126
E. A. Thompson
From parents to offspring, DNA is inherited in long segments, but over multiple
generations, repeated meioses break the IBD DNA in current individuals into
smaller and smaller segments.
6.1.2 From Descent to Gene Mapping
The fundamental framework of genetic epidemiology was formalized by Elston and
Stewart (1971), who defined the three components of a genetic model: population,
transmission, and penetrance. DNA variation in a population results from evolutionary processes and demographic history, arising via mutation, and modified by
selection and random genetic drift. The parameters of the population model are
allele, genotype, and haplotype frequencies, which are often assumed known in
genetic epidemiological studies. The model for transmission of DNA from parents
to offspring is provided by the process of meiosis, as summarized in Mendel’s
first law and the recombination probabilities across the genome (Sect. 6.1.1). The
parameters of the population process normally relate only to the genetic map that
provides recombination probabilities between any two loci, although it could also
include models of segregation distortion or genetic interference.
Finally, the penetrance model defines the probability relationship between an
individual’s genotype at the relevant locus or loci and the observable data. For
genetic markers, this relationship is straightforward. Normally unphased genotypes
at each marker locus are directly observed, although a model for typing error may
be included. For genetic epidemiological traits of interest, the penetrance model is
often the least certain and most complex component of the model, and successful
inference will often require careful analysis of a range of possible models.
The goal of genetic mapping is to determine the genome locations of DNA
that affects a phenotypic trait of interest. This mapping relies on co-inheritance of
DNA at marker loci of known location and of DNA inferred to affect the trait. At
the population level, co-inheritance of DNA leads to linkage disequilibrium (LD),
which is the basis of association mapping. In a defined pedigree (Fig. 6.1), the
dependence in inheritance between a trait and a genetic marker provides evidence
that the DNA affecting the trait is in proximity to the genetic marker locus. In
between these extremes, even in the absence of known pedigree relationships,
evidence that individuals of similar trait phenotype share DNA IBD in particular
regions of the genome provides evidence that these regions harbor causal loci. This
is the basis of IBD-based genetic mapping.
6.1.3 Outline of the Chapter
The remainder of the chapter is divided into three main sections. The focus is on
related individuals, who may therefore share genome IBD, but the relationships
among the individuals may be known or unknown. Within each section we consider
both pedigree data (known relationships) and population-level data (unknown
E. A. Thompson
From parents to offspring, DNA is inherited in long segments, but over multiple
generations, repeated meioses break the IBD DNA in current individuals into
smaller and smaller segments.
6.1.2 From Descent to Gene Mapping
The fundamental framework of genetic epidemiology was formalized by Elston and
Stewart (1971), who defined the three components of a genetic model: population,
transmission, and penetrance. DNA variation in a population results from evolutionary processes and demographic history, arising via mutation, and modified by
selection and random genetic drift. The parameters of the population model are
allele, genotype, and haplotype frequencies, which are often assumed known in
genetic epidemiological studies. The model for transmission of DNA from parents
to offspring is provided by the process of meiosis, as summarized in Mendel’s
first law and the recombination probabilities across the genome (Sect. 6.1.1). The
parameters of the population process normally relate only to the genetic map that
provides recombination probabilities between any two loci, although it could also
include models of segregation distortion or genetic interference.
Finally, the penetrance model defines the probability relationship between an
individual’s genotype at the relevant locus or loci and the observable data. For
genetic markers, this relationship is straightforward. Normally unphased genotypes
at each marker locus are directly observed, although a model for typing error may
be included. For genetic epidemiological traits of interest, the penetrance model is
often the least certain and most complex component of the model, and successful
inference will often require careful analysis of a range of possible models.
The goal of genetic mapping is to determine the genome locations of DNA
that affects a phenotypic trait of interest. This mapping relies on co-inheritance of
DNA at marker loci of known location and of DNA inferred to affect the trait. At
the population level, co-inheritance of DNA leads to linkage disequilibrium (LD),
which is the basis of association mapping. In a defined pedigree (Fig. 6.1), the
dependence in inheritance between a trait and a genetic marker provides evidence
that the DNA affecting the trait is in proximity to the genetic marker locus. In
between these extremes, even in the absence of known pedigree relationships,
evidence that individuals of similar trait phenotype share DNA IBD in particular
regions of the genome provides evidence that these regions harbor causal loci. This
is the basis of IBD-based genetic mapping.
6.1.3 Outline of the Chapter
The remainder of the chapter is divided into three main sections. The focus is on
related individuals, who may therefore share genome IBD, but the relationships
among the individuals may be known or unknown. Within each section we consider
both pedigree data (known relationships) and population-level data (unknown