Behavioural Genetics Lecture Notes

Genetics Basics

• Content Overview:
  • Genetics Basics
  • How did we get to the current research?
  • Key terminology
  • DNA and chromosomes
  • The Central Dogma
  • Gene expression
  • Transcription and translation
  • Environmental Effects
  • Animal studies
  • Twin studies
  • Epigenetics

Lamarck and Evolution

• Evolution by use versus disuse:
  • Lamarck (1802) proposed that animals, throughout their lives, strive for specific biological features to aid sustenance, survival, and reproduction.

Darwin and Evolution

• Evolution by natural selection:
  • Organisms best suited to their environment are more likely to survive and pass on their traits.
  • Example: Long-neck giraffes outcompete short-neck giraffes, leading to the inheritance of long necks in subsequent generations.
  • Darwin (1865) acknowledged that "the laws governing inheritance are quite unknown" in On the Origin of the Species.

Mendelian Genetics

• Mendel's Study:
  • Studied dichotomous traits in true-breeding lines of pea plants.
    • Dichotomous traits: Traits that occur in one form or another, never in combination.
    • True-breeding lines: Interbred members always produce offspring with the same trait.
  • Mendel's work was published in 1865 but not widely accepted until 1900.

Key Genetic Terminology

• Alleles:
  • Multiple possible versions of a gene that control the same trait.
• Homozygous:
  • Trait with two identical alleles (e.g., BB, ww).
• Heterozygous:
  • Trait with two different alleles (e.g., Bw).
• Genotype:
  • Genetic make-up.
• Phenotype:
  • Observable traits.
• Dominant:
  • Gene is displayed in either the homozygous or heterozygous condition.
• Recessive:
  • Only displayed in the homozygous condition.

Mendel’s Findings

• Experiment 1:
  • All offspring plants had brown seeds when true-breeding brown-seed plants were crossed with true-breeding white-seed plants.
  • The gene for brown seeds (B) is dominant over the gene for white seeds (w).
• Experiment 2:
  • Both parents are heterozygous (Bw) – one allele for brown and one allele for white.
  • 75% of offspring had brown seeds, and 25% had white seeds.

DNA: The Basics

• Genetic information is carried in Deoxyribonucleic Acid (DNA).
• A gene is a segment of DNA that encodes specific proteins.
• Alleles are alternate forms of the same gene with small differences in their DNA sequence.
• Humans have between 20,000 and 25,000 genes.
• Typically, we have two copies of each gene, one inherited from each parent.
• DNA is mostly the same across people; less than 1% total differs between individuals.

DNA Structure

• DNA molecules are a double helix of nucleotide bases wrapped around each other.
• Bases:
  • Adenine (A)
  • Thymine (T)
  • Guanine (G)
  • Cytosine (C)
• Base Pairing:
  • A nucleotide (allele) on strand 1 always pairs with a particular nucleotide on the other strand
  • Adenine + Thymine
  • Guanine + Cytosine

DNA Folding

• DNA is tightly coiled around “spools” (histones).
• The package of DNA and histones is called chromatin.
• Chromatin gets packaged further to form a chromosome.
• Chromosomes are paired – Individuals inherit one copy from each genetic parent.

Familial DNA Similarity

• We share genetic material with our family:
  • 50% with parents/ full-blooded sibling/ children
  • 25% with grandparents/ aunts/ uncles
• Non-identical twins are created from different gametes, so same genetic similarity as siblings
• Genetic similarity between identical twins = 100%.
• Identical twins separated at birth are of particular interest for research, as they have different life experiences.

Chromosomes

• Humans have 23 matched pairs of chromosomes, with an allele on each chromosome (located in the same place).
  • 22 autosomes
  • 1 pair of sex chromosomes
• Mitosis:
  • Chromosomes double then split, leading to two daughter cells that have full set of chromosomes.
• Meiosis:
  • Creation of gametes (sperm and egg cells) that have half the full set of chromosomes.

