Monoallelic expression of the human FOXP2 speech gene

Abstract

The recent descriptions of widespread random monoallelic expression (RMAE) of genes distributed throughout the autosomal genome indicate that there are more genes subject to RMAE on autosomes than the number of genes on the X chromosome where X-inactivation dictates RMAE of X-linked genes. Several of the autosomal genes that undergo RMAE have independently been implicated in human Mendelian disorders. Thus, parsing the relationship between allele-specific expression of these genes and disease is of interest. Mutations in the human forkhead box P2 gene, FOXP2, cause developmental verbal dyspraxia with profound speech and language deficits. Here, we show that the human FOXP2 gene undergoes RMAE. Studying an individual with developmental verbal dyspraxia, we identify a deletion 3 Mb away from the FOXP2 gene, which impacts FOXP2 gene expression in cis. Together these data suggest the intriguing possibility that RMAE impacts the haploinsufficiency phenotypes observed for FOXP2 mutations.

Keywords: FOXP2; developmental verbal dyspraxia; language; random monoallelic expression; speech.

Fig. 1.

Proband deletion region and allele-specific expression analysis. (A) Chromosome 7q31 deletion region in proband. Gray bars represent the genes; note that LRRN3 is shown below the line merely to make it clear that it resides within the IMMP2L gene. (B) Comparison of genomic and cDNA showing biallelic FOXP2 expression in control and monoallelic expression in the proband. Another SNP (rs1916980) also revealed monoallelic expression of FOXP2.

Fig. 2.

Proband microarray and expression of genes flanking the deleted region. (A) cDNA genotypes of genes flanking the microdeletion in the proband show biallelic expression. (B) Parental (genomic) DNA genotypes and proband (genomic and cDNA) genotypes at rs1194329 confirm exclusively maternal expression of FOXP2 in the proband. (C) Proband microarray with loss of probes at a 2-Mb locus on 7q31.

Fig. 3.

RMAE assessed in normal cell lines. (A) A representation of the SNP array cDNA data for the FOXP2 gene assessed for one SNP in B-cell subclones from one individual (15) and in T-cell subclones from a second individual. White, no signal; yellow, biallelic signal indicating expression of both alleles; pink, monoallelic maternal; green, monoallelic unknown. (Monoallelic for the paternal allele would have been blue, as in ref. .) H and M are nonclonal cell lines from which subclones (H16 and H7, B-cell clones, and M1 and M2, T-cell clones, respectively) were derived. (B) Electropherograms showing SNP genotypes in nonclonal B cells for individual H, as well as genomic DNA and cDNA genotypes for clone H16 at four different SNP loci showing heterozygosity in genomic and homozygosity in cDNA (arrowed). (C) A clone H7 SNP example is displayed.