👨‍👩‍👦‍👦General Genetics Unit 17 – Epigenetics & Non-Mendelian Inheritance

What's This Unit All About?

• Explores how traits can be inherited and expressed without changes to the DNA sequence itself
• Investigates epigenetic modifications that alter gene expression without altering the genetic code
• Examines non-Mendelian inheritance patterns that deviate from the classic Mendelian ratios (3:1, 9:3:3:1)
• Includes phenomena such as genomic imprinting, X-inactivation, and paramutation
• Highlights the role of environmental factors and cellular processes in shaping phenotypes
• Demonstrates the complexity and flexibility of gene regulation beyond the central dogma
• Provides insights into the interplay between nature (genes) and nurture (environment) in determining traits

Key Concepts You Need to Know

• Epigenetics studies heritable changes in gene expression without changes in the DNA sequence
• DNA methylation involves the addition of methyl groups to cytosine bases, typically silencing gene expression
• Histone modifications (acetylation, methylation, phosphorylation) alter chromatin structure and accessibility
• Genomic imprinting results in parent-of-origin-specific gene expression due to epigenetic marks
  • Imprinted genes are expressed from only one allele (maternal or paternal)
• X-inactivation randomly silences one X chromosome in female mammals for dosage compensation
• Paramutation is an interaction between alleles leading to heritable changes in gene expression
• Non-Mendelian inheritance patterns include incomplete dominance, codominance, and polygenic traits
  • Incomplete dominance results in a blending of traits (pink flowers in snapdragons)
  • Codominance leads to the expression of both alleles simultaneously (AB blood type)

How DNA Gets Modified Without Changing the Sequence

• DNA methylation adds methyl groups to cytosine bases, typically in CpG dinucleotides
  • Methylation is catalyzed by DNA methyltransferases (DNMTs)
  • Methylation patterns are maintained through cell division by maintenance methyltransferases
• Histone modifications alter the chemical properties of histone proteins, affecting chromatin structure
  • Acetylation of lysine residues by histone acetyltransferases (HATs) loosens chromatin, promoting gene expression
  • Deacetylation by histone deacetylases (HDACs) condenses chromatin, repressing gene expression
• Non-coding RNAs (ncRNAs) can regulate gene expression post-transcriptionally
  • microRNAs (miRNAs) bind to complementary mRNA sequences, leading to degradation or translational repression
  • Long non-coding RNAs (lncRNAs) can interact with chromatin-modifying complexes to regulate gene expression
• Prions are misfolded proteins that can induce conformational changes in other proteins, leading to heritable traits

Inheritance Patterns That Break Mendel's Rules

• Incomplete dominance results in a blending of traits, with heterozygotes showing an intermediate phenotype
  • Example: Red and white flower cross yields pink flowers in the F1 generation
• Codominance occurs when both alleles are expressed equally in the heterozygote
  • Example: ABO blood group system, where both A and B alleles are expressed in the AB phenotype
• Polygenic traits are influenced by multiple genes, each with a small additive effect
  • Example: Human height is determined by the combined effects of many genes
• Epistasis is the interaction between genes at different loci, where one gene masks the effect of another
  • Example: Coat color in mice, where the agouti gene masks the effect of the melanin-producing gene
• Penetrance refers to the proportion of individuals with a genotype who express the associated phenotype
  • Incomplete penetrance means not all individuals with the genotype show the phenotype
• Expressivity is the degree to which a genotype is expressed in the phenotype
  • Variable expressivity means the phenotype can vary among individuals with the same genotype

Real-Life Examples and Case Studies

• Agouti mice: Epigenetic changes in the agouti gene lead to yellow fur and obesity in offspring
  • Methylation status of the agouti gene is influenced by the mother's diet during pregnancy
• Dutch Hunger Winter: Children conceived during famine showed increased risk of obesity and metabolic disorders
  • Epigenetic changes in response to maternal malnutrition were passed down to the next generation
• Angelman and Prader-Willi syndromes: Genomic imprinting disorders caused by deletions or epigenetic changes
  • Angelman syndrome results from loss of maternal expression of the UBE3A gene
  • Prader-Willi syndrome is caused by loss of paternal expression of genes on chromosome 15q11-q13
• Calico cats: X-inactivation leads to a mosaic coat color pattern in female cats
  • Random inactivation of one X chromosome in each cell creates patches of different colors
• Paramutation in maize: Interaction between alleles leads to heritable changes in gene expression
  • The $B'$ allele can paramutate the $B-I$ allele, reducing anthocyanin pigmentation in the plant

