New Hebrew University research maps for the first time the differences in maternal and paternal DNA coding in the body's cells, providing new insights into genetic control, parental inheritance, and the impact of genetic diseases
In a new study published in the journal Nature Communications, researchers from the Hebrew University of Jerusalem mapped the DNA marking in the two copies of DNA – maternal and paternal – in the body’s various cells. Methylation, or marking DNA with a methyl residue (CH3), allows the body to turn different genes on and off in different cell types, as well as encode and maintain cellular identity throughout life.
During the study, it was found that there are over 34,000 regions in the human genome where the methylation level in the copy of the gene inherited from the father is different from that in the copy inherited from the mother. Some of the differences are caused by the natural genetic variation that exists between humans, but others are related to the phenomenon of genomic imprinting, in which only the maternal copy of a particular gene is not methylated and therefore remains active, while the paternal copy is methylated and therefore silenced (or vice versa). Parental imprinting has been studied extensively in the past, and is an important example of non-genetic (epigenetic) inheritance – a situation in which a particular gene “remembers” which parent it came from. Parental imprinting has clinical significance in situations where a person inherits a mutant copy of a gene from one parent, but the normal copy from the other parent is imprinted and therefore silenced, for example in syndromes such as Engelman and Prader-Willi. However, the full extent of the phenomenon was not known until now.
The study, led by Prof. Tomi Kaplan and doctoral student Yoni Rozansky from the School of Engineering and Computer Science, and Prof. Yuval Dor from the School of Medicine, identified approximately 325 regions in the human genome that were suspected of showing dramatic methylation differences between the two copies in each cell. In addition, the researchers found approximately 460 regions in the genome that are controlled by parental imprinting – many of which were previously unknown. In a significant proportion of cases, methylation differences between the paternal and maternal copies appear only in certain cell types, which has prevented discoveries until now.
An example of this involves a gene called CHD7, a mutation in one copy of which is responsible for CHARGE syndrome – a rare genetic disease characterized by various defects in embryonic development. The researchers observed that methylation affecting the maternal copy occurs in some tissues, but not in blood cells – the usual source of DNA from patients. The finding could explain the unique inheritance pattern of this syndrome, which was previously not understood, and suggest a mechanism for other diseases that show an inheritance pattern that depends on which parent the mutation came from.
According to Prof. Yuval Dor, “The fact that parental imprinting can be limited to specific cell types helps us better understand how the mechanisms of gene control in the human body work. This opens new horizons for studying the mechanisms underlying genetic diseases, and may in the future provide precise tools for diagnosis and treatment.”
The researchers used a method that allows them to identify where methylation markings were added to each DNA molecule, and developed machine learning algorithms that helped them distinguish between the paternal and maternal copies in each sample. This resulted in a broad methylation atlas, which is an important database for biological and medical research, with an emphasis on studying the inheritance of genetic diseases and the impact of epigenetic processes on our health.
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