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Genomic analysis reveals recombination hot spots and gives insights into Alzheimer’s and Parkinson’s Disease

Written by Miyako Rogers, Science Writer

New research published in Cell involving large-scale genomic analysis of human tissue samples has shown that Alu and L1 elements, once considered “junk DNA”, are recombination “hot spots”. Analysis of somatic recombination profiles has also revealed that these profiles exhibit tissue-specificity, are involved in neuronal differentiation and are altered in Parkinson’s and Alzheimer’s disease.

Alu and L1 elements are recombination “hot spots”

Non-allelic homologous recombination (NAHR) is a process that occurs when highly similar sections of the genome (homologous sequences of non-allelic loci) incorrectly recombine, causing the areas between the two sites to be deleted or duplicated. NAHR is often triggered by the repair of DNA double-strand breaks and its critical role in evolution, cancer and human genetic disorders has been studied extensively. However, how much genomic variation is generated by NAHR and what different repeat element families contribute to this process have yet to be studied until now.

Alu and L1 elements are repeat elements which occupy 30% of the human genome and were until recently labelled as “junk DNA”. However, these elements are often found at breakpoints of NAHR events associated with cancer and other genetic disorders. In this study, researchers examined the somatic NAHR of repeats using capture-seq, an RNA-based capture assay, and developed TE-reX, a new bioinformatics pipeline designed to identify NAHR events. Their analysis showed that somatic recombination of Alu and L1 elements are widespread throughout the genome and that these elements also act as recombination “hotspots”, which explains why they are often found at breakpoints associated with cancer, and genetic diseases.

Changes in somatic recombination profiles

Genome-wide profiling of Alu and L1 NAHR events showed that somatic recombination exhibits tissue-specific characteristics. This was further studied in an in vitro model of neuronal differentiation, where induced pluripotent stem cells (iPSC) differentiate into GABAergic interneurons (inhibitory neurons) over the course of 50 days. The somatic recombination profiles of induced pluripotent stem cells (iPSC) were then compared with the differentiated neurons. This analysis revealed that the process of cell differentiation triggers the emergence of cell-specific recombination profiles.

These results, showing NAHR is involved in normal physiological conditions, led the researchers to investigate how these somatic recombination profiles are affected in disease. Researchers compared the somatic recombination profiles of samples from neurotypical vs neurodegenerative donors and showed that these profiles are altered in Parkinson’s and Alzheimer’s disease. Further understanding of these changes in somatic recombination could lead to insights into the pathology and aetiology of these neurodegenerative diseases.

Future directions

In conclusion, this study shows that somatic recombination of Alu and L1 repeat elements is widespread throughout the genome, driving genomic diversity and allowing for cell differentiation. Furthermore, it also shows how somatic recombination of Alu and L1 may drive the transition of cells from healthy to pathological states, particularly in the context of neurodegenerative diseases. This study is the first of its kind to analyse the contribution of specific repeat families to the process of genomic variation, paving the way for future experiments to explore how somatic recombination events affect different biological processes.