Global survey of haplotype frequencies and linkage disequilibrium at the RET locus

Abstract

We have constructed haplotypes based on normal variation at six polymorphic sites -five single nucleotide polymorphisms (SNPs) and one short tandem repeat polymorphism (STRP) -at the RET locus for samples of normal individuals from 32 populations distributed across the major continental regions of the world. The haplotyped system spans 41.6 kilobases and encompasses most of the coding region of the gene. All of the markers are polymorphic in all regions of the world and in most individual populations. Expected heterozygosities for the six-site haplotypes range from 82 to 94% for all populations studied except for two Amerindian groups from the Amazon basin at 61 and 76%. Individual populations had from four to eight haplotypes with frequencies exceeding 5%. In general, African, southwest Asian and European groups have the highest numbers of total and of commonly occurring haplotypes; the lowest numbers are observed in Amerindian populations. Overall linkage disequilibrium (LD) for the five SNP sites was very significant (Pp0.001) for all the non-African populations, but significant at that level for only one of the seven African populations. In general, the permutation-based n coefficient that quantifies overall LD tends to increase the farther the population is from Africa, but variability of this measure of LD is often large within geographic regions. Pairwise LD measures among the SNPs also show considerable variation among populations. Association of STRP alleles with the SNP-defined background haplotypes is generally higher outside of Africa than in Africa, but is highly variable.

Low RET mutation frequency and polymorphism analysis of the RET and EDNRB genes in patients with Hirschsprung disease in Taiwan

“…The allele frequencies were very close to those reported in Hong Kong (Garcia-Barcelo et al 2003). The allele frequencies in exon 2, 13, and 15 in the normal population were also close to those reported by Chattopadhyay et al (Chattopadhyay et al 2003). The allele frequencies of allele A of c135 G>A (exon2), allele G of c1296 G>A (exon 7), allele G of c2071 G>A (exon 11), allele G of c2307 T>G (exon 13), and allele C of c2712C>G (exon 15) were higher in our HSCR patients than in controls.…”

Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease

“…Of note, variable allelic frequencies are observed according to ethnicity and range from Ͻ5% in South Africa to Ϸ50% in Asia. The European Caucasian population has been thoroughly investigated in France, Italy, Spain, the Netherlands, and Germany, allowing approximation of the frequency of the T HSCR predisposing allele to Ϸ25% in the Caucasian population (30).…”

Extreme population differences across Neuregulin 1 gene, with implications for association studies

“…[33][34][35][36][37][38][39] The general pattern found in the regions examined so far is a series of discrete tracts of low recombination, high LD and therefore with a reduced number of haplotypes, the so-called 'haplotype blocks' bounded by recombination hotspots. Haplotype block structure has been found to vary according to genomic region (due to genomic factors affecting its pattern) and also between different global populations (due to demographic factors), 33,36,[38][39][40][41][42][43][44] see Bertranpetit et al 45 for a review. In fact, the goal of the International HapMap Project (http://www.hapmap.org) is to develop a haplotype map of the human genome, the HapMap, which will describe the common patterns of human DNA sequence variation in four distinct human populations.…”