An quick overview of human genetic linkage analysis

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An quick overview of human genetic linkage
analysis
Stat 246, Lecture 2, Part A
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Purpose of human linkage analysisTo obtain a
crude chromosomal location of the gene or genes
associated with a phenotype of interest, e.g. a
genetic disease or an important quantitative
trait.Examples cystic fibrosis (found),
diabetes, multiple sclerosis, and blood pressure
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Linkage Strategies

• Traditional (from the 1980s or earlier)
• Linkage analysis on pedigrees
• Allele-sharing methods candidate genes, genome
  screen
• Association studies candidate genes
• Animal models identifying candidate genes
• Newer (from the 1990s)
• Focus on special populations (Finland,
  Hutterites)
• Haplotype-sharing (many variants)
• Congenic/consomic lines in mice (new for complex
  traits)

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Linkage analysis

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Allele-sharing methods

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Association Studies
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Animal Models
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Linkage Strategies II

• On the horizon (here)
• Single-nucleotide polymorphism (SNPs)
• Functional analyses finding candidate genes
• Needed (starting to happen)
• New multilocus analysis techniques, especially
• Ways of dealing with large pedigrees
• Better phenotypes ones closer to gene products
• Large collaborations

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Horses for courses

• Each of these strategies has its domain of
  applicability
• Each of them has a different theoretical basis
  and method of analysis
• Which is appropriate for mapping genes for a
  disease of interest depends on a number of
  matters, most importantly the disease, and the
  population from which the sample comes.

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The disease matters

• Definition (phenotype), prevalence, features such
  as age of onset
• Genetics nature of genes (resistance,
  susceptibility), number of genes, nature of their
  contributions (additive, interacting), size of
  effect
• Environment, other relevant variables (e.g. sex)
• Genotype-by-environment interactions

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The population matters

• History pattern of growth, immigration
• Composition homogeneous or melting pot, or in
  between
• Mating patterns family sizes, mate choice (level
  of consanguinity)
• Frequencies of disease-related alleles, and of
  marker alleles
• Ages of disease-related alleles

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Complex traits

• Definition vague, but usually thought of as
  having multiple, possibly interacting loci, with
  unknown penetrances and phenocopies. The terms
  polygenic and oligogenic are also used, but these
  do have more specific meanings.
• There is some evidence that using a range of
  made-up models can help map genes for complex
  traits, but no-one really knows.
• Affected only methods are widely used, with
  variance component methods becoming popular. The
  jury is still out on which, if any will succeed.
• Few success stories so far.
• Important heart disease, cancer susceptibility,
  diabetes, are all complex traits.

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Design of gene mapping studies
How good are your data implying a genetic
component to your trait? Can you estimate the
size of the genetic component? Have you got, or
will you eventually have enough of the right
sort of data to have a good chance of getting a
definitive result? Power studies Simulations.
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Genotyping
Choice of markers highly polymorphic
preferred. Heterozygosity and PIC value are the
measures commonly used. Reliability of markers
important too Good quality data critical errors
can play a surprisingly large role.
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Preparing genotype data for analysis
Data cleaning is the big issue here. Need much
ancillary datahow good is it?
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Analysis
A very large range of methods/programs are
available. Effort to understand their theory
will pay off in leading to the right choice of
analysis tools. Trying everything is not
recommended, but not uncommon. Many
opportunities for innovation.
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Interpretation of results of analysis
An important issue here is whether you have
established linkage. The standards seem to be
getting increasingly stringent. What p-value or
LOD should you use? Dealing with multiple
testing, especially in the context of genome
scans and the use of multiple models and multiple
phenotypes, is one of the big issues.
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Replication of results
This has recently become a big issue with complex
diseases, especially in psychiatry. Nature
Genetics suggested in May 1998 that they will
require replication before publishing results
mapping complex traits. Simulations by Suarez et
al (1994) show that sample sizes necessary for
replication may be substantially greater than
that needed for first detection.
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Topics not mentioned

• Sex-linked traits, sex-specific recombination
  fractions, liability classes, mutations, genetic
  heterogeneity, exclusion mapping, homozygosity
  mapping, interference, variance component
  methods, twin studies, and much more.
• Some of these topics plus the ones are
  covered in two books
• Handbook of Human Genetic Linkage by J.D.
  Terwilliger J. Ott (1994) Johns Hopkins
  University Press
• Analysis of Human Genetic Linkage by J. Ott,
  3rd Edition (1999), Johns Hopkins
  University Press