Blood Ties: Chimerism Can Mask Twin Discordance in High-Throughput Sequencing

Twin studies have long provided a means to separate the contributions of genetic and environmental factors. A recent pioneering report by Baranzini et al. presented an analysis of the complete genomes and epigenomes of a monozygotic (MZ) twin pair discordant for multiple sclerosis. This failed to fi...

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Published inTwin research and human genetics Vol. 14; no. 2; pp. 137 - 143
Main Author Erlich, Yaniv
Format Journal Article
LanguageEnglish
Published Cambridge, UK Cambridge University Press 01.04.2011
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Abstract Twin studies have long provided a means to separate the contributions of genetic and environmental factors. A recent pioneering report by Baranzini et al. presented an analysis of the complete genomes and epigenomes of a monozygotic (MZ) twin pair discordant for multiple sclerosis. This failed to find any difference between the twins, raising doubts regarding the value of whole-genome twin studies for defining disease susceptibility alleles. However, the study was carried out with DNA extracted from blood. In many cases, the hematopoietic lineages of MZ twins are chimeric due to twin-to-twin exchange of hematopoietic stem cells during embryogenesis. We therefore wondered how chimerism might impact the ability to identify genetic differences. We inferred the blood chimerism rates and profiles of more than 30 discordant twin cases from a wide variety of medical conditions. We found that the genotype compositions of the twins were highly similar. We then benchmarked the performance of SNP callers to detect discordant variations using high-throughput sequencing data. Our analysis revealed that chimerism patterns, well within the range normally observed in MZ twins, greatly reduce the sensitivity of SNP calls. This raises questions regarding any conclusions of genomic homogeneity that might be drawn from studies of blood-derived twin DNA.
AbstractList Twin studies have long provided a means to separate the contributions of genetic and environmental factors. A recent pioneering report by Baranzini et al. presented an analysis of the complete genomes and epigenomes of a monozygotic (MZ) twin pair discordant for multiple sclerosis. This failed to find any difference between the twins, raising doubts regarding the value of whole-genome twin studies for defining disease susceptibility alleles. However, the study was carried out with DNA extracted from blood. In many cases, the hematopoietic lineages of MZ twins are chimeric due to twin-to-twin exchange of hematopoietic stem cells during embryogenesis. We therefore wondered how chimerism might impact the ability to identify genetic differences. We inferred the blood chimerism rates and profiles of more than 30 discordant twin cases from a wide variety of medical conditions. We found that the genotype compositions of the twins were highly similar. We then benchmarked the performance of SNP callers to detect discordant variations using high-throughput sequencing data. Our analysis revealed that chimerism patterns, well within the range normally observed in MZ twins, greatly reduce the sensitivity of SNP calls. This raises questions regarding any conclusions of genomic homogeneity that might be drawn from studies of blood-derived twin DNA.
Author Erlich, Yaniv
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Snippet Twin studies have long provided a means to separate the contributions of genetic and environmental factors. A recent pioneering report by Baranzini et al....
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SubjectTerms Blood
Child
Chimerism
Discordance
Disease susceptibility
Diseases in twins
Diseases in Twins - genetics
Diseases in Twins - pathology
DNA - blood
Embryogenesis
Environmental factors
Female
Genetic aspects
Genetic Predisposition to Disease
Genome, Human
Genotype
Genotypes
Hematopoietic stem cells
high throughput sequencing
Human genetics
Humans
Multiple sclerosis
Multiple Sclerosis - genetics
Multiple Sclerosis - pathology
Next-generation sequencing
Nucleotide sequence
Polymorphism, Single Nucleotide - genetics
Risk Factors
Sequence Analysis, DNA
shared circulation
Single-nucleotide polymorphism
Statistical methods
Twin studies
Twins
Twins, Dizygotic - genetics
Twins, Monozygotic - genetics
Variation
Title Blood Ties: Chimerism Can Mask Twin Discordance in High-Throughput Sequencing
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