Nature's Genomic Engineering, Haywired

"One woman told me that she never received a hug from her father. He avoided her [repulsed by a familial, inherited congenital deformity: syndactyly]."
"If a muscle gene turns on in the cartilage of developing digits, you get malformations [such as fused digits of hands]."
Dr. Stefan Mundios, Max Planck Institute for Molecular Genetics

"We were caught up in the idea of genetic information being linear [like a computer code, 'letters' sequencing of genetics: instructions to transform amino acids into proteins] and one-dimensional."
"Genes and regulatory elements are like people. They care about and communicate with those in their own domain, and they ignore everything else."
Dr, Job Dekker, biologist, University of Massachusetts Medical School

The hand of a woman with syndactyly, the congenital fusion of fingers. The deformity may range from a slight degree of webbing to almost complete fusion. SPL/Science Source

 

Dr. Dekker and his colleagues, such as Dr. Edith Heard, director of the genetics and developmental biology department at Institut Curie, France, developed a technology in the study of biology at its most elemental levels, called chromosome conformation capture. That technology has been widely used by researchers to track the deep structure of DNA.

Their studies have led to the discovery that the genome organizes itself into thousands of jurisdictions, and these have been named TADS. Short for topologically associated domains (TADs). These latterly-recognized domains, represent a vast biological data field, divided into a  series of parochial areas strictly partitioned to represent specific biological traits. Should one of those TAD barriers be breached, molecular dysfunction results.

And this became an inherited trait among a family who felt they were cursed. Ten people of the extended family were inflicted with a rare deformity where the thumb and index finger are fused, affecting one or both of their hands. They felt like outcasts, their "strange fingers" setting them apart from others, psychologically estranged from not only friends and neighbours, but members of their intimate family.

The family agreed to take part in a study on the origin and development of limb malformations. They are grateful that Dr. Mundlos has assured them that they are not cursed, that there exists within biological science, "a rational answer for their condition", but not however, a prevention or a correction of syndactyly through surgery.

The family's limb anomaly has been identified by the investigating scientists connecting to a class of genetic defects, rare in occurrence, but a finding that holds out promise that a long list of mysterious diseases may be linked to the same biological process gone awry that has so profoundly affected this family, with each new birth that reflects a continuation of the deformity.

Researchers have succeeded in linking a number of disorders through the study of TADs where boundaries separating genomic domains have been breached, producing cancers of the colon, esophagus, brain and blood. It has been a half-century since genetic research focused on DNA coding;' instructions' for amino acids to be transformed into proteins, preserving life.

The genetic switches and enhancers representing non-coding sequences which nature designed to turn on protein production, accelerate it and when appropriate calming the process by deceleration, have long been known to science. What is new in research is that switches and enhancers respond on specific genes only, whose protein codes are located within their specific precincts.

Disruption of a binding site "broke up the neighbourhood and allowed an outside enhancer to push [the gene TALI with its potential to cause leukemia] TALI  to the point of tumorigenesis", producing leukemia.  This, the discovery of Richard A. Young of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts. Explaining how TAD disruptions could represent a common cause of cancer, as well as developmental disorders such as syndactyly.

"Suddenly a lot of things are falling into place. We're coming into a renaissance time for understanding how the genome works", stated Dr. Edith Heard, at the Institut Curie, in France.

Syndactyly (Greek Syn=together; Dactylos=digit) is a digital malformation in which adjacent fingers and/or toes are webbed because they fail to separate during limb development. It is one of the most common hereditary limb malformations depicting a prevalence of 3–10 in 10 000 births, though higher estimates ranging from 10–40/10 000 have been reported.
European Journal of Human Genetics