The value of haplotypes

The major sources of genetic information used to map disease genes are cosegregation of markers and disease in linkage or association studies. This thesis builds on previous work by Van der Meulen, Nolte, Spijker and te Meerman to investigate the usefulness of using measures of coalescence of DNA to unobserved ancestors who lived many generations ago.

The current density of DNA markers used in whole genome screens is very high, on average more than 1 polymorphic marker per 3,000–10,000 positions. This density is so high that marker alleles have stayed together in a measurable way from the moment of introduction in the population or from the time of mutation to a new allele. We demonstrate this by showing that the older ancestral alleles that are common to mammal species have less haplotype sharing surrounding them than newer mutant alleles. This shows that differences in time to coalescence to ancestral DNA are reflected in measurable haplotype sharing differences.

Using a simulation model for a disease weakly influenced by a genetic mutation, we demonstrate that a statistical test based on haplotype sharing differences is not only more powerful than a standard chi2-association test, but is also almost independent of it under the null hypothesis. This means that the tests can be combined to result in a more powerful test.

As a practical application, we show that there are very large differences in haplotype sharing when rare and relatively recent mutations in the primer sequence cause a reduced signal intensity in Illumina genotyping arrays.

	Title and contents
	Chapter 1
	Chapter 2
	Chapter 3
	Chapter 4
	Chapter 5
	Chapter 6
	Chapter 7
	Summary
	Discussion and future perspectives
	Samenvatting
	Dankwoord
	Complete thesis

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