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Table 1 Examples of genes and specific sequences that support or reject the hypothesis that genotype predisposes transgenerationally inherited epitype and phenotype

From: The influence of DNA sequence on epigenome-induced pathologies

Genes/Sequences affected

Genotype contribution

Known aberrant epitype/gene expression

Phenotype of epimutation or epigenetic change

Species

Supports/rejects hypothesis

A. Direct analysis of trans-generational inheritance

1. RYR1 ryanodine-receptor

Unknown

Cytosine hypermethylation/silenced

hyperthermia, core myopathies

human

Rejects

2. MLH1 (Homolog of mismatch repair protein MutL)

Allele specific silencing

Cytosine hypermethylation/silenced

Colorectal or endometrial cancers

human

Weakly supports

3. AGOUTI (paracrine signaling peptide)

Alleles with retrotransposon

Cytosine hypomethylation/activation

Yellow, obese

mouse

Supports

4. AXIN1-FUSED

Alleles with retrotransposon

Cytosine hypomethylation, histone acetylation/activation

Axin-fused kinked tail

mouse

Supports

5. CNR Colorless Non-Ripening

Native CpG rich region

Cytosine hypermethylation/silenced

Carotenoid synthesis

tomato

Rejects

6. CYC – cycloidea (transcription factor)

Native CpG rich region and possible genotype difference

Cytosine hypermethylation/silenced

Floral morphology

Linaria vulgaris

Likely supports

7. H3K4Me2 demethylase

None identified

Histone H3 lysine4 dimethylation retained causing gene activation

Germ line immortality

Caenorhabditis elegans

Likely rejects

8. Quantitative epigenetic trait loci ( for example, many loci)

DNA DEMETHYLATION1 ddm1/ddm1 restored to DDM1/DDM1

Cytosine re-methylation and re-silencing

Flowering time and plant height

Arabidopsis thaliana

Supports

9. Reprogramming of 5Me C by dsRNA

siRNA, miRNA, piRNA, and other dsRNAs

Cytosine re-methylation and re-silencing

Complex, molecular, and developmental

Arabidopsis, mice

Supports

10. Somatic cell nuclear transfer

Genome-wide

Cytosine re-methylation and histone modifications

Embryonic and fetal development

Mice, sheep, pigs, cows

Mostly supports

B. Indirect analysis using sequence conservation and gene duplication

1. RRRRRYYYYY repeat throughout the genome

10.5 bp repeats position most nucleosomes

N.M.

N.M.

Diverse animal species

Supports

2a. Histone H2AZ in >1,000 nucleosomes

10 bp repeat of G + C and A + T rich dinucleotides

Histone H2AZ variant positioning

Potentiated for expression. N.M.

Yeast, human, Arabidopsis

Supports

2b. H2AZ in FLC, MAF4, MAF5

Subfamily of three recently duplicated MADS box genes

Bimodal distribution of H2AZ enriched nucleosomes/activated

Altered flowering time and gene expression

Arabidopsis

Supports

3. Histone CenH3 in ~100,000 nucleosomes

10 bp repeat of AA or TT dinucleotides

Histone CenH3 variant positioning

Essential for chromosomal segregation. N.M.

maize

Supports

4. Blood plasminogen genes (PMGs)

Cytosine methylation in 208 bp region upstream of four PMG genes

N.M.

Demethylation activates four linked PMG alleles genes in liver. Methylation silences in other organs.

human

Supports

5. 1600 segmental duplications

Duplicated gene sequences

Several different histone side chain modifications

Duplicate alleles generally silenced relative to active parental allele. N.M.

human

Rejects

6. HoxD cluster

Five gene duplicated HOXD genes

Modestly conserved nucleosomal and H3K4Me2 patterns

N.M.

human

Supports

7. DNA loops and microsatellites

Concatenated DNA loops and trans-chromosomal contacts

Binding by HMG box proteins to control gene expression

N.M.

mammals

Modestly supports

  1. N.D., no data; N.M., not based on a mutational study.