than those obtained from coding sequences (Bohossian et al 2000;Zhao et al 2000;Chen et al 2001;Mathews et al 2001;Yu et al 2001). This observation is not a random chance occurrence due to paucity of data, because these studies have involved direct comparisons of long intergenic regions (Bohossian et al 2000;Zhao et al 2000;Chen et al 2001) and relatively large numbers of coding genes (Wolfe et al 1989;Keightley and Eyre-Walker 2000;Duret et al 2002;Kumar and Subramanian 2002). This difference between coding and noncoding regions in interspecies comparisons is also seen in within-species analysis of single nucleotide polymorphisms (SNPs) that show higher nucleotide diversity in the synonymous sites of exons compared to the noncoding DNA (Moriyama and Powell 1996;Cargill et al 1999;Halushka et al 1999;Zwick et al 2000).…”

“…In comparative sequence analysis, mutation rates are inferred by estimating the rate at which neutral substitutions accumulate, because the rate of mutation and substitution is expected to be the same for neutral mutations (Kimura 1983;Kondrashov and Crow 1993;Nei and Kumar 2000). Pseudogenes, introns, intergenic regions, and synonymous sites in exons are largely free from selection in mammals and are therefore routinely used in comparative sequence analysis for this purpose (Wolfe et al 1989;Li and Graur 1991;Keightley and Eyre-Walker 2000;Nachman and Crowell 2000;Zhao et al 2000;Kumar and Subramanian 2002).…”

Divergent patterns of linkage disequilibrium and haplotype structure across global populations at the interleukin-13 (IL13) locus

“…Comparison of the ratio of polymorphisms to fixed differences at IL13 with a 10 kb noncoding region of chromosome 22 39 and intron 44 of the DMD gene 40 (both assumed to be evolving under neutrality), using an HKA test, showed no significant difference (P40.13), indicating that the IL13 gene does not show an excess or depletion of variation compared to these other loci. Additionally, sliding window analysis of differences in the ratio of polymorphism/fixed differences across the gene using several statistics (K R , D KS and G mean 31 ) indicates no evidence for significant heterogeneity in the pattern of genetic diversity across the IL13 Table 4 Continued Position 2043 (bold characters) is the only nonsynonymous substitution (Arg130Gln).…”