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Detecting Deletions by Analysis of Genetic Markers in Pedigrees

Johansson, Anna LU (2007)
Abstract
A deletion is defined as a missing piece of a chromosome, ranging in size from as small as a single base pair to as much as an entire arm of a chromosome. Deletions can cause diseases, but may also have a neutral effect in the genome. In this thesis, I describe how inherited deletions can be detected by analysis of the segregation pattern of genetic markers in pedigrees. These methods are based on the fact that a deletion encompassing a genetic marker constitutes a null allele for that marker. Thus, a heterozygote for a null allele will appear to be homozygous for the other allele. The methods I present for detecting deletions for a single marker also apply for detecting null alleles. The thesis consists of both theoretical work on the... (More)
A deletion is defined as a missing piece of a chromosome, ranging in size from as small as a single base pair to as much as an entire arm of a chromosome. Deletions can cause diseases, but may also have a neutral effect in the genome. In this thesis, I describe how inherited deletions can be detected by analysis of the segregation pattern of genetic markers in pedigrees. These methods are based on the fact that a deletion encompassing a genetic marker constitutes a null allele for that marker. Thus, a heterozygote for a null allele will appear to be homozygous for the other allele. The methods I present for detecting deletions for a single marker also apply for detecting null alleles. The thesis consists of both theoretical work on the probabilities to detect deletions in different pedigree structures and applications of the methods to identify deletions in families with Protein S deficiency and von Willebrand disease type 1.



In the first paper, deletions in the PROS1 gene are indicated during a linkage study on eight families with Protein S deficiency, a dominant coagulation disorder. The second paper describes how the probabilities to detect a deletion causing a dominant disease using genetic markers depend on the allele frequencies of the marker and the size of the pedigree. The formulae are general and can be applied to a pedigree of any size. The method is shown to be efficient in pedigrees of the size that were used in paper I. In the third paper, large deletions in the PROS1 gene are identified in three of the eight families with Protein S deficiency. In the fourth paper, the probabilities to detect a neutral deletion for various pedigree structures given a fixed total sample size are calculated. It is shown that for biallelic markers it is more efficient to add children than to add grandparents to a parent-offspring trio. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

En deletion innebär att det fattas en bit DNA i en kromosom. Deletioner kan variera i storlek från enstaka baspar till en stor del av en kromosom. Deletioner kan orsaka sjukdomar, men det finns också exempel på deletioner som inte ger någon påvisbar effekt på individen. Genom att analysera genetiska markörer i familjer kan man hitta mönster som kan förklaras av deletioner. En genetisk markör är en bit DNA där det finns variation mellan individer som man har utvecklat en metod för att observera. Med de flesta metoder som man använder för att studera genetiska markörer så går det inte att skilja på en individ som vid en genetisk markör är heterozygot (har två olika alleler) för en deletion och en... (More)
Popular Abstract in Swedish

En deletion innebär att det fattas en bit DNA i en kromosom. Deletioner kan variera i storlek från enstaka baspar till en stor del av en kromosom. Deletioner kan orsaka sjukdomar, men det finns också exempel på deletioner som inte ger någon påvisbar effekt på individen. Genom att analysera genetiska markörer i familjer kan man hitta mönster som kan förklaras av deletioner. En genetisk markör är en bit DNA där det finns variation mellan individer som man har utvecklat en metod för att observera. Med de flesta metoder som man använder för att studera genetiska markörer så går det inte att skilja på en individ som vid en genetisk markör är heterozygot (har två olika alleler) för en deletion och en annan allel från en individ som är homozygot (har två likadana alleler) för den andra allelen. Om ett barn har ärvt en deletion från sin ena förälder och föräldern och barnet har olika alleler på kromosomen som inte har en deletion så kommer det att se ut som om barnet och föräldern är homozygota för olika alleler. Detta är inte möjligt med normal nedärvning och kan därför användas som bevis för att det finns en deletion. Jag har gjort teoretiska studier där jag har beräknat sannolikheten för att hitta en deletion i familjer av olika storlekar. Jag har också hittat deletioner genom att analysera verkliga data för genetiska markörer i familjer med Protein S-brist och von Willebrands sjukdom.



