Gene Environment Interaction
In many genetic disorders, evidence indicates that individuals who carry the same mutation in the same gene do not necessarily have the same disease manifestations. This is true even in families that harbor the same mutation.
One question that arises is to what extent modifier genes influence expression.
Another important question is whether environmental factors, internal or external, interact with specific gene mutations and alter their impact. Penetrance of a specific allele that impacts the phenotype is defined as the probability that an individual who carries that allele will manifest the corresponding phenotype.
Evidence also indicates that individuals with mutations in a specific gene occur more frequently in some regions of the world. The question that arises whether natural selection operates and whether heterozygotes for specific mutations have a selective advantage in particular environments.
The Epigenetic Inheritance of X Chromosomes:
Variation in the number of X chromosomes in mammals poses a problem for gene regulation. If X-linked genes are expressed equally in each sex, females will have twice as much of the X genetic content as males. However, this does not happen and is prevented by dosage compensation, which equalizes the level of expression of X-linked genes in both male and female sexes.
In mammals, one of the X chromosomes is inactivated completely. This inactivation of X chromosome is mediated by a gene called ‘Xic—X chromosome inactivation centre’. Inactivation spreads from Xic along the entire X chromosome. As the result, females have only one active X chromosome just like the males. This active X chromosomes of females and the single X chromosome of males are expressed equally.
The inactive X chromosome is perpetuated in a heterochromatic state whereas the active X chromosome is euchromatic. Once the inactive state is established, it is inherited by descendant cells. This is an example of epigenetic inheritance as it is not dependant on the DNA sequence.
Epigenetic studies over the past decade have revealed that acetylation of amino acid residues in histones takes place primarily in the chromatin of expressed genes. Enzymes with histone acetyltransferase activity carry out histone acetylation. Enzymes with histone deacetylase activity remove acetyl groups from histones, and deacetylated histone occurs more commonly in genes that show reduced expression. Specific amino acid residues in histone may also undergo phosphorylation or methylation.
Post-translational modification occurs primarily on lysine residues, but it may occur on arginine and serine residues as well. Histones may also undergo ubiquitination, ADP ribosylation, and sumoylation.
Epigenetic studies in phenotypically discordant monozygotic twins:
Because monozygotic (MZ) twins are derived from the fusion of a single egg and a single sperm, they are assumed to be genetically identical. However, phenotypic differences between MZ twins are sometimes observed. These differences may result from epigenetic factors or from post-zygotic structural changes or mutations in DNA. The fertilized egg has many mitochondria. Differences in MZ twins may also arise because of differential segregation of mitochondria in the early stages of cell division.
Factors that impact penetrance and expressivity:
Factors that influence penetrance include age, genetic background and environmental factors. Examples of the impact of age on disease penetrance include neurodegenerative disorders, such as Huntington’s disease, which follow Mendelian inheritance patterns yet result in disease symptoms only in middle age or later.
Variable expressivity refers to the observation that, even in disorders with clear-cut Mendelian inheritance, the specific manifestation of the disease may vary among family members. Variable expressivity may be influenced by modifier genes, subsequent somatic mutations or rearrangements, or environmental factors.
Penetrance in adult-onset hemochromatosis:
In Northern Europeans, the predominant cause of adult-onset hemochromatosis is homozygosity for the C282Y mutation in the protein encoded by the HFE gene (hemochromatosis gene, also known as high iron) on chromosome 6p21.3. The prevalence of C282Y homozygosity is 1 in 200 in these populations. However, not all homozygotes for this allele present with clinical features of hemochromatosis or with biochemical evidence of iron overload.
DNA damage and repair:
Lesions in DNA may result from hydrolytic reactions and can be induced by reactive oxygen species. Environmental agents that damage DNA include UV light, ionizing radiation, heavy metals, and chemical pollutants such as those present in tobacco.
Signatures of environmentally induced DNA damage:
The risk of lung cancer is 20 times greater in smokers than in nonsmokers; more than 60 different mutagens are present in tobacco smoke. Pleasance, et al. (2010), used massively parallel DNA sequencing to investigate somatic mutations in a small-cell lung cancer line. Their sequence analyses revealed more than 22,910 somatic mutations in the tumor cells.
They reviewed tobacco carcinogen-related mutagenesis and noted that three processes are involved. These include mutagen-induced chemical modification of purine nucleotides, failure of repair, and incorrect nucleotide incorporation during replication. They found that guanine-to-thymidine (G-to-T) transversions were highest in the tumor cells. These transversions have been linked to exposure to aromatic hydrocarbons and acrolein.
Pleasance, et al., also found increased guanine-to-cytosine (G-to-C) transversions, particularly at unmethylated CpG sites. They noted that previous reports have indicated that G-to-C transversions are associated with exposure to polycyclic aromatic hydrocarbons that contain a cyclopentane ring.
Their studies revealed that transcription-coupled repair and expression-coupled repair are more common in tumors. Somatic acquired unbalanced genomic rearrangements were also identified in the tumor cells. A number of these involved chromosomes 1p32-p36 and 4q25-q28. Rearrangements of chromodomain helicase CHD7 were also common in small-cell cancer cell lines.