Global Patterns of Human DNA Sequence Variation in a 10-kb Region on Chromosome 1

Abstract

Human DNA variation is currently a subject of intense research because of its importance for studying human origins, evolution, and demographic history and for association studies of complex diseases. A approximately 10-kb region on chromosome 1, which contains only four small exons (each <155 bp), was sequenced for 61 humans (20 Africans, 20 Asians, and 21 Europeans) and for 1 chimpanzee, 1 gorilla, and 1 orangutan. We found 52 polymorphic sites among the 122 human sequences and 382 variant sites among the human, chimpanzee, gorilla, and orangutan sequences. For the introns sequenced (8,991 bp), the nucleotide diversity (pi) was 0.058% among all sequences, 0.076% among the African sequences, 0.047% among the Asian sequences, and 0.045% among the European sequences. A compilation of data revealed that autosomal regions have, on average, the highest pi value (0.091%), X-linked regions have a somewhat lower pi value (0.079%), and Y-linked regions have a very low pi value (0.008%). The lower polymorphism in the present region may be due to a lower mutation rate and/or selection in the gene containing these introns or in genes linked to this region. The present region and two other 10-kb noncoding regions all show a strong excess of low-frequency variants, indicating a relatively recent population expansion. This region has a low mutation rate, which was estimated to be 0.74 x 10 per nucleotide per year. An average estimate of approximately 12,600 for the long-term effective population size was obtained using various methods; the estimate was not far from the commonly used value of 10,000. Fu and Li's tests rejected the assumption of an equilibrium neutral Wright-Fisher population, largely owing to the high proportion of low-frequency variants. The age of the most recent common ancestor of the sequences in our sample was estimated to be more than 1 Myr. Allowing for some unrealistic assumptions in the model, this estimate would still suggest an age of more than 500,000 years, providing further evidence for a genetic history of humans much more ancient than the emergence of modern humans. The fact that many unique variants exist in Europe and Asia also suggests a fairly long genetic history outside of Africa and argues against a complete replacement of all indigenous populations in Europe and Asia by a small Africa stock. Moreover, the ancient genetic history of humans indicates no severe bottleneck during the evolution of humans in the last half million years; otherwise, much of the ancient genetic history would have been lost during a severe bottleneck. We suggest that both the "Out of Africa" and the multiregional models are too simple to explain the evolution of modern humans.

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

“…This point estimator of the mutation rate is lower, though not significantly different, than values observed for other autosomal loci. 20,21 Among the populations studied, the African populations have higher levels of diversity compared to nonAfrican populations, with West Africans having the highest level of diversity and Europeans having the lowest level of diversity (Tables 1 and 2). Across all the Figure 1 Genomic structure of the IL13 gene and distribution of SNPs identified in this study.…”

High Nucleotide Polymorphism and Rapid Decay of Linkage Disequilibrium in Wild Populations of Caenorhabditis remanei

“…Loci from some other species of nematodes also demonstrate diversity at nuclear loci as high as the $10% seen in C. remanei, such as b-tubulin in Haemonchus contortus (Beech et al 1994) and ITS1-rDNA of Longidorus biformis (Ye et al 2004), although most reports indicate levels of silent-site diversity of #2% (Anderson et al 1998;Cutter et al 2006). Similarly high levels of nucleotide polymorphism have also been reported in several species of mycophagous Drosophila Shoemaker et al 2004), suggesting that intraspecific per-nucleotide diversities of 5-10% may not be unusual in a variety of taxa, in spite of the predominent view of low-to-moderate levels of genetic variation within genetic model organisms: Drosophila melanogaster p si $ 1.6% (Andolfatto 2001), Arabidopsis thaliana u si $ 1.6%, maize u si $ 1.5% (Wright and Gaut 2005), and human p si $ 0.08% (Zhang 2000;Yu et al 2001).…”

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).…”