“Cis” comes from the Latin for “on this side,” and “trans” means “across” or “on the other side.” In genetics, cis marks things that share the same stretch of DNA, and trans marks things on separate pieces of DNA or reaching in from elsewhere in the cell. The pair is less a single definition than a reusable idea, applied to gene variants, gene switches, RNA editing and even the shapes of proteins. Once you know which DNA molecule something sits on, most uses of the words fall into place.
Cis and Trans for Two Variants on Paired Chromosomes
Most of your cells hold chromosomes in matched pairs, with one copy from each parent. Each version of a gene on a copy is called an allele. So a person carrying two different variants at two nearby genes can have them arranged in two ways. When both changed alleles sit on one copy and both normal alleles on the other, geneticists call the arrangement cis, or coupling.1Open Genetics Lectures. What Is the Difference Between Cis and Trans in Genetics? When each copy carries one changed and one normal allele, it is called trans, or repulsion.2Introduction to Genetics. 9.4 Coupling and Repulsion (cis and trans) Configuration
A plant example shows the notation. A plant with genotype CcSs can be written CS/cs in cis, with both dominant alleles on one chromosome.3Plant & Soil Sciences eLibrary. Cis Versus Trans The slash in that notation separates the two chromosome copies, so letters on the same side travel together on one copy. The same plant could instead be Cs/cS in trans, with one dominant allele on each copy.4Plant & Soil Sciences eLibrary. Cis Versus Trans Two individuals with identical gene lists can therefore differ in arrangement.
Arrangement changes what offspring inherit. A parent usually passes one whole copy of a region to each child. In cis, both variants tend to be passed on together. In trans, a child usually gets only one of the two. Reshuffling between the copies can occasionally break these pairings.
The clearest case is a recessive condition caused by loss of a gene’s function. Imagine a person with one harmful variant at each of two different spots in that gene. If both sit on the same copy (cis), the other copy is untouched and usually makes enough working protein, so the person is typically a healthy carrier. If they sit on opposite copies (trans), neither copy works fully, and the person can be affected, a pattern called compound heterozygosity. The variant list is identical in both cases, which is why the arrangement has to be known.
That is why a genetic test report may say that phasing is needed. Standard sequencing often cannot tell which variants share a copy, because it reads short fragments from both copies mixed together. Testing the parents can settle it: if one parent carries both variants, they must be in cis in the child, and if each parent carries one, they must be in trans. Some newer methods read long stretches of a single DNA molecule, which can show the arrangement directly.
Where Cis and Trans Matter in Cancer and Medicine
Tumors can gain two driver mutations in the same gene, described as cis, more often than in different genes.5PubMed Central. Anticancer drug resistance: an update and perspective A second hit in the same gene may give a stronger push to growth and drug resistance.6PubMed Central. Anticancer drug resistance: an update and perspective Cancer sources sometimes use “cis” more loosely, to mean the same gene versus different genes.
Arrangement can decide whether a drug keeps working. In some leukemia patients on IDH inhibitor drugs, resistance arose from a second mutation on the other copy of the IDH2 gene, in trans.7PubMed Central. Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations The drug is designed to block the faulty protein made from the mutated copy. The second mutation can produce a different faulty protein the drug does not block well, and because each copy makes its own protein, the two mutant proteins work side by side in the same cell. Resistance to a related drug also appeared through a second mutation on the same copy, in cis.8PubMed Central. Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations Doctors tracking resistance may therefore need to know not just which mutations exist but where they sit.
Some tumor sequencing reports note whether two variants are on the same allele. It is reasonable to ask your oncologist whether the arrangement affects drug choice.
Cis-Acting Switches and Trans-Acting Factors
Stretches of DNA such as promoters and enhancers control when and how much a gene is used.9PubMed. Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence Enhancers are short DNA sequences that act on promoters by grabbing regulatory proteins.10PubMed Central. Cis-Regulatory Elements in Mammals Because these elements only affect genes on the same DNA molecule, they are called cis-acting elements.
A cis variant can weaken or strengthen the binding of a regulatory protein. The protein-coding part of the gene is unchanged, so the protein is normal but made in different amounts. Because the change is on one copy, the two copies of a gene in the same person can be switched on to different degrees.
