Genetics and

Analysis of
Quantitative Traits
Michael Lynch
Bruce Walsh

Contents
CONTENTS
FREFACE

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I.

FOUNDATIONS OF QUANTITATIVE GENETICS

1.

AN OVERVIEW OF QUANTITATIVE GENETICS

The Adaptationist Approach to Phenotypic Evolution

Quantitative Genetics and Phenotypic Evolution
Histrica! Background
The Major Goals of Quantitative Genetics
The nature of quantitative-trait variation
The consequences of inbreeding and outcrossing
The constraints on the evolutionary process
The estimation of breeding vales
The developrnent of predictive models for evolutionary change
Mathematics in Biology

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2.

PROPERTIES OF DISTRIBUTIONS
Parameters of Univariate Distributions
The Normal Distribution
The truncated normal distribution
Confdence Intervals

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3.

COVARIANCE, REGRESSION, AND CORRELATION

Jointly Distributed Random Variables
Expectations of jointly distributed variables
Covariance
Useful identities for variances and covariances
Regression
Derivation of the least-squares linear regression
Properties of least-squares regressions
Correlation
A Taste of Quantitative-Genetic Theory
Directional selection differentials and the Robertson-Price identity
The correlation between genotypic and phenotypic vales
Regression of offspring phenotype on parental phenotype

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CONTENTS

4.

PROPERTIES OF SINGLE LOCI

Alele and Genotype Frequencies
The Transmission of Genetic Information
The Hardy-Weinberg principie
Sex-linked loci
Polyploidy
Age structure
Testing for Hardy-Weinberg proportions
Characterizing the Influence of a Locus on the Phenotype
The Basis of Dominance
Fisher's Decomposition of the Genotypic Valu
Partitioning the Genetic Va nance
Additive Effects, Average Excesses, and Breeding Vales
Extensions to Mltiple Aleles and Nonrandom Mating
Average excess
Additive effects
Additive genetic variance

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5.

SOURCES OF GENETIC VARIATION FOR

MULTILOCUS TRAITS
Epistasis
A General Least-Squares Model for Genetic Effects
Extensin to haploids and polyploids
Linkage
Estimation of gametic phase disequilibrium
Effect of Disequilibrium on the Genetic Variance
The evidence

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6.

COMPONENTS OF ENVIRONMENTAL VARIATION

Extensin of the Linear Model to Phenotypes
Special Environmental Effects
Within-individual variation
Developmental horneostasis and homozygosity
Repeatability
General Environmental Effects of Maternal Influence
Genotype x Environment Interaction

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7.

RESEMBLANCE BETWEEN RELATIVES

Measures of Relatedness
Coefficients of identity
Coeffcients of coancestry and inbreeding
The coefficient of fraternity
The Genetic Covariance Between Relatives
The Effects of Linkage and Gametic Phase Disequilibrium

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CONTENTS

8.

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Linkage
Gametic phase disequilibrium
Assortative Mating
Polyploidy
Environmental Sources of Covariance Between Relativas
The Heritability Concept
Evolvability

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INTRODUCTION OF MATRIX ALGEBRA

AND LINEAR MODELS
Mltiple Regression
An application to multivariate selection
Elementary Matrix Algebra
Basic notation
Partitioned matrices
Addition and subtraction
Multiplicador!
Transposition
Inverses and solutions to systems of equations
Determinante and minors
Computing inverses
Expectations of Random Vectors and Matrices
Covariance Matrices of Transformed Vectors
The Multivariate Normal Distribution
Properties of the MVN
Overview of Linear Models
Ordinary least squares
Generalized least squares

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ANALYSIS OF LINE CROSSES

Expectations for Line-cross Means
Estimacin of Composite Effects
Hypothesis testing
Line crosses in Nicotiana rustica
Additional data
The Genetic Interpretation of Heterosis and Outbreeding Depression
Variance of Line-cross Derivatives
Biometrical Approaches to the Estimation of Gene Number
The Castle-Wright estimator
Effect of the leading factor
Extensions to haploids
Other Biometrical Approaches to Gene Number Estimation
The inbred-backcross technique
Genotype assay

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CONTENTS

10.

INBREEDING DEPRESSION
The Genetic Basis of Inbreeding Depression
A more general model
Methodologjcal Considerations
Single-generation analysis
Multigenerational analyses
Ritland's method
Epistasis and inbreeding depression
Variance in inbreeding depression
The Evidente
Purging Inbreeding Depression
Nurnber of Lethal Equivalents
Rcsults from vertebrares
Results from Dmsoplia
Results from plants
Partial Recessives vs. Overdominance
The (A+B)/A ratio
Estimating the average dcgree of dominance
Inferences from molecular markers

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11.

MATTERS OF SCALE
Transformations to Achieve Normality
Log-normal distributions and the log transform
Tests for normality
Stabilizing the Variance
Kleckowski's transformation
General variance stabilizing-transformations
The Roginskii-Yablokov effect
The Kluge-Kerfoot phenomenon
Allometry: the Scaling Implications of Body Size
Removing Interaction Effects
Developmental Maps, Canalization, and Genetic Assimilation
Estimating developmental maps
Selection and canalization
Genetic assimilation

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12.

