Segments containing alternating purine and pyrimidine dinucleotides: patterns of polymorphism in humans and prevalence throughout phylogeny

Abstract

Tandem dinucleotide repeats of GT or AC [(GT)n/(AC)n] where n greater than or equal to 14 are highly polymorphic and other simple repeats such as (CT)n/(AG)n and (A)n(T)n are also polymorphic. The uniformity of these sequences precludes a mechanistic differentiation between recombination or polymerase slippage. Since (GT)n/(AC)n or (CT)n/(AG)n segments of desired size were not available in our gene of interest, we analyzed a 187+ bp segment in the factor IX gene with multiple short dinucleotide repeats. This sequence contains a melody of short dinucleotide repeats which includes a 142+ bp segment of alternating purines and pyrimidines. Amplification of this sequence in 167 individuals of different ethnicity and direct sequencing of 106 individuals (23 kb of sequence) failed to reveal simple variation in the number of tandem dinucleotide repeats. However, polymorphism in the 142+ alternating purine and pyrimidine segment (RY)n was detected due to the insertion of two related repeat units of 24 bp (A) and 26 bp (B). Two previously described alleles (AB, A2B2) and two novel presumptive recombinants were found (A2B, A3B2) for a total of four alleles. An analysis of (RY)n segments in GenBank revealed an extraordinary enrichment in the genome of mammals, invertebrates, and yeast and a marked reduction in bacteria. Rodent (RY)n were larger and substantially more frequent than those in primates. When a second (RY)n was examined in the exon 8 of human factor IX gene, it was polymorphic at short repeats of (GT)n/(AC)n (n = 3-6) in Western Europeans and Koreans. In addition, an (RY)n in the dystrophin gene had four polymorphic alleles involving AT and GT dinucleotides. Thus (RY)n segments appear to be abundant and highly polymorphic. The asymmetric patterns of polymorphism and the absence of simple dinucleotide variation in 23 kb of sequence are compatible with recombination or sister chromatid exchange, but not polymerase slippage. By inference, recombination should underlie the polymorphisms at (GT)n/(AC)n since they are a subset of (RY)n and they commonly occur in the context of longer (RY)n.

The Third Human Homolog of a Murine Gene Encoding an Inhibitor of Stem Cell Proliferation Is Truncated and Linked to a CpG Island-Containing Upstream Sequence

“…They are possible sites of Z-DNA formation and recombination hotspots (Sarkar et al, 1991). Consistent with the latter, there is a repeat region at the 3' flank of the CUS where it joins the G0S19 sequence (Figs.…”

Haemophilia A and haemophilia B: molecular insights

“…55 The intron 1 (RY)n motif comprises two units, A and B, with consensus sequence GT(AC) 3 (AT) 3 (GT(AT) I (I = 4 for the A unit and 5 for the B unit). 68 The polymorphism is caused by variability in the number of A and B units present. Both microsatellites show variation between racial groups.…”

“…Instead, the patterns of variation observed are compatible with sister chromatid exchange (homologous recombination). 68 There is strong circumstantial evidence that (RY)n sequences are involved in homologous recombination. 68 In this light, it is interesting to note that the BamHI RFLP which is 5′ to the intron 1 (RY)n is in linkage equilibrium with polymorphisms located between this (RY)n and the exon 8 (RY)n. 68 Similarly, the HhaI RFLP 3′ to the exon 8 (RY)n is in linkage equilibrium with polymorphisms between this (RY)n and the intron 1 (RY)n. 68 In contrast, the polymorphisms between the intron 1 and exon 8 (RY)n are in strong linkage disequilibrium.…”

“…68 There is strong circumstantial evidence that (RY)n sequences are involved in homologous recombination. 68 In this light, it is interesting to note that the BamHI RFLP which is 5′ to the intron 1 (RY)n is in linkage equilibrium with polymorphisms located between this (RY)n and the exon 8 (RY)n. 68 Similarly, the HhaI RFLP 3′ to the exon 8 (RY)n is in linkage equilibrium with polymorphisms between this (RY)n and the intron 1 (RY)n. 68 In contrast, the polymorphisms between the intron 1 and exon 8 (RY)n are in strong linkage disequilibrium. 26 50 72 If the (RY)n sequences of the factor IX gene truly are involved in homologous recombination events, this has evident implications for linkage studies (the loss of linkage between polymorphic loci and the defect in the factor IX gene).…”

Nine independentF9 mutations in the Mexican hemophilia B population: Nonrandom recurrences of point mutation events in the human germline

“…Identification of polymorphic haplotypes confirmed the segregation patterns of alleles within the family pedigrees, the independence of identical mutations, and, for three, the germline origin. The MseI, BamHI, HinfI, XmnI, TaqI, 3´(RY)i, and HhaI polymorphisms within F9 were analyzed (Winship et al, 1993;Gostout et al, 1993;Jacobson et al, 1993;Sarkar et al, 1991).…”