Computational and experimental identification of novel human imprinted genes

Abstract

Imprinted genes are essential in embryonic development, and imprinting dysregulation contributes to human disease. We report two new human imprinted genes: KCNK9 is predominantly expressed in the brain, is a known oncogene, and may be involved in bipolar disorder and epilepsy, while DLGAP2 is a candidate bladder cancer tumor suppressor. Both genes lie on chromosome 8, not previously suspected to contain imprinted genes. We identified these genes, along with 154 others, based on the predictions of multiple classification algorithms using DNA sequence characteristics as features. Our findings demonstrate that DNA sequence characteristics, including recombination hot spots, are sufficient to accurately predict the imprinting status of individual genes in the human genome.

Figure 1.

Genome-wide distribution of genes proved (filled triangles) or predicted with high confidence (unfilled triangles) to be imprinted. Red downward triangles, blue upward triangles, and black dots indicate genes predicted to be maternally, paternally, or biallelically expressed, respectively. Light blue bars highlight a 3-Mb region centered on the linkage regions presented in Supplemental Table 6.

Figure 2.

Sequence comparisons of conceptus and maternal genomic DNA versus conceptus cDNA; arrow denotes polymorphic site. (A) The conceptus is polymorphic (G/A, dbSNP accession rs2235112) in DLGAP2, whereas the mother (maternal decidua) is homozygous (A/A). DLGAP2 isoforms 24, 25, 26, and 27 are expressed monoallelically in the testis from the paternal allele (representative DNA sequences from one individual out of eight informative conceptuses demonstrated to be imprinted at the DLGAP2 locus). (B) The conceptus is polymorphic (C/T, dbSNP accession rs2615374) in KCNK9, whereas the mother (maternal decidua) is homozygous (C/C). KCNK9 is expressed monoallelically in the brain from the maternal allele (representative DNA sequences from one individual out of nine informative conceptuses demonstrated to be imprinted at the KCNK9 locus).