What does epigenetics study, and how does it differ from classical genetics?
A: Epigenetics studies mutations in the DNA sequence that accumulate across generations; classical genetics studies inheritance without mutations
B: Epigenetics studies heritable changes in gene expression that do not involve changes to the DNA sequence itself — the "software" regulating how the genetic "hardware" is read
C: Epigenetics is synonymous with genetics; both study DNA sequence variation and its consequences for phenotype
D: Epigenetics studies only inter-generational (transgenerational) inheritance; within-generation gene expression is studied by classical genetics
Correct: Epigenetics studies heritable changes in gene expression that do not involve changes to the DNA sequence itself — the "software" regulating how the genetic "hardware" is read
Epigenetics (from Greek epi- = above/upon) refers to mechanisms that regulate gene expression without altering the underlying DNA sequence. Where classical genetics asks "what does the DNA say?", epigenetics asks "which parts of the DNA are currently being read, and how loudly?" Key mechanisms include DNA methylation, histone modification, and non-coding RNA regulation. Epigenetic marks can be stable across cell divisions (explaining how liver cells and neurons — genetically identical — maintain such different gene expression profiles) and in some cases can be transmitted across generations. Critically, epigenetic marks are modifiable by experience, nutrition, stress, and drugs — providing a molecular mechanism by which environment gets "under the skin" to alter gene expression in lasting ways.
What is DNA methylation and what is its typical effect on gene expression?
A: The addition of a phosphate group to cytosine residues, which typically activates gene transcription
B: The addition of a methyl group (–CH₃) to cytosine residues in CpG dinucleotides, typically silencing nearby gene expression
C: The removal of adenine bases from the DNA sequence, permanently altering the genetic code
D: A post-translational modification of histone proteins that loosens chromatin and increases gene transcription
Correct: The addition of a methyl group (–CH₃) to cytosine residues in CpG dinucleotides, typically silencing nearby gene expression
DNA methylation involves the addition of a methyl group (–CH₃) to the 5-carbon position of cytosine residues, typically at CpG dinucleotides (cytosine followed by guanine). Methylation in gene promoter regions typically silences transcription by: (1) physically blocking transcription factor binding; (2) recruiting methyl-binding proteins that condense chromatin. DNA methylation is maintained through cell division by DNMT1 (a "maintenance methyltransferase") and is de novo added by DNMT3A and DNMT3B. In the context of stress and adversity, altered methylation of genes like the glucocorticoid receptor gene (NR3C1) provides a molecular mechanism linking early experience to long-term changes in stress reactivity — as demonstrated in both rodent and human studies.
How do histone modifications regulate gene expression?
A: Histones bind directly to RNA polymerase and prevent it from initiating transcription at any gene near a methylated histone
B: Chemical modifications to histone tails (acetylation, methylation, phosphorylation) alter chromatin compaction — histone acetylation generally opens chromatin and activates transcription; histone methylation has context-dependent effects
C: Histones are only relevant during DNA replication; modifications are removed after each cell division and cannot carry epigenetic information
D: Histone modifications exclusively silence gene expression; activation is controlled by DNA methylation alone
Correct: Chemical modifications to histone tails (acetylation, methylation, phosphorylation) alter chromatin compaction — histone acetylation generally opens chromatin and activates transcription; histone methylation has context-dependent effects
DNA is wrapped around histone octamers to form nucleosomes. The protruding histone tails are subject to numerous post-translational modifications — the "histone code" — that collectively regulate chromatin accessibility and transcription. Key modifications: (1) Histone acetylation (HATs add, HDACs remove): acetylation neutralises the positive charge on lysine residues, loosening DNA-histone binding → open chromatin → gene activation. Histone deacetylase inhibitors (HDACi) are explored as epigenetic drugs. (2) Histone methylation: effects depend on which residue and how many methyl groups — H3K4me3 marks active promoters; H3K27me3 marks repressed genes. (3) Histone phosphorylation: involved in chromatin condensation during mitosis and DNA damage response. Together, DNA methylation and histone modifications form the epigenome — a dynamic regulatory layer responsive to experience.
What is the diathesis-stress model and what does it predict about who develops psychological disorders?
A: All people carry equal genetic risk; the accumulation of sufficient environmental stress alone determines who develops disorders
B: Some people carry genetic or biological vulnerabilities (diatheses); exposure to sufficient environmental stress activates these vulnerabilities to produce disorder — neither alone is sufficient in most cases
C: Genetic diatheses inevitably produce disorders regardless of environment; stress only determines the timing of onset
D: The diathesis-stress model applies only to schizophrenia; other disorders are either purely genetic or purely environmental
Correct: Some people carry genetic or biological vulnerabilities (diatheses); exposure to sufficient environmental stress activates these vulnerabilities to produce disorder — neither alone is sufficient in most cases
The diathesis-stress model (Meehl, 1962; Monroe & Simons, 1991) proposes that psychological disorders arise from the interaction of a pre-existing vulnerability (diathesis — genetic, neurobiological, or psychological) with environmental stress. Neither the diathesis alone nor the stress alone is typically sufficient: a person with high diathesis may develop the disorder under moderate stress; a person with low diathesis requires severe stress or may never develop the disorder. Classic application: schizophrenia — high genetic loading (e.g., having a schizophrenic identical twin) combined with environmental risk factors (cannabis use in adolescence, urban stress, migration, obstetric complications) substantially increases risk, while low-diathesis individuals with the same stressors rarely develop schizophrenia. The model predicts that genetic risk identifies who is most sensitive to stress, not who inevitably becomes ill.
