Genotype refers to an organism's complete genetic makeup, the DNA sequence inherited from parents that provides the blueprint for potential traits. The genotype interacts with environmental factors to produce the phenotype (observable characteristics). In evolutionary medicine, understanding genotype-phenotype relationships explains how populations adapted to past environments and why modern environments create disease through gene-environment mismatch.
The genotype consists of all DNA sequences in an organism's genome, including coding genes, regulatory regions, and non-coding DNA. Gene expression is regulated through epigenetic modifications (DNA methylation, histone modifications) that respond to environmental signals without changing DNA sequence. Natural selection acts on phenotypes, but only genotypes that produce beneficial phenotypes in a given environment are passed to offspring. Different genotypes can produce similar phenotypes (genetic redundancy), and the same genotype can produce different phenotypes in different environments (phenotypic plasticity). Mutations create new genetic variants, with selection pressuring which variants persist in populations.
Understanding genotype helps explain individual variation in disease susceptibility, drug responses, and optimal diet. The 'thrifty genotype' hypothesis proposes that genes promoting fat storage (adaptive in food-scarce environments) now cause obesity in food-abundant environments. The farmer vs. hunter genotype concept explains why some individuals develop early obesity (farmer genotype with rapid insulin response) while others resist until later (hunter genotype). However, most chronic diseases result from genotype-environment mismatch rather than 'bad genes.' The cPNI approach emphasizes that genotype creates vulnerability, but phenotype is determined by lifestyle.
- Human genotype is 99.9% identical across all individuals
- Single nucleotide polymorphisms (SNPs) account for most genetic variation
- Genotype has remained largely unchanged for 50,000+ years (Paleolithic genome)
- Modern chronic diseases result from Paleolithic genotype in modern environment
- Farmer genotype shows rapid insulin response to carbohydrates; hunter genotype shows delayed response
- Some genotypes (e.g., MTHFR variants) require specific nutritional support
- Epigenetics allow same genotype to produce different phenotypes
- phenotype — genotype provides the genetic blueprint that interacts with environment to produce phenotype
- epigenetic — epigenetic modifications regulate how genotype is expressed as phenotype
- natural selection — selection acts on phenotypes but preserves genotypes producing advantageous traits
- evolutionary medicine — evolutionary medicine examines disease through lens of genotype-environment mismatch
- mutations — mutations create new genetic variants in genotypes
- gene expression — gene expression translates genotype information into functional molecules
- DNA methylation — methylation modifies genotype expression without changing DNA sequence
- histone modification — histone modifications regulate which parts of genotype are accessible for transcription
- metabolic syndrome — metabolic syndrome results from mismatch between Paleolithic genotype and modern environment
- obesity — thrifty genotype promotes fat storage, beneficial ancestrally but maladaptive in modern environment
- insulin resistance — insulin resistance may reflect genotype adapted for intermittent food availability
- hunter-gatherer — modern human genotype reflects hunter-gatherer adaptations
- farmer — some populations show genetic adaptations to agricultural diets (farmer genotype)
- lactase persistence — lactase persistence is genetic adaptation in populations with dairying history
- AMY1 gene copy number — AMY1 copies vary by ancestral diet, affecting starch digestion capacity
- MTHFR — MTHFR genotype variants affect folate metabolism and methylation capacity
- phenotypic plasticity — same genotype can produce different phenotypes in response to environment
- thrifty genotype — hypothesis that genotypes promoting fat storage cause modern obesity
- personalized medicine — personalized medicine tailors interventions to individual genotype
- mismatch — mismatch diseases result from Paleolithic genotype in modern environment