Syndactyly is a condition that results in webbed fingers or toes. It is one of the most common congenital limb abnormalities, affecting one in every 2,000-3,000 newborns. Its severity ranges from simple, involving just skin tissue, to complex, involving bone malformations. There are various suspected causes of syndactyly. A few of them include smoking, having Down syndrome, and using hydantoin during pregnancy.
Image Source: China Photos / Stringer
As scientists continue to study how syndactyly can be prevented and how certain genetic mechanisms lead to the fusion of limbs, their attention has been directed to newly discovered features of the human genome known as Topologically Associating Domains (TADs).
TADs are long stretches of DNA that are physically isolated from one another. They are thought to play a major role in determining the folding protocol of the genome. Their borders serve as “folding instructions” for the DNA, much like the dotted lines on a paper model kit, as said by Dr. Dekker. It is thought that folding along these instructions leads to a three-dimensional structure that physically isolates each TAD from one another. The elements within each TAD can interact with each other but cannot interact with the elements of a different TAD.
In order to learn more about the significance of TADs, scientists have turned to identifying the effects of broken down TAD boundaries. In a study that was published in the journal Science, Dr. Young and his colleagues analyzed the TAD boundary near the TAL1 gene. Improper activation of TAL1 was associated with an increased risk of leukemia. In the study, they mutated the TAD boundary near the TAL1 gene to prevent proteins from binding to it. As a result, a difference was noted in TAL1 gene expression that could lead to tumorigenesis (formation of tumors). The study concluded that the control elements of a neighboring TAD were now able to influence and drive gene expression within the TAD that included TAL1. This helped to prove that TAD boundary disruptions might play a role in causing cancer.
Similar studies have shed light on how TAD disruptions can lead to congenital limb malformations, such as syndactyly. Such conditions could take place when the wrong control elements are allowed to influence genes in neighboring TADs in a manner that might be untimely and disruptive.
There is still a lot that needs to be understood in the realm of genomic science, but the discovery of TADs and the effect of their boundary disruptions on gene expression have surely started to clear up a few things. Precisely what happens when TAD boundaries are mutated and how that knowledge can be used to prevent and cure syndactyly still remains to be understood.