How does Jay Belsky's differential susceptibility hypothesis differ from the diathesis-stress model?
A: Differential susceptibility proposes that some genotypes confer greater sensitivity to environmental quality in BOTH directions — for-better AND for-worse — not merely greater vulnerability to adverse environments
B: Differential susceptibility proposes that all people are equally sensitive to positive environments; only negative environments produce differential effects based on genotype
C: The models are identical; "differential susceptibility" is a relabelling of the diathesis-stress model
D: Differential susceptibility applies only to parenting effects; diathesis-stress applies only to clinical disorders
Correct: Differential susceptibility proposes that some genotypes confer greater sensitivity to environmental quality in BOTH directions — for-better AND for-worse — not merely greater vulnerability to adverse environments
Belsky (1997, 2005) proposed differential susceptibility as an evolutionary refinement of diathesis-stress: certain genotypes (or temperamental characteristics) confer heightened plasticity — greater sensitivity to environmental influences in both positive and negative directions. Where diathesis-stress predicts that high-risk genotypes + bad environment = bad outcome (and implies high-risk genotype + good environment ≈ low-risk outcome), differential susceptibility predicts a cross-over interaction: sensitive genotypes do worse in adverse environments AND do better in supportive environments than low-sensitivity genotypes. The "orchid and dandelion" metaphor: dandelion children flourish in almost any environment; orchid children wilt in adversity but bloom spectacularly in nurturing conditions. Evidence includes 5-HTTLPR genotype moderating responses to both negative parenting AND positive parenting interventions.
What did Michael Meaney and colleagues demonstrate in their studies of maternal licking and grooming in rats?
A: That high maternal licking causes gene mutations in the glucocorticoid receptor gene of offspring
B: That high maternal licking and grooming epigenetically programmes offspring for lower stress reactivity by increasing methylation of the glucocorticoid receptor gene promoter
C: That high maternal licking and grooming epigenetically programmes offspring for lower stress reactivity — via decreased methylation of the glucocorticoid receptor gene promoter, increasing receptor expression and improving negative feedback on the HPA axis
D: That maternal behaviour has no lasting effect on offspring biology; all stress reactivity differences are genetically determined at conception
Correct: That high maternal licking and grooming epigenetically programmes offspring for lower stress reactivity — via decreased methylation of the glucocorticoid receptor gene promoter, increasing receptor expression and improving negative feedback on the HPA axis
Meaney, Szyf, and colleagues (Weaver et al., 2004, Nature Neuroscience) showed a landmark epigenetic mechanism for maternal programming of stress reactivity in rats. Pups raised by high-licking/grooming (LG) mothers showed lower HPA axis reactivity to stress as adults compared to pups of low-LG mothers — and crucially, cross-fostering reversed this effect (low-LG pups raised by high-LG mothers showed low reactivity). The mechanism: high LG increases serotonergic signalling in the hippocampus → activates NGFI-A transcription factor → binds GR gene promoter → decreases DNA methylation (demethylation) at a specific CpG site → increased glucocorticoid receptor expression → stronger negative feedback on the HPA axis → lower cortisol response to stress. This provides a molecular account of how early caregiving experience — without changing DNA sequence — produces lasting biological differences in stress regulation.
Caspi et al. (2003) published a landmark GxE study on 5-HTTLPR and depression. What were the key findings and their significance?
A: The short 5-HTTLPR allele directly caused depression regardless of life stress; the study was the first to identify a gene for depression
B: Carriers of the short 5-HTTLPR allele showed greater increases in depression following stressful life events, but short-allele carriers without stressful events were not at elevated risk — demonstrating gene-environment interaction, not gene main effect
C: The long 5-HTTLPR allele protected against all forms of depression; short-allele carriers were universally at higher risk regardless of environment
D: The study found no GxE interaction; both alleles showed equal depression risk, but the long allele showed faster recovery with SSRIs
Correct: Carriers of the short 5-HTTLPR allele showed greater increases in depression following stressful life events, but short-allele carriers without stressful events were not at elevated risk — demonstrating gene-environment interaction, not gene main effect
Caspi et al. (2003, Science) followed the Dunedin cohort and found that individuals carrying one or two copies of the short (s) allele of the serotonin transporter promoter region (5-HTTLPR) showed greater depressive symptoms and major depression episodes in response to stressful life events between ages 21–26, compared to long (l/l) homozygotes exposed to similar stress levels. Crucially, the s allele alone — without stressful events — did not predict depression. The finding suggested that 5-HTTLPR moderates sensitivity to stress (a GxE interaction) rather than acting as a "depression gene." The study generated enormous follow-up research: subsequent meta-analyses were mixed (Risch et al. 2009 found no replication; Karg et al. 2011 meta-analysis did find the interaction using childhood maltreatment as the stressor). It remains one of the most influential and contested GxE findings in psychiatric genetics — a case study in the difficulty of replication in this area.
Epigenetics & Gene–Environment Interaction
What does epigenetics study, and how does it differ from classical genetics?
About this quiz
The genome is not a fixed blueprint — it is a dynamic document that can be read differently depending on experience, stress, nutrition, and timing. Epigenetics describes how the environment leaves lasting marks on gene expression without altering the DNA sequence itself.
This quiz covers the mechanisms of epigenetic regulation (methylation, histone modification), gene–environment interaction (GxE), the diathesis-stress and differential susceptibility models, and landmark studies demonstrating how early experience shapes biology.