Sex Chromosomes

• Sex chromosomes determine mammalian sex:
  • Female (XX)
  • Male (XY)
• Sex Chromosomes
  • Look different and carry different genes (sex-linked genes)
  • Sex-linked traits: almost all controlled by genes on the X chromosome, as it is larger and has more genes.
  • Traits controlled for by genes on the X chromosome occur more frequently in one sex than the other:
    • Dominant traits: more likely in females as twice the chance
    • Recessive traits: less likely in females as they need the recessive gene on both X chromosomes (e.g., colour blindness).

The Central Dogma

• How do we get from genes to behaviour?

DNA \rightarrow RNA \rightarrow Protein \rightarrow Disease

• Gene Expression
• Phenotype

Gene Expression

• Transcription:
  • Gene segment of DNA strands unwinds and used to generate Ribonucleic Acid (RNA).
  • Messenger RNA (mRNA) synthesised from DNA by attracting complementary nucleotides.
  • mRNA leaves nucleus & attaches to ribosome in the cell’s cytoplasm.
• Translation:
  • Ribosome creates a chain of amino acids according to 3-base sequences (codons) of mRNA.
  • Sequence of amino acids folded to create a protein.
• Regulation of gene expression:
  • Enhancers/ promoters: Stretches of DNA that determine whether structural genes initiate protein synthesis.
  • Transcription factors: Proteins that bind to DNA and influence the extent to which genes are expressed.

The Human Genome Project

• If we identify genetic variations that are linked to disease, medical treatment becomes much easier.
• Discovered humans have relatively few genes.
• Same as mice and less than corn.

The Human Genome Project

• No single gene encodes for depression or height.
• Interactions between genes difficult to parse.
  • E.g., Serotonin and depression.
• Pleiotropic:
  • Genes affect multiple characteristics, and multiple genes affect each physical trait.
• "New Hope" with Whole Genome/ Exome Sequencing and Machine Learning.
• What other methods do we have to understand how the genome affects health?

Environmental Effects

• Several study approaches exemplify the interplay between environmental and genetic factors:
  • Animal models (i.e., selective breeding).
  • Twin studies/ Segregation.
  • Disorders with specific genetic contribution.
    • e.g., Phenylketonuria.
  • Epigenome methylation studies.

Animal Studies

• Rats were trained to run a maze with a food reward when they reached the goal.

  • Step 1:
    • Rats that were more successful running the maze were bred with each other.
    • Rats that were less successful running the maze were bred with each other.
  • Finding: Offspring of successful maze runners were more successful at running the maze than offspring of unsuccessful maze runners.

• Control: Offspring of successful maze runners reared by unsuccessful maze runners and vice versa è same results. SO!

  1. Genes can affect behaviour, and selective breeding for certain behaviours is possible
  2. Some behavioural traits are passed to the next generation

Animal Studies – Environmental Effects

• Step 2:

  • Expose different sets of rats to different environments (impoverished and enriched).

• Finding: Maze-dull rats did not make significantly more errors than maze-bright rats when both groups were reared in an enriched environment (Adapted from Cooper & Zubek, 1958).

  1. Despite the influence of genes, the environment is crucial, and there is a gene-by-environment effect (GxE).

Environmental Influence on the Genome

• DNA Methylation (Epigenetics)

DNA \rightarrow RNA \rightarrow Protein \rightarrow Disease

• Transcription
• Translation

Epigenetic Influences

• Psychological state
• Diet
• Social Interactions
• Genetic
• Alternative medicine
• Therapeutic Drugs
• Diurnal/Seasonal correlations
• Disease exposure
• Toxic Chemicals
• Drugs of Abuse
• Microbiome
• Exercise
• Socioeconomic status

Twin Studies

1. Minnesota study of twins reared apart:
   • Monozygotic twins more similar than dizygotic twins on all psychological dimensions
   • All children were raised by middle-class, tightly scrutinised families in highly industrialised countries, yielding little differences in environment
2. Epigenetic effects in monozygotic and dizygotic twins:
   • Monozygotic twins are indistinguishable early in life but accumulate different sets of epigenetic marks throughout lifespan
   • Monozygotic and dizygotic twins accumulate different sets of epigenetic marks at a high concordance rate (i.e., no substantial differences in accumulation between dizygotic and monozygotic twin pairs)
3. Environmental effects in monozygotic twins:
   • Heritability estimate for IQ dependent on environmental conditions
   • Similar to maze-bright and maze-dull rats
   • Enriched environments more important for IQ than inheritance

Phenylketonuria (PKU)

• Neurological disorder characterised by intellectual disability, vomiting, seizures, hyperactivity, irritability, brain damage, and strange urinal odours.
• Pattern of transmission of PKU suggested single recessive gene disorder.
  • 75% to 25% ratio in the phenotypes.
• PKU homozygotes lack phenylalanine hydroxylase.
  • Enzyme that converts the amino acid phenylalanine to tyrosine.
• Environmental factor (diet) can significantly reduce health burden of the disorder.

