Pervasive Inter-Individual Variation in Allele-Specific Expression in Monozygotic Twins

Ronaldo Da Silva Francisco Junior,Juan Carlo Santos E Silva,Ana Beatriz Garcia,Gustavo Simões Carnivali,Yasmmin Côrtes Martins,Douglas Terra Machado,Enrique Medina-Acosta,Cristina Dos Santos Ferreira,Victor Ramos

doi:10.3389/fgene.2019.01178

Abstract

Despite being developed from one zygote, heterokaryotypic monozygotic (MZ) co-twins exhibit discordant karyotypes. Epigenomic studies in biological samples from heterokaryotypic MZ co-twins are of the most significant value for assessing the effects on gene- and allele-specific expression of an extranumerary chromosomal copy or structural chromosomal disparities in otherwise nearly identical germline genetic contributions. Here, we use RNA-Seq data from existing repositories to establish within-pair correlations for the breadth and magnitude of allele-specific expression (ASE) in heterokaryotypic MZ co-twins discordant for trisomy 21 and maternal 21q inheritance, as well as homokaryotypic co-twins. We show that there is a genome-wide disparity at ASE sites between the heterokaryotypic MZ co-twins. Although most of the disparity corresponds to changes in the magnitude of biallelic imbalance, ASE sites switching from either strictly monoallelic to biallelic imbalance or the reverse occur in few genes that are known or predicted to be imprinted, subject to X-chromosome inactivation or A-to-I(G) RNA edited. We also uncovered comparable ASE differences between homokaryotypic MZ twins. The extent of ASE discordance in MZ twins (2.7%) was about 10-fold lower than the expected between pairs of unrelated, non-twin males or females. The results indicate that the observed within-pair dissimilarities in breadth and magnitude of ASE sites in the heterokaryotypic MZ co-twins could not solely be attributable to the aneuploidy and the missing allelic heritability at 21q.

Highlights

Monozygotic (MZ) twinning entails the partitioning of progenitor cells derived from one zygote collapsing into two sets that form two separate fetuses of nearly identical genotypes
We selected the transcriptome study by Letourneau and collaborators (2014) on a pair of MZ co-twins who were karyotypically discordant for trisomy 21 (T21) of maternal origin (Dahoun et al, 2008), and are heterokaryotypic twins
Between the MZ co-twins discordant for T21, we identified 1,227 (3.8%) allele-specific expression (ASE) sites whose allelic patterns were discordant in fibroblasts and 3,295 (6%) such sites in induced pluripotent stem cells (iPSC) (Figure 2A, Dataset S3)

Summary

Introduction

Monozygotic (MZ) twinning entails the partitioning of progenitor cells derived from one zygote collapsing into two sets that form two separate fetuses (co-twins) of nearly identical genotypes. MZ co-twins develop through monochorionic or dichorionic placentation as a result of when the sets of progenitor cells are split. Heterokaryotypic MZ co-twins may be discordant for structural chromosomal rearrangements (Leung et al, 2009; Essaoui et al, 2013), including genomewide copy number variation (CNV) that is commonplace in homokaryotypic MZ twins (Abdellaoui et al, 2015; Huang et al, 2019). Other likely causes for genotypic discordance in MZ monochorionic co-twins include alterations in gene expression (Buil et al, 2015), parent-of-origin effects associated to abnormal non-random (skewed) X-chromosome inactivation (XCI) (Orstavik et al, 1995), and genomic imprinting (Weksberg et al, 2002; Begemann et al, 2018). Most of the reported cases are spontaneous pregnancies, rather than associated with assisted reproductive technology

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