3.20 Gene Interaction & Epigenetics

• The observable characteristics of an organism are its phenotype
• Phenotypic variation is the difference in phenotypes between organisms of the same species
• In some cases, phenotypic variation is explained by genetic factors
  • For example, the four different blood groups observed in human populations are due to different individuals within the population having two of three possible alleles for the single ABO gene
• In other cases, phenotypic variation is explained by environmental factors
  • For example, clones of plants with exactly the same genetic information (DNA) will grow to different heights when grown in different environmental conditions
• Phenotypic variation can also be explained by a combination of genetic and environmental factors
  • For example, the recessive allele that causes sickle cell anaemia has a high frequency in populations where malaria is prevalent due to heterozygous individuals being resistant to malaria
• The complete phenotype of an organism is determined by the expression of its genotype and the interaction of the environment with this:

Phenotype = Genotype + Environment

Genetic variation

• Organisms of the same species will have very similar genotypes, but two individuals (even twins) will have differences between their DNA base sequences
• Considering the size of genomes, these differences are small between individuals of the same species
• The small differences in DNA base sequences between individual organisms within a species population is called genetic variation
• Genetic variation is transferred from one generation to the next and it generates phenotypic variation within a species population
• Genes can have varying effects on an organism's phenotype:
  • Some characteristics (i.e. the phenotype) are controlled by a single gene - these characteristics are known as monogenic
    • These characteristics usually show discontinuous variation (e.g. blood group)
  • Other characteristics are controlled by several genes - these characteristics are known as polygenic
    • These characteristics usually show continuous variation (e.g. height, mass, skin colour)
• Specifically, the different alleles an organism has at a single gene locus can determine the phenotype:
  • Remember - diploid organisms will inherit two alleles of each gene, these alleles can be the same or different
  • For example, the F8 gene that codes for the blood-clotting protein Factor VIII. The different alleles at the F8 gene locus dictate whether or not normal Factor VIII is produced and whether the individual has the condition haemophilia

Environmental factors

• The environment that an organism lives in can also have an impact on its phenotype
• Different environments around the globe experience very different conditions, including (amongst many factors):
  • Length of sunlight hours (which may be seasonal)
  • Supply of nutrients (food)
  • Availability of water
  • Temperature range
  • Oxygen levels
• Changes in the factors above can affect how organisms grow and develop
  • For example, plants with a tall genotype growing in an environment that is depleted in minerals, sunlight and water will not be able to grow to their full potential size determined by genetics (their phenotype is being affected by their environment)
• Variation in phenotype caused solely by environmental pressures or factors cannot be inherited by an organism's offspring (only alterations to the genetic component of gametes will ever be inherited)

Examples of how the environment can affect phenotypic variation

• Diet in animals:
  • The fruit fly (Drosophila melanogaster) is normally grey but there is a genetic mutant that is yellow (a genotypic characteristic that is expressed regardless of the environment)
  • If the larvae of normal grey flies are given a diet of silver salts, they develop the yellow colour regardless of their genotype
  • This means that flies that should be grey (according to their genes) can become yellow due to an environmental factor (their diet)
• Growing conditions for plants:
  • Plants that are grown in the dark or that cannot access enough magnesium become yellow even though, genetically, they should be green
    • This condition is known as chlorosis and occurs because the synthesis of chlorophyll is slowed down or stops completely
  • Plants that are grown in the dark may also develop long stems with small, curled leaves even though, genetically, they should develop normally
    • This is known as etiolation

• An organism’s internal or external environment can influence gene expression patterns
  • The levels of regulatory proteins or transcription factors can be affected in response to environmental stimuli such as light, and chemicals including drugs and hormones
  • For example, enzymes are activated in response to ultraviolet radiation and increase the expression of melanin-producing genes (and therefore production of melanin), leading to skin pigmentation
• Epigenetics is the control of gene expression by factors other than an individual’s DNA sequence
  • Epigenetics involves the switching-on and switching-off of genes, but without changing the actual genetic code
• In eukaryotic cells, nuclear DNA is wrapped around proteins called histones to form chromatin
• Chromatin can be chemically modified in different ways to alter gene expression, including:
  • Methylation of DNA (chemical addition of -CH₃ groups)
  • Histone modification via acetylation of amino acid tails
• Such modifications are called epigenetic tags and collectively, all the epigenetic tags in an organism is called the epigenome
• The epigenome can undergo changes due to environmental factors
  • Smoking, stress, exercise and diet can cause epigenetic changes
  • Internal signalling from the body's own cells can also cause modifications to occur
• Epigenetic modification is independent (i.e. DNA methylation or histone modification in one area is not linked to modification in another)
• The chemical modification of histones and DNA controls how tightly the DNA is wound around them as the intermolecular bonding between the histones and DNA changes
  • If the DNA is wound more tightly in a certain area, the genes on this section of DNA are 'switched off' as the gene and promoter regions are more hidden from transcription factors and RNA polymerase
• The modification of histones is reversible and therefore can be different in different cell types and can vary with age

DNA is coiled around histone proteins to make chromatin

DNA methylation causes the inactivation of genes

• One method of epigenetic control involves the methylation of DNA
• Methyl groups (-CH₃) can be directly added to DNA to change the activity of a gene
• DNA methylation commonly involves the direct addition of a methyl group to cytosine bases which can influence gene expression
• Methylation of DNA suppresses the transcription of the affected gene by inhibiting the binding of transcription factors and enzymes needed for transcription (e.g. RNA polymerase)
  • Cells use this mechanism to lock genes in the ‘off’ position
  • The gene is said to be repressed or inactivated
• DNA methylation can be affected by many environmental, lifestyle or age-related factors

Acetylation of histones affects gene expression

• Acetyl groups (-COCH₃) can be added to lysine amino acids on histone proteins
• Lysine has a positively charged R group, this forms ionic bonds with the negatively charged phosphate backbone of DNA
  • This helps DNA to coil tightly around the histone protein core
• Adding acetyl groups (acetylation) to lysine residues removes the positive ion and therefore removes a bond between the histone protein and the DNA, this causes the DNA to be less tightly wrapped
  • When the DNA is less tightly wrapped, RNA polymerase and transcription factors can bind more easily and therefore gene expression can occur
  • The gene is said to be activated
• Removal of acetyl groups (deacetylation) returns lysine to its positively charged state which has a stronger attraction to the DNA molecule and therefore inhibits transcription and once again stops the gene from being expressed

Acetylation of histones causes chromatin to become less condensed, allowing genes to be transcribed

Epigenetic changes can be passed on following cell division

• Like the genome, the epigenome is heritable (i.e. when a cell divides and replicates, epigenetic changes affecting the expression of genes in the DNA of that cell may be passed on to daughter cells)
  • For example, during gamete production, DNA in the parent cell usually undergoes de-methylation (the methyl groups are removed) but often methyl groups are not removed and therefore are present in the DNA on the sperm or egg cells
  • One potential explanation for why this occurs is that if an epigenetic change occurs in response to an environmental factor, it may be beneficial for this epigenetic change to also occur in daughter cells (or gametes, for example) so that they are also better adapted for the environmental factor (in the same way the parent cell was)
  • Mounting evidence demonstrates that modifications to the epigenome in one generation can be passed on to the next generation at the cellular or whole organism level