👨‍👩‍👦‍👦General Genetics Unit 15 – Quantitative Genetics and Complex Traits

Key Concepts and Terminology

• Quantitative traits are characteristics that exhibit continuous variation and are influenced by multiple genes and environmental factors
• Complex traits are traits that do not follow simple Mendelian inheritance patterns and are determined by the combined effects of multiple genes and the environment
• Polygenic inheritance involves the cumulative effects of many genes, each with a small individual effect, on a phenotypic trait
• Additive genetic variance is the variance in a trait that can be attributed to the additive effects of individual alleles across multiple loci
• Narrow-sense heritability ($h^2$) is the proportion of phenotypic variance in a population that is due to additive genetic variance
• Broad-sense heritability ($H^2$) is the proportion of phenotypic variance in a population that is due to all genetic variance, including additive, dominant, and epistatic effects
• Genotype-by-environment interaction (GxE) occurs when the effect of a genotype on a phenotype varies depending on the environment

Genetic Basis of Quantitative Traits

• Quantitative traits are controlled by multiple genes, each with a small effect on the phenotype, rather than a single gene with a large effect
• The combined effects of these genes, along with environmental influences, result in a continuous distribution of phenotypes in a population
• Allelic variation at multiple loci contributes to the genetic basis of quantitative traits
• Additive effects of alleles across loci are a major component of the genetic basis of quantitative traits
  • Additive effects occur when the effect of an allele on the phenotype is independent of the effects of other alleles
• Dominance and epistatic effects can also contribute to the genetic basis of quantitative traits
  • Dominance effects occur when the phenotypic effect of a heterozygous genotype deviates from the average of the two homozygous genotypes
  • Epistatic effects occur when the effect of one gene on the phenotype depends on the genotype at another gene
• Examples of quantitative traits include height, weight, and yield in crops

Heritability and Genetic Variance

• Heritability is a measure of the proportion of phenotypic variance in a population that is attributable to genetic variation
• Narrow-sense heritability ($h^2$) estimates the proportion of phenotypic variance due to additive genetic variance
  • $h^2 = V_A / V_P$, where $V_A$ is the additive genetic variance and $V_P$ is the total phenotypic variance
• Broad-sense heritability ($H^2$) estimates the proportion of phenotypic variance due to all genetic variance, including additive, dominant, and epistatic effects
  • $H^2 = V_G / V_P$, where $V_G$ is the total genetic variance and $V_P$ is the total phenotypic variance
• Heritability estimates are specific to a particular population and environment and can change over time
• Genetic variance can be partitioned into additive, dominance, and epistatic components
  • Additive genetic variance is the variance due to the additive effects of alleles across loci
  • Dominance genetic variance is the variance due to dominance effects at individual loci
  • Epistatic genetic variance is the variance due to interactions between alleles at different loci
• Understanding heritability and genetic variance is crucial for predicting the response to selection in breeding programs

Quantitative Trait Loci (QTL) Analysis

• QTL analysis is a method for identifying genomic regions associated with quantitative traits
• QTL mapping involves crossing two inbred lines that differ in a quantitative trait and analyzing the phenotypes and genotypes of the resulting progeny
• Linkage mapping is used to identify genomic regions that co-segregate with the quantitative trait in the progeny population
• LOD (logarithm of odds) scores are used to assess the statistical significance of the association between a genomic region and the quantitative trait
  • Higher LOD scores indicate a stronger association between the genomic region and the trait
• Confidence intervals for QTL positions can be determined based on the LOD scores and the density of genetic markers
• Fine mapping can be used to narrow down the genomic region containing the QTL and identify candidate genes
• QTL analysis has been used to identify genomic regions associated with traits such as yield, disease resistance, and quality in crops

Genome-Wide Association Studies (GWAS)

• GWAS is a method for identifying genetic variants associated with complex traits in populations
• GWAS involves genotyping a large number of individuals for a dense set of genetic markers (usually SNPs) and testing for associations between the markers and the trait of interest
• Population structure and relatedness among individuals can lead to spurious associations in GWAS and must be accounted for using statistical methods
  • Principal component analysis (PCA) and mixed linear models (MLMs) are commonly used to control for population structure and relatedness
• Multiple testing correction is necessary to control the false discovery rate in GWAS due to the large number of statistical tests performed
  • Bonferroni correction and false discovery rate (FDR) methods are commonly used for multiple testing correction
• GWAS has identified numerous genetic variants associated with complex traits such as height, body mass index, and disease risk in humans
• GWAS results can be used to develop polygenic risk scores for predicting an individual's risk of developing a complex trait or disease

Gene-Environment Interactions

• Gene-environment interactions occur when the effect of a genetic variant on a phenotype depends on the environment
• The same genotype can result in different phenotypes in different environments due to gene-environment interactions
• Gene-environment interactions can be classified as additive or non-additive
  • Additive interactions occur when the effect of the genotype and the environment on the phenotype are independent and combine linearly
  • Non-additive interactions occur when the effect of the genotype on the phenotype varies depending on the environment
• Statistical methods for detecting gene-environment interactions include stratified analysis, interaction terms in regression models, and machine learning approaches
• Understanding gene-environment interactions is important for predicting the phenotypic effects of genetic variants across different environments
• Examples of gene-environment interactions include the effect of diet on the association between genetic variants and obesity risk

Statistical Methods in Quantitative Genetics

• Analysis of variance (ANOVA) is used to partition phenotypic variance into genetic and environmental components
  • ANOVA can be used to estimate heritability and genetic variance components
• Linear regression models are used to test for associations between genetic markers and quantitative traits
  • Marker regression can be used to estimate the effects of individual genetic markers on the phenotype
• Mixed linear models (MLMs) are used to account for population structure and relatedness in GWAS and QTL mapping
  • MLMs include fixed effects for genetic markers and random effects for population structure and relatedness
• Bayesian methods are used to estimate genetic parameters and predict breeding values in animal and plant breeding
  • Bayesian methods can incorporate prior information and estimate the uncertainty in parameter estimates
• Machine learning methods, such as random forests and support vector machines, are used to predict phenotypes from genotypes and identify important genetic features
• Structural equation modeling (SEM) is used to model the relationships between multiple variables, including genetic and environmental factors, and their effects on the phenotype

Applications in Breeding and Medicine

• Marker-assisted selection (MAS) uses genetic markers associated with quantitative traits to select individuals with desirable genotypes in breeding programs
  • MAS can increase the efficiency and accuracy of selection compared to traditional phenotypic selection
• Genomic selection uses genome-wide markers to predict breeding values and select individuals with the highest genetic merit
  • Genomic selection has been widely adopted in animal and plant breeding to accelerate genetic improvement
• Polygenic risk scores (PRS) are used to predict an individual's risk of developing a complex disease based on their genotype at multiple genetic variants
  • PRS can be used for personalized medicine and targeted disease prevention strategies
• Gene editing technologies, such as CRISPR-Cas9, can be used to modify the genetic basis of quantitative traits in crops and livestock
  • Gene editing can be used to introduce desirable alleles or knock out undesirable alleles associated with quantitative traits
• Understanding the genetic basis of complex traits can inform the development of new drugs and therapies for human diseases
  • Identifying the genes and biological pathways underlying complex diseases can provide targets for drug development and personalized treatment strategies