Parental effect of DNA (Cytosine-5) methyltransferase 1 on grandparental-origin-dependent transmission ratio distortion in mouse crosses and human families

Abstract

Transmission ratio distortion (TRD) is a deviation from the expected Mendelian 1:1 ratio of alleles transmitted from parents to offspring and may arise by different mechanisms. Earlier we described a grandparental-origin-dependent sex-of-offspring-specific TRD of maternal chromosome 12 alleles closely linked to an imprinted region and hypothesized that it resulted from imprint resetting errors in the maternal germline. Here, we report that the genotype of the parents for loss-of-function mutations in the Dnmt1 gene influences the transmission of grandparental chromosome 12 alleles. More specifically, maternal Dnmt1 mutations restore Mendelian transmission ratios of chromosome 12 alleles. Transmission of maternal alleles depends upon the presence of the Dnmt1 mutation in the mother rather than upon the Dnmt1 genotype of the offspring. Paternal transmission mirrors the maternal one: live-born offspring of wild-type fathers display 1:1 transmission ratios, whereas offspring of heterozygous Dnmt1 mutant fathers tend to inherit grandpaternal alleles. Analysis of allelic transmission in the homologous region of human chromosome 14q32 detected preferential transmission of alleles from the paternal grandfather to grandsons. Thus, parental Dnmt1 is a modifier of transmission of alleles at an unlinked chromosomal region and perhaps has a role in the genesis of TRD.

Figure 1.—

Failure to erase imprints on maternal alleles. The solid lines correspond to maternally imprinted chromosomes, and the dashed lines correspond to paternally imprinted chromosomes. The offspring that inherited the grandmaternal (GM) correctly imprinted chromosome from the mother has normal imprinting. The offspring that inherited the incorrectly paternally imprinted grandpaternal (GP) chromosome from the mother has two paternally imprinted chromosomes and shows LOI.

Figure 2.—

Effect of DNMT1 on transmission ratios in mouse chromosome 12 and human chromosome 14q32. (A) Genetic map of the distal region of chromosome 12. Positions of markers used for genotyping are based on the Mouse Genome Informatics integrated map. The approximate position of the IG DMR is indicated by an open oval. (B) Genetic (top) and physical (bottom) maps of the human chromosomal region 14q32 that harbors the imprinted domain. Male-specific genetic map positions of markers used for genotyping are based on the Marshfield genetic map. Physical distance between the same markers is also based on data from the Ensembl database. The approximate position of the IG DMR is indicated by an open oval. (C) Diagrams of the mouse crosses used in the study. The presence of the Dnmt1 mutation in heterozygous state is indicated as “Dnmt1.”

Figure 3.—

Reduced mRNA abundance of Dnmt1 isoforms in oocytes and testicular tubules of heterozygous mutant mice. Each graph represents the results of quantitative RT–PCR assays in oocytes or testicular tubules. The isoform assayed in each experiment is indicated in the top left corner of each graph. Solid bars correspond to RNA levels in heterozygous mutant mice; shaded bars correspond to RNA levels in wild type (wt) mice. The mean RNA levels in wild-type mice were assigned a 100% value and RNA levels in heterozygous mutant mice were calculated as a percentage of the wild-type levels.

Figure 4.—

Methylation patterns of the IG DMR in sperm of heterozygous mutant males and their wild-type littermates. Each row corresponds to an allele with a specific methylation profile. Solid circles correspond to methylated CGs, and open circles correspond to unmethylated CGs. The number on the right shows the number of clones with the respective methylation pattern.

Figure 5.—

Comparison of grandparental-origin-dependent inheritance patterns in the homologous regions of human chromosome 14q32 and mouse chromosome 12. Solid areas indicate alleles of the grandmother, whereas open areas indicate the alleles of the grandfather. The percentage of transmitted alleles to offspring of both sexes is given.