What are microsatellites?
Microsatellites, or repetitive DNA, defined as tandem repeats of 1- to 6-mer motifs, are pervasive throughout the human genome in both coding and non-coding regions. An example is the DNA sequence, CAGCAGCAGCAGCAG, where the motif (CAG) is repeated 5 times. There are approximately one million such repeat-containing loci in the human genome.
Microsatellites are mostly known for their role in forensics and paternity testing. About 20 microsatellite loci, which are known to vary among individuals, are measured for all forensics and paternity testing. There are also tests known as microsatellite instability testing which compares tumor DNA to germline DNA for a few microsatellite loci. Orbit Genomics™ explores all one million microsatellite loci in the genome and our technology is very different from these tests. Standard sequencing algorithms are optimized for genetic mutation analysis and don’t accurately analyze microsatellites. OrbiSeq’s proprietary algorithms accurately analyze all one million microsatellite loci in the genome.
How are they different from other DNA sequence variations in the human genome?
Most genetic and genomic studies have focused on Single Nucleotide Polymorphisms, called SNPs. These variants, where a single DNA base (or nucleotide) changes, for example a G to an A, are often studied for their role in disease. Although they have been studied extensively, they fall far short of explaining the known or suspected genetic components of disease, especially complex diseases such as cancer, heart or neurological diseases. Over 50 hereditary cancer syndromes have been identified; yet, inherited mutations only account for 5-10% of all cancers. Complex diseases are caused by a combination of genetic mutations and environmental factors.
Because of their repeating nature, microsatellites tend to be more susceptible to unstable genomic processes. Microsatellites mutate by changing in length. They are more sensitive to cellular stressors and mutate ten thousand times faster than SNPs and other genetic mutations. When stress decreases, the mutations are reversible. As a result, microsatellites are excellent readouts of genome stability and they reflect both inherited risk and risk acquired from lifestyle and environmental exposures.
The ~ 1 million microsatellites, repetitive DNA, operate under fundamentally different biological process for replication and error correction than SNPs, which is why they are both more mutable and more responsive to cellular stressors and selection pressure. Thus, they are a very sensitive readout of overall cellular/organ/organism status/disease/health. Microsatellites also have virtually an infinite number of possible alleles/states where SNPs have but 4 at each base. Consequently, they are referred to as “nature’s tuning knobs”, and “genomic rapid response elements”.
How does Orbit Genomics use microsatellites?
Standard sequencing algorithms are optimized for SNP detection and do not correctly analyze microsatellites, in fact, they misread them 80% of the time. Orbit Genomics’ OrbiSeq™ technology platform uses proprietary algorithms to accurately call the one million microsatellite loci in the human genome. This technology is based on 20 years of research which includes 5 NIH Grants totaling $9.65 Million resulting in over 40 scientific published studies co-authored by our CSO, Skip Garner. Through the analysis of thousands of human germline genome sequences, comparing diseased and healthy genomes, we have identified clinically actionable microsatellite markers which are specific to different diseases and conditions. Orbit Genomics has also used this technique to compare different traits in responders and non-responders to a given therapy to develop companion diagnostics for new or established drugs.
The OrbiSeq™ technology platform is applicable to many diseases and conditions beyond cancer. Because microsatellites reflect overall genome stability and mutate rapidly, they are an ideal marker for diseases and conditions of the aged. We’ve demonstrated the ability to detect disease early, predict drug efficacy in individuals (CDx) and determine genetic age.