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Gene Discovery

Positional Cloning, Complex DiseasesApproaches for Identifying Genes

Gene discovery is the process of identifying genes that contribute to the development of a trait or phenotype. Researchers often try to discover the genes that are involved in specific diseases. They also try to find the genes that contribute to many other traits.

Polymorphic markers along the chromosomes (here shown as different colored bars) are examined to determine which is coinherited with the disease (shaded circle and square). The red marker in the third position is found only in the two family members with the disease.

Gene discovery begins with clearly defining a trait of interest and determining if that trait has a genetic and/or environmental basis. This is done using several approaches, such as sibling recurrence risk ratio, familial aggregation, and twin and adoption studies. The sibling recurrence risk ratio is the frequency of a disease among the relatives of an affected person, divided by the frequency of the disease in the general population. The greater the ratio, the stronger the genetic component of the disease.

A trait also is suspected of having a strong genetic component when familial aggregation, which is the clustering of patients in a single family, occurs. Familial aggregation can sometimes be misleading, however. Since families often share the same environment, it is difficult to know whether environmental or genetic factors are the cause of clustering.

In twin studies, concordance rates play a critical role. Concordance is the percentage of second twins that exhibit a trait when the trait occurs in the first twin. Twins generally also share environments, so concordance rates are often compared between monozygotic twins, who are genetically identical, and dizygotic or "fraternal" twins, who share on average 50 percent of their genetic material. The greater the difference in concordance rates between monozygotic and fraternal twins, the stronger the genetic contribution to the trait. The combination of evidence from all these approaches indicates whether a particular phenotype is likely to have a genetic basis.

Once genetic influence has been established, two research approaches are commonly used to identify the specific genes involved. These are the candidate gene approach and the genomic screening approach.

Candidate Gene Approach.

In the candidate gene approach, genes are selected based on their known or predicted biological function and on their hypothesized relation to the disease or trait. These genes are subject to mutation analysis to determine whether they are really involved. The problem with the candidate gene approach is that it relies on assumptions about the molecular mechanisms underlying the development of a trait. However, diseases are usually studied because little is known about their causes, so initial ideas about these "molecular mechanisms" often prove to be wrong.

In addition, the candidate gene approach can be very time consuming, and it has been successful only infrequently. Chromosomal abnormalities, such as deletions, inversions, or translocations, in individuals exhibiting a trait, as well as animal models mimicking the trait, are especially important for a candidate gene approach, since they provide clues to the genetic basis of the trait.

Genomic Screen Approach.

A genomic screen is a systematic survey in which polymorphic DNA markers, evenly spaced along all the chromosomes, are used to determine if a marker is inherited along with the trait, indicating genetic linkage. This is performed taking the DNA from each individual in the study and identifying the type of marker each has on his chromosomes. These data are then analyzed using statistical programs to see if the marker and the trait that is being studied travel together through families significantly more often than would be expected just by chance. If a DNA marker is found to be linked with a trait, it suggests that the marker and the gene responsible for the trait are rarely separated by crossing over and are therefore near each other on a region of a chromosome. Further fine mapping of this region with more closely spaced markers can narrow the region where the gene of interest lies.

Genomic screening does not require prior biological understanding of the pathophysiology of a disease. It requires large sets of data from families containing multiple members who are affected with the trait, and it tends to be the more expensive of the two approaches.

Genomic screening usually leads to the identification of one or several loci, or relatively large areas in the genome, that are linked with a trait but that contain many different genes. The genes in such regions need to be prioritized.

Genes are considered to be good candidates when their putative functions fit with the known or predicted pathway of the disease. If any known gene in the linkage region appears to be a good candidate gene, it is subjected to mutation analysis to determine if there is a potentially disease-causing mutation that segregates only with the affected individuals.

Both the gene candidate and the genetic screen approach require collecting data from a large number of families. Recruiting and medically evaluating affected and unaffected individuals for participation in a genetic study, and collecting their DNA samples, is a long and complicated phase of gene discovery.

Additional topics

Medicine EncyclopediaGenetics in Medicine - Part 2