Lab Techniques and Experiments

• Bisulfite sequencing: Converts unmethylated cytosines to uracil, allowing for methylation profiling
  • Treated DNA is amplified and sequenced, revealing the methylation status of each cytosine
• Chromatin immunoprecipitation (ChIP): Identifies proteins associated with specific DNA sequences
  • Antibodies are used to pull down proteins bound to chromatin, followed by sequencing of the associated DNA
• DNA microarrays: Measure gene expression levels by hybridizing cDNA to complementary probes on a chip
  • Allows for the simultaneous analysis of thousands of genes in a single experiment
• CRISPR-Cas9 epigenome editing: Targeted modification of epigenetic marks at specific genomic loci
  • Catalytically inactive Cas9 (dCas9) is fused to epigenetic modifiers (DNMTs, HATs) and guided by sgRNAs
• Twin studies: Compare the phenotypic concordance between monozygotic and dizygotic twins
  • Higher concordance in monozygotic twins suggests a strong genetic influence on the trait
• Transgenerational inheritance studies: Investigate the transmission of epigenetic marks across multiple generations
  • Expose organisms to environmental stressors and monitor the phenotypes of their offspring and grand-offspring

Why This Stuff Matters in Genetics and Beyond

• Epigenetic modifications provide a mechanism for environmental influences on gene expression and phenotype
  • Allows for the fine-tuning of gene regulation in response to external stimuli
• Epigenetic changes can be inherited across generations, contributing to the heritability of complex traits
  • Transgenerational epigenetic inheritance may explain some of the "missing heritability" in genome-wide association studies
• Epigenetic dysregulation is implicated in various diseases, including cancer, neurological disorders, and metabolic syndromes
  • Aberrant DNA methylation and histone modifications are hallmarks of many cancers
  • Epigenetic therapies (DNMT inhibitors, HDAC inhibitors) are being developed to treat these diseases
• Non-Mendelian inheritance patterns explain the complex nature of many traits and diseases
  • Polygenic traits and epistatic interactions contribute to the genetic architecture of common diseases (diabetes, heart disease)
• Understanding epigenetics and non-Mendelian inheritance is crucial for personalized medicine and risk assessment
  • Epigenetic biomarkers can be used for early detection and prognosis of diseases
  • Incorporating non-Mendelian inheritance into genetic counseling can improve risk estimates for complex disorders

Tricky Topics and Common Confusions

• Distinguishing between epigenetic modifications and genetic mutations
  • Epigenetic changes do not alter the DNA sequence, while mutations involve changes in the nucleotide sequence
• Understanding the relationship between epigenetics and gene expression
  • Epigenetic marks can activate or repress gene expression, but the relationship is not always straightforward
  • Some epigenetic changes may be a consequence, rather than a cause, of altered gene expression
• Differentiating between genomic imprinting and X-inactivation
  • Genomic imprinting is parent-of-origin-specific, while X-inactivation is random and affects only females
  • Genomic imprinting can occur on any chromosome, while X-inactivation is limited to the X chromosome
• Recognizing the limitations of the Mendelian inheritance model
  • Mendel's laws are based on simple, single-gene traits, but many traits are complex and involve multiple genes
  • Non-Mendelian inheritance patterns do not follow the classic Mendelian ratios (3:1, 9:3:3:1)
• Interpreting the results of epigenome-wide association studies (EWAS)
  • EWAS identify epigenetic markers associated with a trait or disease, but causality cannot be inferred
  • Epigenetic changes may be a cause or consequence of the phenotype, or they may be confounded by other factors