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Identification of two maternal transmission ratio distortion loci in pedigrees of the Framingham heart study.

ABSTRACT: Transmission ratio distortion (TRD) is indicated by the recovery of alleles in offspring in non-Mendelian proportions. An assumption of Mendelian proportion is central to many methods to identify disease-associated markers. This seems reasonable as, while TRD cases have been occasionally observed in various species few instances have been identified in humans. Here we search for evidence of paternal or maternal TRD with genome-wide SNP data of pedigrees from the Framingham Heart Study. After excluding many examples as better explained by genotyping errors we identified two maternal-specific TRD loci for autosomal SNPs rs6733122 and rs926716 (corrected P = 0.029 and P = 0.018) on LRP2 and ZNF133, respectively. The transmission ratios were as high as 1.7~1.8:1. Genotyping validation and further replication is still necessary to confirm the TRD. This study shows that there may be large-effect maternal-specific TRD loci of common SNPs in the human genome but that these are rare.

SUBMITTER: Liu Y

PROVIDER: S-EPMC3701898 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Identification of two maternal transmission ratio distortion loci in pedigrees of the Framingham heart study.

Liu Yang Y Zhang Liangliang L Xu Shuhua S Hu Landian L Hurst Laurence D LD Kong Xiangyin X

Scientific reports 20130101

Transmission ratio distortion (TRD) is indicated by the recovery of alleles in offspring in non-Mendelian proportions. An assumption of Mendelian proportion is central to many methods to identify disease-associated markers. This seems reasonable as, while TRD cases have been occasionally observed in various species few instances have been identified in humans. Here we search for evidence of paternal or maternal TRD with genome-wide SNP data of pedigrees from the Framingham Heart Study. After exc ...[more]

PMID: 23828458

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Project description:Significant departures from expected Mendelian inheritance ratios (transmission ratio distortion, TRD) are frequently observed in both experimental crosses and natural populations. TRD on mouse Chromosome (Chr) 2 has been reported in multiple experimental crosses, including the Collaborative Cross (CC). Among the eight CC founder inbred strains, we found that Chr 2 TRD was exclusive to females that were heterozygous for the WSB/EiJ allele within a 9.3 Mb region (Chr 2 76.9 - 86.2 Mb). A copy number gain of a 127 kb-long DNA segment (designated as responder to drive, R2d) emerged as the strongest candidate for the causative allele. We mapped R2d sequences to two loci within the candidate interval. R2d1 is located near the proximal boundary, and contains a single copy of R2d in all strains tested. R2d2 maps to a 900 kb interval, and the number of R2d copies varies from zero in classical strains (including the mouse reference genome) to more than 30 in wild-derived strains. Using real-time PCR assays for the copy number, we identified a mutation (R2d2WSBdel1) that eliminates the majority of the R2d2WSB copies without apparent alterations of the surrounding WSB/EiJ haplotype. In a three-generation pedigree segregating for R2d2WSBdel1, the mutation is transmitted to the progeny and Mendelian segregation is restored in females heterozygous for R2d2WSBdel1, thus providing direct evidence that the copy number gain is causal for maternal TRD. We found that transmission ratios in R2d2WSB heterozygous females vary between Mendelian segregation and complete distortion depending on the genetic background, and that TRD is under genetic control of unlinked distorter loci. Although the R2d2WSB transmission ratio was inversely correlated with average litter size, several independent lines of evidence support the contention that female meiotic drive is the cause of the distortion. We discuss the implications and potential applications of this novel meiotic drive system.

Dataset Information

Identification of two maternal transmission ratio distortion loci in pedigrees of the Framingham heart study.

Publications

Identification of two maternal transmission ratio distortion loci in pedigrees of the Framingham heart study.

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