Linkage and Genetic Screens


The entire DNA sequence of many organisms has been elucidated; these organisms include humans and many of the species researchers use to perform genetic studies. So, in an age in which we know the location of every gene (and every sequence that looks like a gene) in a particular species' genome, why would chromosome maps and linkage matter? The answer to this question is simple: Maps and linkage matter because we don't know what many of these species' so-called "genes" do.

The important thing to realize about linkage is that it helps researchers identify the locations on chromosomes at which specific genes exist. Indeed, linkage is critical for mapping and identifying genes when we are trying to discover which gene is responsible for a specific phenotype.

In a genetic screen, mapping allows scientists to link genes to their functions. To better understand how a genetic screen works, it helps to consider an example experiment. In this case, the example experiment seeks to answer the following question: What genes are responsible for blood vessel development and patterning?

Choosing the right model organism for an experiment is one of the most important aspects of experimental design. For instance, if you want to study the vascular system, you should not use the worm C. elegans, as members of this species do not have a vascular system. However, Danio rerio, or zebrafish, are particularly useful for vascular studies. Zebrafish embryos are transparent, and they are so small for the first several days that even if there is a mutation that causes a fish's vasculature to be completely disrupted, the embryo can still survive by way of the oxygen that is diffusing through its tiny mass.

One of the predominant systems for genetic screens related to the vasculature of zebrafish was developed by scientist Brant Weinstein (Lawson & Weinstein, 2002). In this system, green fluorescent protein (GFP) is used to tag all of a fish's developing vessels.

A forward genetic screen is used to look for mutations that affect a biological process. In our example experiment, we are looking for mutations that alter how a zebrafish's vasculature develops. Thus, our first step is to induce mutations. To do this, we must treat the male fish with a chemical; here, we opt for ethylnitrosourea (ENU), which causes mutations in zebrafish spermatogonia. The male fish that carry this mutation are then crossed to wild-type females.

Next, from this initial P cross, we collect the male fish that should be heterozygous for the mutant recessive allele. These fish are the F1 males, and they are crossed to wild-type females. Each F1 pair thus generates an F2 family of fish, half of which are expected to be heterozygous for the mutation and the other half of which are expected to be homozygous for the wild-type allele. After that, we cross males and females from the same family, investigate the F3 progeny from thousands of different families, and look for a phenotype of interest in the F3 generation. This is a large-scale genetic screen.

Zebrafish have numerous described polymorphisms, and each year more are added to a shared database at the Zebrafish International Resource Center. The closer a marker is linked to our phenotype (meaning we observe fewer recombination events), the more confidence we have that we know where the mutation is on the chromosome. In other words, the infrequency of recombination (when our marker and our phenotype diverge) suggests a physical closeness of the marker with the gene responsible for the phenotype under study. Indeed, such distances are denoted by a unit measure called the centimorgan (cM), which is related to the frequency of meiotic recombination and the pattern of segregation and inheritance of different markers within families. A genetic distance of 1 cM corresponds to roughly 1 megabase (Mb), or one million nucleotides.

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