QUANTITATIVE TRAIT LOCI

FOLYGENES AND POLYGENIC MUTATION
The Gene tic Basis of Quantitative-Genetic Variation
Major genes and isoalleles
The molecular nature of QTL variation
The Mutational Rate of Production of Quantitative Variation

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CONTENTS

13.

Estirnation from divergente experiments

Bristle numbers in Dwsophila
Additional data
The Deleterious Effects of New Mutations
The Bateman-Mukai technique
Results from flies, plants, and bacteria
Analysis of natural populations
The persistente of new mutations

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DETECTING MAJOR GENES

Elementar}' Tests
Departures from normality
Tests based on sibship variances
Major-gene ndices (MGI)
Konpararnetric line-cross tests
Mixture Models
The distribution under a mixture model
Parameter estimation
Hypothesis testing
Complex Segregation Analysis
Likelihood functions assuming a single major gene
Common-family effects
Polygenic background
Other extensions
Ascertainment bias
Estimating individual genotypes
Analysis of Discrete Characters
Single-locus penetrante model
Major gene plus a polygenic background

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14. PRINCIPLES OF MARKER-BASED ANALYSIS

Classical Approaches
Chromosomal assays
Thoday's method
Genetics o Drosophila bristle number
Genetics of Dwsophila speciation
Molecular Markers
Genetic Maps
Map distance vs. recombination frequencies
How many markers are needed?
Marker-trait Associations
Selective genotyping and progeny testing
Recornbinant inbred lines (RILs)
Bulked segregant analysis

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CONTENTS
QTL mapping by marker changes in populations under selection
Marker-based Analysis Using Nearly Isogenic Lines (NILs)
Marker-based introgressions
Fine Mapping of Major Genes Using Population-level Disequilibrium
LD mapping in expanding populations
Candidate Loci
The transmission/disequilibrium test
Estimating effects of candidate loci
Templeton and Sing's method: Using the histrica!
information in haplotypes
Cloning QTLs
Transposon tagging
Positional cloning and comparative mapping

15.

MAPPING AND CHARACTERIZING QTLS:

INBRED LINE CROSSES
Foundations of Line-Cross Mapping
Experimental designs
Conditional probabilities of QTL genotypes
Expected marker-class means
Marker variance and higher-order moments
Overall significance leve! with mltiple tests
QTL Detection and Estimation Using Linear Models
QTL Detection and Estimation via Mximum Likelihood
Likelihood maps
Precisin of ML estimates of QTL position
ML interval mapping
Approximating ML interval mapping by Haley-Knott regressions
Dealing with Mltiple QTLs
Marker-difference regression
Interval rnapping with marker cofactors
Detecting mltiple linked QTLs using standard marker-trait regressions
Sample Size Required for QTL Detection
Power under selective genotyping
Power and repeatabilty of mapping experiments
Selected Applications
The nature of transgressive segregation
QTLs involved in reproductive isolation in Minndus
QTLs involved in protein regulation
QTLs in the Illinois long-term selection maize lines
QTLs involved in the differences between maize and teosinte
QTLs for age-specific growth in mice
Summary o QTL mapping experiments

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CONTENTS
16.

MAPPING AND CHARACTERIZING QTLS:

OUTBRED POPULATIONS
Measures of Informativeness
Sib Analysis: Linear Models
A single half-sib farnly
Several half-sib families
Power of Nested ANOVA Designs
A single full-sib family
Several full-sib families
Sib Analysis: Mximum Likelihood
Constructing likelihood functions
Mximum Likelihood over General Pedigrees: Variance Componente
Estimating QTL position
The Haseman-Elston Regression
Derivation of the Haseman-Elston regression
Estimating the number of marker genes ibd
Power and improvements
Interval mapping by a modified Haseman-Elston regression
Mapping Dichotomous Characters
Recurrent and relative risks of pairs of relatives
Affected sib-pair tests
Power of ASP tests and related issues
Genomic scanning
Exclusin mapping and information content mapping
Affected pedigree member tests

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III. ESTIMATION PROCEDURES

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17.

PARENT-OFFSPRING REGRESSION
Estimation Procedures
Balanced data
Unequal family sizes
Standardizaron of data from the different sexes
Precisin of Estimates
Optimum Experimental Designs
Assortative mating
Estimation of Heritability in Natural Populations
Linearity of the Parent-Offspring Regression

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18.

SIB ANALYSIS
Half-sib Analysis
One-way analysis of variance
Hypothesis testing

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CONTENTS
Sampling variance and standard errors
Confidence nter vals
Negativo estimares of heritability
Optimal experimental design
Unbalanced data
Resampling procedures
Full-sib Analvsis
Nested analvsis of variance
Hypothesis testing
Sampling error
Optimal design

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19. TWINS AND CLONES

The Classical Approach
Heritability estimation
The Monozygotic-Twin Half-sib Method
Clonal Analysis

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20.