I den första artikeln såg vi att det kunde finnas deletioner i PROS1-genen i familjer med Protein S-brist som är en koagulationssjukdom med dominant nedärvning. Den andra artikeln visar hur sannolikheten att hitta en deletion som orsakar en sjukdom med dominant nedärvning kan beräknas. Sannolikheten att hitta en deletion med hjälp av genetiska markörer visade sig vara hög i familjer av den storlek som undersöktes i den första artikeln. I den tredje artikeln hittades deletioner i tre av åtta familjer med Protein S-brist. I den fjärde artikeln jämfördes sannolikheterna att hitta en neutral deletion för olika sorters familjer. Där visade det sig att om man har ett bestämt antal individer är det effektivare att analysera fler barn i en familj än att analysera far- eller morföräldrar. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Wiuf, Carsten, University of Aarhus
organization
publishing date
type
Thesis
publication status
published
subject
keywords
cytogenetics, Genetik, Genetics, Biologi, genetic marker, pedigree, Protein S deficiency, Biology, PROS1, deletion, null allele, cytogenetik
pages
96 pages
publisher
Department of Cell and Organism Biology, Lund University
defense location
Genetikhusets aula, Sölvegatan 29, Lund
defense date
2007-06-09 10:00:00
ISBN
978-91-85067-32-9
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Genetics (Closed 2011) (011005100)
id
8b435f66-2f7c-4950-9994-a9ddeb0df5f5 (old id 548706)
date added to LUP
2016-04-04 10:36:31
date last changed
2018-11-21 20:59:45
@phdthesis{8b435f66-2f7c-4950-9994-a9ddeb0df5f5,
  abstract     = {{A deletion is defined as a missing piece of a chromosome, ranging in size from as small as a single base pair to as much as an entire arm of a chromosome. Deletions can cause diseases, but may also have a neutral effect in the genome. In this thesis, I describe how inherited deletions can be detected by analysis of the segregation pattern of genetic markers in pedigrees. These methods are based on the fact that a deletion encompassing a genetic marker constitutes a null allele for that marker. Thus, a heterozygote for a null allele will appear to be homozygous for the other allele. The methods I present for detecting deletions for a single marker also apply for detecting null alleles. The thesis consists of both theoretical work on the probabilities to detect deletions in different pedigree structures and applications of the methods to identify deletions in families with Protein S deficiency and von Willebrand disease type 1.<br/><br>
<br/><br>
In the first paper, deletions in the PROS1 gene are indicated during a linkage study on eight families with Protein S deficiency, a dominant coagulation disorder. The second paper describes how the probabilities to detect a deletion causing a dominant disease using genetic markers depend on the allele frequencies of the marker and the size of the pedigree. The formulae are general and can be applied to a pedigree of any size. The method is shown to be efficient in pedigrees of the size that were used in paper I. In the third paper, large deletions in the PROS1 gene are identified in three of the eight families with Protein S deficiency. In the fourth paper, the probabilities to detect a neutral deletion for various pedigree structures given a fixed total sample size are calculated. It is shown that for biallelic markers it is more efficient to add children than to add grandparents to a parent-offspring trio.}},
  author       = {{Johansson, Anna}},
  isbn         = {{978-91-85067-32-9}},
  keywords     = {{cytogenetics; Genetik; Genetics; Biologi; genetic marker; pedigree; Protein S deficiency; Biology; PROS1; deletion; null allele; cytogenetik}},
  language     = {{eng}},
  publisher    = {{Department of Cell and Organism Biology, Lund University}},
  school       = {{Lund University}},
  title        = {{Detecting Deletions by Analysis of Genetic Markers in Pedigrees}},
  year         = {{2007}},
}