Nullomers
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Nullomers are short sequences of
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
that do not occur in the genome of a species (for example, humans), even though they are theoretically possible. * Nullomers must be under selective pressure - for example, they may be toxic to the cell. Some nullomers have been shown to be useful to treat
leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...
,
breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...
, and
prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
. They are not useful in healthy cells because normal cells adapt and become immune to them. Nullomers are also being developed for use as DNA tags to prevent cross contamination when analyzing
crime scene A crime scene is any location that may be associated with a committed crime. Crime scenes contain physical evidence that is pertinent to a criminal investigation. This evidence is collected by crime scene investigators (CSI) and law enforcement. ...
material. *


Background

Nullomers are naturally occurring but potentially unused sequences of
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
. Determining these "forbidden" sequences can improve the understanding of the basic rules that govern sequence evolution. Sequencing entire genomes has shown that there is a high level of non-uniformity in genomic sequences. When a codon is artificially substituted with a synonymous codon, it often results in a lethal change and cell death. This is believed to be due to ribosomal stalling and early termination of protein synthesis. For example, both AGA and CGA code for arginine in bacteria; however, bacteria almost never use AGA, and when substituted it proves lethal. Such codon biases have been observed in all species, and are examples of constraints on sequence evolution. Other sequences may have selective pressure; for example, GG-rich sequences are used as sacrificial sinks for
oxidative damage Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal r ...
because
oxidizing agents An oxidizing agent (also known as an oxidant, oxidizer, electron recipient, or electron acceptor) is a substance in a redox chemical reaction that gains or " accepts"/"receives" an electron from a (called the , , or ''electron donor''). In ot ...
are attracted to regions with GG-rich sequences and then induce strand breakage. Moreover, it has been shown that statistically significant nullomers (i.e. absent short sequences which are highly expected to exist) in virus genomes are restriction recognition sites indicating that viruses have probably got rid of these motifs to facilitate invasion of bacterial hosts.Nullomers Database
provides a comprehensive collection of minimal absent sequences from hundreds of species and viruses as well as the human and mouse proteomes.


Cancer Treatment

Nullomers have been used as an approach to
drug discovery In the fields of medicine, biotechnology, and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or ...
and development. Nullomer peptides were screened for anti-cancer action. Absent sequences have short polyarginine tails added to increase solubility and uptake into the cell, producing peptides called PolyArgNulloPs. One successful sequence, RRRRRNWMWC, was demonstrated to have lethal effects in
breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...
and
prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
. It damaged
mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
by increasing
ROS Ros or ROS or RoS may refer to: Organizations * Raggruppamento Operativo Speciale, the Anti-organized Crime Branch of the Italian Carabinieri * Registers of Scotland, a Scottish authority responsible for compiling and maintaining records * Repart ...
production, which reduced ATP production, leading to
cell growth Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...
inhibition and
cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as di ...
. Normal cells show a decreased sensitivity to PolyArgNulloPs over time.


Forensics

Accidental transfer of biological material containing DNA can produce misleading results. This is a particularly important consideration in forensic and crime labs, where mistakes can cause an innocent person to be convicted of a crime. There was no way to detect if a reference sample was mislabeled as evidence or if a forensic sample is contaminated, but a nullomer barcode can be added to reference samples to distinguish them from evidence on analysis. Tagging can be carried out during sample collection without affecting genotype or quantification results. Impregnated filter paper with various nullomers can be used to soak up and store DNA samples from a crime scene, making the technology simple and effective. Tagging with nullomers can be detected—even when diluted to a million-fold and spilled on evidence, these tags are still clearly detected. Tagging in this way supports National Research Council's recommendations on quality control to reduce fraud and mistakes.


References

{{reflist Amino acids DNA Genetics techniques Genomics Human mitochondrial genetics Nucleotides