Nature: Does DNA repeats depend on what causes disease?
DNA repeats are very common in the human genome. Repeat sequences have been proposed as an evolutionary mechanism, but they may be associated with human disease. Now, scientists at the Max Planck Institute for Molecular Genetics and Charité – Universit? tsmedizin Berlin have demonstrated whether DNA repeats are associated with human disease, depending on their location in the genome, and sequence repeats may lead to new functions. Units - called Topology Related Domains (TADs).
In a paper published in the journal Nature, the researchers described how DNA repeats of different sizes, how to generate new TADs, and how new genes can be acquired. This mechanism is a possible mechanism of "how new genetic functions appear in evolution" and has far-reaching implications for the interpretation of human genetic mutations.
Topologically related domains (TADs) are spatially separated regions of the genome. They are DNA fragments of one million bases in length and contain one or more genes and their regulatory elements (called enhancers). The latter controls when and in which cells a gene is turned on or off. TADs are separated from each other by boundary elements such that the activity of a gene in a TAD is independent of the activity of genes in adjacent TADs.
Scientists at the Development & Disease Research Group at the Max Planck Institute for Molecular Genetics discovered a previously unknown function of TADs by studying various repetitive fragments of varying sizes in the SOX9 gene region. The SOX9 gene is responsible for the expression of a transcription factor that plays an important role in bone and male sexual development. By analyzing the three-dimensional structure of the genome, the researchers demonstrated that two large TADs are located in the SOX9 gene region. One of the TADs contains the SOX9 gene and its regulatory elements; the other TAD contains two genes, KCNJ2 and KCNJ16, two potassium channels and their regulatory elements.
Various types of repetition
Repeats in the SOX9 gene region result in completely different clinical phenomena. To understand these differences, the researchers investigated three replicates, all of which included regulatory elements of the SOX9 gene and other DNA fragments of various lengths.
The first repetition detected can lead to a gender reversal of humans from female to male. Although the affected individual has two X chromosomes, it is male in form. The scientists found that this duplication only affects the DNA and regulatory elements that occur within the SOX9 TAD. Surprisingly, however, larger repeats—including this region but extending to the adjacent genes KCNJ2 and kcnj16 to contain fragments of adjacent TADs, have no clinical effect on sex determination. In contrast, larger repeats—not only the non-coding DNA in SOX9 but also the adjacent KCNJ2 gene, can lead to Cooks syndrome, a hereditary hand/foot abnormality characterized by no nails. , fingers and toes shortened.
Duplication between TAD and TAD
Stefan Mundlos, head of the study, said: "We have to distinguish between TAD and TAD, depending on their location. In the case of gender reversal, the regulatory elements within the TAD (within the TAD) are repetitive, and The effect is still limited to the TAD. Therefore, only the gene in the TAD is misregulated, which means that it is activated too much or too little. In the case of the SOX9 gene, the activity of the gene is increased, resulting in male gender. Development, even if the affected individual is genetically female."
Because TADs are functionally separated from one another, repeating within a TAD affects only one TAD and has no effect on adjacent TADs. In contrast, in the case of repetition between TADs, not only the regulatory elements of the SOX9 region are repeated, but also the boundaries between the two TADs are repeated. The repeated boundaries define a new TAD (called neo-TAD) that includes the repeat region of the genome and leaves it from the remaining genetic components.
Mundlos said: "The impact of a neo-TAD depends on the genomic components it contains. If neo-TAD contains only regulatory elements, but no genes, then it has no effect on the body. Neighboring genes circumvent regulatory elements of the TAD boundary, and However, if a neo-TAD contains two regulatory elements and a gene from a neighboring TAD, the latter can be regulated by a regulatory element (enhancer) within the neo-TAD, resulting in a mis-expression of the gene, which may Can cause an abnormality or disease.
TAD repeat with genes and regulatory elements
This is the third repetitive case studied by researchers that triggers the Cooks syndrome. This new TAD contains not only the regulatory elements of the SOX9 gene, but also a copy of the KCNJ2 gene. Then, the KCNJ2 gene in neo-TAD is regulated by the regulatory elements of the SOX9 gene. Therefore, it is activated during the wrong time and in the wrong tissue during development, causing abnormalities associated with this syndrome.
By using TAD structures for the interpretation of genetic variation, scientists can make more accurate predictions of the effects of genetic mutations than before. For example, this involves the repetition of genetic diseases and changes in cancer cells, where repetition often occurs.
Repetition is a driving force for evolution. The repetition of a gene allows its copy to develop new properties that are different from the original gene, which is still unaffected by this process. By enabling a new combination of regulatory elements and gene duplications in neo-TADs, these duplications may represent an evolutionary mechanism for the emergence of new gene functions.
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