CROSS-CLASSIFIED DESIGNS
North Carolina Design TI
The average degree of dominance
The Cockerham-Weir model
Diallels
Pooled reciprocis, no self crosses
Reciprocis, no self crosses
Complete diallels
Partial diallels
Hayman-Jinks analysis
North Carolina Design III and the Triple Test Cross
Some Closing Statistical Considerations

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21.

CORRELATIONS BETWEEN CHARACTERS

Theoretical Composition of the Genetic Covariance
Estimation of the Genetic Covariance
Pairwise comparison of relatives
Nested analvsis of variance and covariance
Regression of family means
Components of Phenotypic Correlation
Phenotypic correlations as surrogate estmales of genetic correlations
Statistical Issuos
Hypothesis tests
Standard errors
Bias due to selection
Applications

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CONTENTS

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Genetic basis of population differentiation

The homogeneity of genetic covariance matrices among species
Evolutonary allometry
Evolution of life-history characters

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22.

GENOTYPE x ENVIRONMENT INTERACTION

Genetic Correlation Across Two Environments
Estimation procedures
Two-way Analysis of Varance
Relationship to Falconer's correlation across environments
Further Characterization of Interaction Effects
Joint-regression analysis
Testing for Cross-over Interaction
Concepts of Stability and Plasticity
Additional issues
The Quantitative Genetics of Genotype x Environrnent Interaction

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23.

MATERNAL EFFECTS
Components of Variance and Covariance
Cytoplasmic transmission
Postpollination reproductive traits in plants
Cross-fostering experiments
Body weight in mice
Eisen's Approach
Bondari's experiment
Falconer's Approach
Extensin to Other Types of Relatives

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24.

SEX LINKAGE AND SEXUAL DIMORPHISM

Sex-Hnked Loci and Dosage Compensation
Sex-modified Expression of an Autosomal Locus
Gametic imprinting
Extensin to Mltiple Loci and the Covariance Between Relatives
Variation for Sexual Dimorphism

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25.

THRESHOLD CHARACTERS
Heritability on the Underlying Scale
Mltiple Thresholds
Genetic Correlation Among Threshold Traits
Heritability on the Observed Scaie

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26.

ESTIMATION OF BREEDING VALES

The General Mixed Model
Estimating Fixed Factors and Predicting Random Effects

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CONTENTS
Estimability o fxed factors
Standard errors
Models for he Estimation of Breeding Vales
The animal model
The gametic model
The reduced animal model
Simple Rules for Computing A and A"1
Allowing for mutation when computing A
Joint Estimation of Several Vectors of Random Effects
BLUP estmales of dominance vales
Repeated records
Maternal effects
Mltiple traite

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IV.
Al.

VARIANCE-COMPONENT ESTIMATION WITH

COMPLEX PEDIGREES
ME versus REME Estimates of Variance Components
A simple exaniple of ML versus REML
ME Estimates of Variance Components in the General Mixed Model
Standard errors of ML estimates
Restricted Mximum Likelihood
Multivariate analysis
ML/REML estimation in populations undcr selection
Solving ML/REML Equations
Derivan've-based methods
EM methods
Additional approaches
A Molecular-marker Based Method for Inferring Variance Components

APPENDICES
EXPECTATIONS, VARIANCES, AND COVARIANCES
OF COMPOUND VARIABLES
The Delta Method
Expectations of complex variables
Variances of complex variables
Covariances of complex variables
Variance of Variances and Covariances
Expectations and Variances of Products
Expectations and Variances of Ratios
Sampling variance of regression and correlations coefficients
Sampling variance of a coefficient of variation

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. . . . 800

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CONTENT5

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A2.

PATH ANALYSIS
Univariate Analysis
Bivariate Analysis
Applications
Phenotypic correlation between parents and offspring
Correlations between characters
Growth analysis

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A3.

FURTHER TOPICS IN MATRIX ALGEBRA AND

LINEAR MODELS
Generalized Inverses and Solutions to Singular Systems of Equations
Generalized inverses
Consistency and solutions to consistent systems
Estmability of fixed factors
The Square Root of a Matrix
Derivation of the GLS Estimators
Quadratic Forms and Sums of Squares
Moments of quadratic forms
The sarnple variance as a quadratic form
Sums of squares expressed as a quadratic form
Testing Hypotheses About Linear Models
Equivalent Linear Models
Derivativas of Vectors and Matrices

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MXIMUM LIKELIHOOD ESTIMATION AND

LIKELIHOOD-RATIO TESTS
Likelihood, Support, and Score Functions
Large-sample properties of MLEs
The Fisher information matrix
Likelihood-ratio tests
The G-test
Likelihood-ratio tests for the general linear model
Iterativa Methods for Solving ML Equations
Newton-Raphson methods
Expectation-maximization methods
EM for mixture model likelihoods
EM rnodifications for QTL mapping

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COMPUTING THE POWER OF STATISTICAL TESTS

Power of Normally Distributed Test Statistics
One-sided tests
Two-sided tests
Applications: Parent-offspring regressions

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A4.

A5.