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Evaluating the evidence for transmission distortion in human pedigrees
Wynn K Meyer1, Barbara Arbeithuber, Carole Ober
1Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA. wynn@uchicago.edu
Genetics
|March 2, 2012
Summary
Researchers investigated transmission distortion (TD) in human genetics using the transmission disequilibrium test (TDT) across large datasets. They identified potential TD loci but noted challenges with genotyping errors and replication, highlighting the complexity of studying TD in humans.
Area of Science:
- Human Genetics
- Population Genetics
- Genomic Studies
Background:
- Mendelian inheritance predicts equal allele transmission from heterozygous parents.
- Deviations, termed transmission distortion (TD), occur via meiotic drive, gamete competition, or selection, but are unconfirmed in humans.
- Genome-wide scans are crucial for identifying TD phenomena in human populations.
Purpose of the Study:
- To conduct a comprehensive genome-wide search for transmission distortion in human populations.
- To apply the transmission disequilibrium test (TDT) to large human pedigree datasets.
- To identify and characterize candidate regions exhibiting TD and assess potential confounding factors.
Main Methods:
- Genome-wide transmission disequilibrium test (TDT) applied to three large human pedigree sets: Framingham Heart Study (FHS), a European founder population (HUTT), and Autism Genetic Resource Exchange (AGRE).
- Rigorous quality control and analysis to mitigate genotyping errors, a significant confounder.
- Investigation of specific candidate regions for TD signals, including replication attempts and functional assays (sperm competition, allelic imbalance).
Main Results:
- Genotyping errors complicated signal interpretation in FHS and HUTT datasets.
- The AGRE dataset revealed multiple signals across SNPs, suggesting genuine TD, with a genome-wide significant locus at 10q26.13 (combined sexes) and a paternal signal at 6p21.1.
- Replication in FHS failed for identified loci; maternal transmissions showed enrichment of top signals in cell junction genes, not near centromeres/telomeres.
Conclusions:
- The TDT is a valuable tool for studying human transmission distortion, despite challenges like genotyping errors and replication difficulties.
- Identified candidate regions, particularly 10q26.13 and 6p21.1, warrant further investigation for their roles in TD.
- Findings suggest potential mechanisms for TD, including enrichment in cell junction genes, and underscore the need for robust methodologies in human genetic studies.
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