For decades, biomedical research has largely focused on the 1.5 per cent of the human genome that codes for proteins, dismissing the rest as “junk DNA”. However, in light of recent insights into the millions of repetitive DNA sequences it comprises, this “junk” has now been recast as the “dark genome”.

Future Horizons:

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5-yearhorizon

Understanding transposable elements

The interplay between coding and non-coding regions of the genome is elucidated. The basic understanding of the dark genome — which elements to repress and with which drugs — is established as a new field.^¹⁸ Using biomarkers to establish causality, researchers figure out if these can be used for therapy. Early start-up trials yield results repurposing old drugs against neurodegeneration in ALS and autoimmune diseases like lupus, and more such trials ensue.

10-yearhorizon

AI assists dark-genome research

AI identifies many of the functions of non-coding elements and their effects on healthspan. It becomes possible to biochemically separate adaptive from maladaptive changes induced by jumping genes. First drugs developed to target specific transposable elements. Dark genome yields anti-cancer drugs.

25-yearhorizon

Research identifies harmful elements of dark genome

Identification of specific, harmful elements that carry no hidden benefits to an organism leads to improved therapies with reduced side effects. We untangle the other ways activation of the dark genome affects multiple, often unrelated, traits that affect apparently unrelated tissues and cell types.

Of particular interest for geroscience are transposons: repeating, self-replicating DNA sequences that can alter their location in the genome.^¹⁰ Also known as “jumping genes”, they make up about half of the genome. Their activity — which increases with an organism’s age — can alter chromosome structure, destabilise the genome, trigger immune response and inflammation,^¹¹ and create other conditions that have been tied to poor health outcomes in old age.^¹² Turning them off seems to have broad health benefits, as revealed in HIV antiretroviral therapies that turn off the “LINE” transposons (among the most prevalent repeating sequences, and major contributors to human genetic variation).^¹³ This reverses the age-accelerating effects of HIV with no health trade-offs.^¹⁴ Doing so holds promise for other diseases associated with LINE-1, such as rheumatoid arthritis^¹⁵ and lupus.^¹⁶

However, manipulating the dark genome will be more complex than simply finding a general-purpose “off” switch. Preclinical trials are beginning to show that, under certain conditions, some parts of the dark genome might have beneficial effects. Also, a better understanding of how non-coding elements interact with coding elements may yield a rich new source of new biomarkers and potentially even therapies. Our understanding of the dark genome has been hampered by technological limitations of DNA and RNA sequencing requiring fragmentation followed by aligning to reference sequences to forecast the underlying sequence. New technologies, including nanopore, which allows direct reading of long sequences of DNA and RNA, are advancing our understanding of the dark genome,^¹⁷ but more research into these intricate relationships and how to balance the trade-offs is needed. Excitingly, the dark genome appears to be responsive to rejuvenation, so a better understanding of rejuvenation may also shed light on it.

Dark genome - Anticipation Scores

The Anticipation Potential of a research field is determined by the capacity for impactful action in the present, considering possible future transformative breakthroughs in a field over a 25-year outlook. A field with a high Anticipation Potential, therefore, combines the potential range of future transformative possibilities engendered by a research area with a wide field of opportunities for action in the present. We asked researchers in the field to anticipate:

The uncertainty related to future science breakthroughs in the field
The transformative effect anticipated breakthroughs may have on research and society
The scope for action in the present in relation to anticipated breakthroughs.

This chart represents a summary of their responses to each of these elements, which when combined, provide the Anticipation Potential for the topic. See methodology for more information.