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One Family's 'Curse' Provides a Better Understanding of the Human Genome


Unlocking the Human GenomeSyndactyly is a congenital deformity in which one or more fingers don't completely separate during embryologic development. A rare form in which the index finger and thumb are fused together has become what one family describes as a "curse." It has affected 10 people in the extended family. While studying their genetics to debunk the theory of a curse, Dr. Stefan Mundlos and his team made new discoveries about the human genome.

Mutations Affect Part of the Genetic Code

The family agreed to participate in a study of the origin and development of limb malformations at the Max Planck Institute for Molecular Genetics in Germany. During DNA analysis, the scientists found a new class of genetic mutations that sheds light on many mysterious diseases and helps scientists better understand how genetic coding works. This is because it affects the topologically associating domains or TADs, which are a part of the genetic code.

There's a vast amount of information in the genetic code, and a TAD is just one region or neighborhood in that code. The size of this region can range from thousands to millions of DNA bases, much like how a neighborhood can range from one to several communities. Physical interactions occur frequently within a TAD but infrequently across its boundary.

Learning More About TAD Boundaries

Scientists learned a long time ago that a variety of genetic enhancers and switches control protein codes in the human genome. They trigger and control the intensity of protein production. However, the new research shows that TAD boundaries dictate their engagement.

The enhancers and switches only act on the protein codes within a TAD. For example, an enhancer can amplify the activity of a gene within its genomic region. However, it can't cross the TAD boundary to affect genes in other regions of the genetic code.

It's the construction of TAD boundaries that prevents neighboring TADs, their genes and other elements from becoming entangled. Scientists aren't totally sure what the boundaries are made of. Preliminary testing indicates that they include genetic sequences that attract cohesin and CTCF proteins. These proteins adhere to the boundary to create a thick insulation. Between the clusters are chromatin strands that act like ribbons to form the barrier.

What Happens When There Is No TAD Boundary?

A number of disorders can develop when there's no boundary to keep genetic enhancers and switches within a TAD from mixing into other genomic regions. Scientists have identified that damage to DNA that eliminates or shuffles a boundary is linked to diseases such as blood, brain, colon and esophagus cancer. This is because the enhancers within a TAD gain access to genes that they aren't meant to amplify.

Now that they understand what to look for, researchers may be able to identify breakdowns in TAD boundaries as a common cause of cancer. This could hold true for developmental disorders such as syndactyly. With the discovery of the role that TAD boundaries have, further three-dimensional and real-time study can help scientists better understand how the human genome can work properly after being stretched out, coiled and compressed.

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