Abstract
BackgroundMonoallelic expression of autosomal genes has been implicated in human psychiatric disorders. However, there is a paucity of allelic expression studies in human brain cells at the single cell and genome wide levels.ResultsIn this report, we reanalyzed a previously published single-cell RNA-seq dataset from several postmortem human brains and observed pervasive monoallelic expression in individual cells, largely in a random manner. Examining single nucleotide variants with a predicted functional disruption, we found that the “damaged” alleles were overall expressed in fewer brain cells than their counterparts, and at a lower level in cells where their expression was detected. We also identified many brain cell type-specific monoallelically expressed genes. Interestingly, many of these cell type-specific monoallelically expressed genes were enriched for functions important for those brain cell types. In addition, function analysis showed that genes displaying monoallelic expression and correlated expression across neuronal cells from different individual brains were implicated in the regulation of synaptic function.ConclusionsOur findings suggest that monoallelic gene expression is prevalent in human brain cells, which may play a role in generating cellular identity and neuronal diversity and thus increasing the complexity and diversity of brain cell functions.
Highlights
Monoallelic expression of autosomal genes has been implicated in human psychiatric disorders
We reasoned that a subset of heterozygous single nucleotide polymorphism (SNP) in an individual subject could be discovered directly by pooling scRNAseq data from all cells, since the two alleles of a gene could be expressed in different single cells [12, 31, 32]
We excluded the scRNA-seq data of four zygotes and four early 2-cell embryos (Fig. 1b) because we found very few heterozygous SNPs (hetSNPs) from those data, which is consistent with the fact that the paternal genome is not fully activated at these two stages and the maternal alleles were the predominant alleles for most genes [12]
Summary
Monoallelic expression of autosomal genes has been implicated in human psychiatric disorders. Random monoallelic expression can contribute to developmental disorders when this occurs in a gene containing heterozygous. A known example is the Xlinked MECP2 gene. It is mutated in Rett Syndrome and approximately half of the cells in a female patient would be expected to express the mutated copy, leading to disrupted cellular functions [17, 18]. Autosomal genes undergoing monoallelic expression may be implicated in human disorders. The AGC1 gene, which leads to a severe developmental abnormality with loss of function mutations, has been shown to be expressed monoallelically in a random manner in mice [19]. The functional impacts of monoallelic gene expression, remain largely unclear
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