Determination of ancestral alleles for human single-nucleotide polymorphisms using high-density oligonucleotide arrays

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Here we report the application of high-density oligonucleotide array (DNA chip)-based analysis to determine the distant history of single nucleotide polymorphisms (SNPs) in current human populations. We analysed orthologues for 397 human SNP sites (identified in CEPH pedigrees from Amish, Venezuelan and Utah populations1) from 23 common chimpanzee, 19 pygmy chimpanzee and 11 gorilla genomic DNA samples. From this data we determined 214 proposed ancestral alleles (the sequence found in the last common ancestor of humans and chimpanzees). In a diverse human population set, we found that SNP alleles with higher frequencies were more likely to be ancestral than less frequently occurring alleles. There were, however, exceptions. We also found three shared human/pygmy chimpanzee polymorphisms, all involving CpG dinucleotides, and two shared human/gorilla polymorphisms, one involving a CpG dinucleotide. We demonstrate that microarray-based assays allow rapid comparative sequence analysis of intra- and interspecies genetic variation.

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Figure 1: Flowchart of SNP genotype analysis in higher primates.
Figure 2: Nucleotide composition effects.
Figure 3: 5´-nearest neighbour effects.
Figure 4: 3´-nearest neighbour effects.
Figure 5: Correlations between human allele frequencies and ancestral states.


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We thank P.A. Morin for assistance in obtaining chimpanzee DNA samples. Partial support for this work was provided by 5POLHGO1323-03 (S.P.A.F.).

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Correspondence to Francis S. Collins.

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