The “Warrior” Gene

• MAOA (Monoamine Oxidase A) gene
  • Encodes enzymes that breakdown neurotransmitters such as dopamine, norepinephrine, and serotonin
• First GxE study in humans
  • Risk allele was associated with increased aggression and decreased empathy only with individuals who had been exposed to moderate abuse in their childhood environment

Epigenetics in PTSD

• POC in Atlanta with both PTSD and childhood trauma showed more epigenetic changes across the genome than those with only PTSD
• Study in Australian combat veterans of the Vietnam war showed more genes had epigenetic changes among veterans with PTSD than among veterans without

Intergenerational Transmission of Memories

• Smells bind to specific receptors on the olfactory bulb
  • Acetophenone (cherry blossom) to smell receptor M71
• Step 1:
  • Male mice were conditioned to associate the smell of acetophenone with an electric shock and became fearful of the smell
• Finding:
  • The mice developed more M71 receptors, which enabled them to detect acetophenone at significantly lower levels
• Step 2:
  • Sperm from the conditioned mice was inseminated in female mice
  • The offspring were then exposed to acetophenone without the electrical shocks
• Finding:
  • When the offspring were exposed to acetophenone they were more jumpy than when they smelled a neutral odour – even though they had never smelled acetophenone before
  • The same was true of their grand pups

Intergenerational Transmission of Memories

• Epigenetic marks on the gene encoding for M71 that weren't seen in control mice were found in the sperm cells of the conditioned mice and their offspring
• Mice conditioned to fear acetophenone transmitted this ‘memory’ to the next generation
• What does this mean for humans?
  • In Australian veterans, DNA methylation in sperm cells predicted mental health status in their children

Current Epigenetic Research at QUT

• Systematic Reviews:
  • A Systematic Review of DNA Methylation and Gene Expression Studies in Posttraumatic Stress Disorder, Posttraumatic Growth, and Resilience
  • Childhood maltreatment and DNA methylation: A systematic review

Psychological and Epigenetic Changes after Trauma Exposure in Paramedic Students

• First study to investigate longitudinal psychological and epigenetic predictors of trauma response
• First study to provide a holistic view on post-trauma responses (PTSD, depression, resilience & posttraumatic growth)
• Identified key genes and pathways that drive a person’s response to stress (cause vs effect)

Longitudinal Biopsychosocial Markers of Post-Trauma Outcomes in First Responders

• Follow-up from the study of paramedic students, began data collection 2022
• Population: professional paramedics, firefighters, and emergency medical dispatchers
• Almost 700 participants at baseline

Environmental Factors May Reverse Epigenetic Changes

• Socioeconomic status
• Positive experiences can act as a protective buffer against genetic risk factors
• Exercise associated with epigenetic changes in BDNF in a veteran population
• Social and environmental factors mediate/moderate the epigenome

Trajectories of Psychological Disease

• Preexisting genetic risk factors (Genome)
• Environmental triggers
• Epigenome
• Resilience
• Posttraumatic growth
• Depression, PTSD substance abuse, anxiety

The Future of Epigenetics Research

• Identifying the drivers of positive and negative trajectories after trauma exposure
• Relationships between factors in different populations
  • High-risk and general
  • Longitudinal analysis
  • Chicken-egg conundrum
• Genes and pathways with DNA methylation that can be targeted as an intervention/ treatment strategy for psychiatric disorders
• Identify social and environmental factors influencing DNA methylation and influencing mental health outcomes

Dynamic Model of Behaviour

• The interaction of genes and environment is complex
• Lamarckism versus Darwinism?
• Or is it Lamarckism-Darwinism?