What is true about linkage analysis in familial gene disorders?
Characteristic DNA polymorphism in a family is associated with disorders [Ref: Harrison 17/e p4031 We are not able to make sense of the options, but let's see what linkage analysis is all about. At least this could help somewhat... Prepare you for the correct options or other options in the exams. The human genome is very large and contains many thousands of genes. Therefore, finding the paicular gene or genes responsible for any given human disease is very difficult. Traditionally, the search for a disease gene begins with linkage analysis. In this approach, the aim is to find out the rough location of the gene relative to another DNA sequence called a genetic marker, which has its position already known. The principle of linkage analysis: Two fundamental principles are essential for understanding the concept of linkage. 1) When two genes or alleles are close together on a chromosome, they are usually transmitted together. Thus they are said to be linked. For example, in fruit flies the genes affecting eye color and wing length are inherited together because they appear on the same chromosome. Alleles for genes on different chromosomes are usually not linked, due to independent assoment of chromosomes during meiosis. 2)Because there is some crossing over of DNA when the chromosomes segregate, even linked alleles on the same chromosome can be separated and go to different daughter cells. There is a greater probability of this happening if the alleles are far apa on the chromosome, as it is more likely that a cross-over will occur between them. The odds of crossing over, or recombinant event, between two linked genes is propoional to the distance that separates them. Thus, genes that are far apa are more likely to undergo a recombination event than genes that are very close together. Thus by working out the number of recombinants it is possible to obtain a measure for the distance between the genes. This distance is called a genetic map unit (m.u.), or a centimorgan and is defined as the distance between genes for which one product of meiosis in 100 is recombinant. A linkage map is created by finding the map distances between numbers of traits that are present on the same chromosome, ideally avoiding having significant gaps between traits to avoid the inaccuracies that will occur due to the possibility of multiple recombination events. Linkage mapping is critical for identifying the location of genes that cause genetic diseases. A linkage map is a chromosome map of a species or experimental population that shows the position of its known genes and/or markers relative to each other in terms of recombination frequency, rather than as specific physical distance along each chromosome. Polymorphism is essential for linkage studies because they provide a means to distinguish the maternal and paternal chromosomes in an individual. All chromosomes are paired, one inherited from our mother and one from our father. Each pair of chromosomes contains the same genes in the same order, but the sequences are not identical. This means it should be easy to find out whether a paicular sequence comes from our mother or father. These sequence variants are called maternal and paternal alleles. Genetic markers are DNA sequences that show polymorphism (variations in size or sequence) in the population. They are present in everyone and they can be typed (the allele can be identified) using techniques such as the polymerase chain reaction . Disease genes are mapped by measuring recombination against the panel of different markers spread over the entire genome. In most cases, recombination will occur frequently, indicating that the disease gene and marker are far apa. Some markers however, due to their proximity, will tend not to recombine with the disease gene and these are said to be linked to it. Ideally, close markers are identified that flank the disease gene and define a candidate region of the genome between 1 and 5 million bp in length. The gene responsible for the disease lies somewhere in this region. Linkage is expressed as a lod (logarithm of odds score)- the ratio of the probability that the disease and marker loci linked rather than unlinked. By convention, a lod score greater than 3.0 is considered evidence for linkage. (A score of +3.0 means the likelihood of observing the given pedigree if the two loci are not linked is less than 1 in 1000). On the other hand, a lod score less than -2.0 is considered evidence to exclude linkage. Markers that are closest to the disease gene are less likely to undergo recombination events and therefore receive a higher linkage score. Linkage analysis is possible only for familial diseases, wherein pedigree analysis of the disease is done in that family. All the family is screened for the presence of all known polymorphisms. Then the polymorphism that is present in all the affected cases is identified as the linked allele and based on the location of this polymorphism, the possible location of the disease gene can be identified.
Useful to make pedigree cha to show affected and non-affected family members
Used to make pedigree cha to show non-paternity
Characteristic DNA polymorphism in a family is associated with disorders
Pedigree cha to identify disease frequency