Basic Concept of the Retrobiome and Canine Genome Plasticity
Our understanding of the underlying mechanisms of aging and the importance
of studying dogs in this field
The Concept of the Retrobiome
Approximately 65 million years ago, fragments of ancient viruses were integrated into mammalian genomes and became repeats of LINE1s and SINEs, two types of repetitive DNA sequences found in the genomes of many organisms, including humans. This event is believed to have occurred around the same time that rodent-like mammalian ancestors underwent a sudden and extensive diversification into a tremendous amount of phenotypic varieties.
Fragments of ancient viruses make up nearly
half of the mammalian genome.
Until recently, they were thought to be nothing more than genomic junk, having been silenced over the course of evolution.
However, there is mounting evidence that these repetitive retro-elements can become activated, as several groups have detected LINE1 proteins in various types of cancer cells.
LINE1s are a type of transposable element that can move around within the genome by a copy-and-paste mechanism.
Intact L1 sequences are roughly 6 kilobases in length and encode two polypeptides: open reading frame 1 (ORF1p) and 2 (ORF2p). ORF1p is an RNA-binding protein, while ORF2p is a multifunctional protein that combines reverse transcriptase (RT) and endonuclease (integrase) activities that are essential for the replication and expansion of L1 and other non-autonomous retrotransposons.
L1 insertion into the genome can occasionally disrupt or alter genes, leading to mutations or genetic disorders. In addition, L1s can insert themselves into regulatory regions of the genome, such as promoter or enhancer sequences, which can affect the expression of nearby genes. Furthermore, L1s can cause double-stranded DNA breaks during the insertion process, which can result in genomic instability.
Thus, it appears that the activation of retroelements increases genomic instability, which in turn promotes tumor initiation and progression.
Recent research by Dr. Andrei Gudkov, the founder of Vaika, and his group at the Roswell Park Comprehensive Cancer Center, has shown that aging is associated with an increase in the number of copies of repetitive elements within the genomes of humans, mice, and dogs.
In a 2018 paper published in the journal Cell Cycle, Dr. Gudkov and his colleagues proposed the concept of the Retrobiome as a collection of endogenous retroelements and their associated proteins that can impact various biological processes, including aging and cancer. The term has since been used in various scientific publications to refer to the retroelement content of genomes and its potential impact on cellular processes.
Internal Aging Clock
In addition to new integrations of repetitive elements, the activity of the retrobiome causes genomic instability and introduces multiple mutations, leading to the development of cancers and various other age-related diseases. Therefore, the activation of the retrobiome acts as an internal clock mechanism that determines aging.
We hypothesize that this clock could be stopped by inactivating the enzyme essential for the activity of repetitive elements: reverse transcriptase. Proof of concept has been demonstrated in multiple experiments in mice, where inhibition of reverse transcriptase results in cancer prevention and extended lifespan.
Watch Dr. Gudkov discussing the Retrobiome concept
Canine Genome Plasticity
The diversity of mammals can be partly explained by the widespread invasion of retroelements in the genomes of ancient ancestors. Among all existing mammalian species, dogs are known for their high degree of phenotypic diversity and plasticity. This is partly due to the fact that their retroelements were less silenced over the course of evolution and are more easily activated.
As a result, the canine genome exhibits a high degree of plasticity and adaptability, which has enabled dogs to evolve and diversify into many different breeds with unique physical and behavioral traits. The study of canine genome plasticity may have implications for understanding the evolution and diversity of other mammalian species, including humans.
Diversity of Canines
Diversity in domestic dog phenotypes is linked to a variety of new insertions of repetitive elements that occur in different locations and with differing frequency across breeds.
Among the various types of repetitive elements in the canine genome, short interspersed nuclear elements (SINEs) are particularly important for generating genetic diversity, with the most common SINE element, SINE_CAN, accounting for 7% of the dog genome.
The location of SINE insertions in the genome varies between breeds and can serve as an accurate breed-specific hallmark. For example, brachycephaly, which is the shortening of the snout and widening of the hard palate, is caused by a LINE1 insertion into the SMOC2 gene [Marchant et al, 2017]. Similarly, appendicular chondrodysplasia, which is the shortening of the legs, is caused by LINE-1 mediated retrotransposition of the FGF4 retrogene [Parker et al, 2009].
Overall, these findings illustrate the important role of repetitive elements in shaping the genetic diversity and phenotypic variability of domestic dogs.
The activity of repetitive elements has been associated with various diseases in dogs. For example:
Swedish Vallhund dogs develop retinopathy as a result of the insertion of a LINE-1 element into the MERTK gene [Cooper et al, 2014].
Tibetan spaniels with late-onset progressive retinal atrophy have a SINE insertion in an intron of the FAM161A gene that creates a reading frame shift and exon skipping [Downs LM et al, 2014].
Canine narcolepsy in Doberman Pinschers and Labrador Retrievers has been linked to a SINE insertion in the HCRTR2 gene [Lin L et al, 1999].
The amount of repetitive elements in circulating DNA has been associated with tumor progression and poor prognosis in dogs [Gelati et al, 2014].
These findings suggest that the activity of repetitive elements can have significant consequences for the health and well-being of domestic dogs, and may have implications for understanding the genetic basis of disease in other mammalian species as well.
The study of the Retrobiome and canine genome plasticity offers a unique perspective for understanding the genetic basis of aging, cancer, and other diseases. By investigating the mechanisms by which retroelements impact gene expression and genomic stability, researchers can potentially develop new strategies for the prevention and treatment of age-related diseases.