Trans-acting factors are usually proteins or RNAs made from a gene elsewhere in the genome.11CSIR NET LIFE SCIENCE COACHING | NTA NET LIFE SCIENCE | CSIR LIFE SCIENCE. Understanding Cis-acting and Trans-acting Elements in Genetics They can drift through the cell and bind cis switches far from their own gene.12CSIR NET LIFE SCIENCE COACHING | NTA NET LIFE SCIENCE | CSIR LIFE SCIENCE. Understanding Cis-acting and Trans-acting Elements in Genetics Transcription factors, the gene-regulating proteins that switch genes on or off, are the classic example.13CSIR NET LIFE SCIENCE COACHING | NTA NET LIFE SCIENCE | CSIR LIFE SCIENCE. Understanding Cis-acting and Trans-acting Elements in Genetics One stress-responsive transcription factor, Egr1, appears to steer many brain genes in trans in the amygdala of mice.14PubMed Central. Differential contribution of cis and trans gene transcription regulatory mechanisms in amygdala and prefrontal cortex and modulation by social stress
A factor finds its target by recognizing a specific short DNA sequence in a switch. Any gene carrying that sequence can be controlled by the same factor, which is how one factor coordinates many genes. The gene encoding the factor can sit on a different chromosome from every gene it controls. A change in a cis switch affects only the gene copy on its own chromosome, while a change in a trans factor can affect every gene that factor controls.
Even so, trans effects are harder to find. In human blood cell studies, nearby cis variants affected the activity of about 3,500 genes.15PubMed Central. Cis and Trans Effects of Human Genomic Variants on Gene Expression Distant trans variants could be detected for only 48 genes.16PubMed Central. Cis and Trans Effects of Human Genomic Variants on Gene Expression Each trans variant’s effect is spread across many genes, making each effect smaller and harder to detect.
Why Cis and Trans Changes Shape Evolution and Drug Response
In yeast, deleting a trans regulator changed many more traits than deleting a cis switch for the same gene.17PubMed Central. Network Topology Can Explain Differences in Pleiotropy Between Cis- and Trans-regulatory Mutations Trans deletions also tended to be more harmful to growth.18PubMed Central. Network Topology Can Explain Differences in Pleiotropy Between Cis- and Trans-regulatory Mutations A trans regulator typically controls many genes, so changing it alters many traits at once. Among many simultaneous changes, some are likely to disrupt something important, and natural selection tends to remove them. A cis change affects one gene, so the damage is more contained and can survive across generations.
That helps explain why trans changes contribute less to expression differences as species evolve.19PubMed Central. Pleiotropic effects of trans-regulatory mutations on fitness and gene expression Cis changes allow fine adjustments, such as altering a gene’s activity in one tissue without disturbing others.
Hybrids let scientists separate the two kinds. A hybrid has one copy from each parent in the same cells, and both copies share the same trans factors. Any difference between the copies must therefore come from cis. In hybrid mice, most differences between strains in immune cells came from cis variants.20PubMed Central. Allele-specific gene expression in F1 hybrid mice reveals structural variants affecting macrophage characteristics
Both kinds matter in people. Both cis and trans variants in human livers have been linked to how much CYP2D6, a key drug-processing enzyme, is made.21PubMed Central. Novel Independent Trans- and Cis-Genetic Variants Associated with CYP2D6 Expression and Activity in Human Livers CYP2D6 handles many common drugs, including some antidepressants and painkillers, and people range from slow to very fast processors. Pharmacogenetic tests can check this, sometimes before a drug is prescribed.
Cis and Trans in RNA Splicing and Gene Memory
Genes contain coding pieces separated by filler. Cells cut out the filler and stitch the coding pieces into a message, a process called splicing. Cis-splicing does this within a single RNA copy of a gene.22PubMed Central. Evolutionary Insights into RNA trans-Splicing in Vertebrates Trans-splicing joins parts of two separate RNA molecules, often made from separate genes or places.23PubMed. Trans-splicing The result is a single message that no single stretch of DNA encodes in that order. Both depend mostly on the same cell machinery.24PubMed. Trans-splicing
For most human genes, cis-splicing is the standard way messages are assembled. Trans-splicing is routine for some genes in certain organisms but is a rarer event in humans, so a hybrid message can sometimes show up in studies of disease or unusual cells.
Memory of a gene’s state can also sit on one copy. In a plant flowering gene, one copy can stay switched off while the other stays on in the same cells.25eLife. Local chromatin environment of a Polycomb target gene instructs its own epigenetic inheritance That mixed state is passed through many cell divisions, so the memory is stored in cis.26eLife. Local chromatin environment of a Polycomb target gene instructs its own epigenetic inheritance In female mammals, the RNA Xist builds up on one X chromosome to silence it, another case of control on one copy.27Cell / Elsevier. X chromosome inactivation is mediated by Xist RNA stabilization
Other Places You Will Meet Cis and Trans
Viruses use the same logic. Hepatitis B needs a 137-letter cis sequence on its own RNA to be packaged.28PubMed Central. A short cis-acting sequence is required for hepatitis B virus pregenome encapsidation and sufficient for packaging of foreign RNA The proteins that do the packaging can be supplied in trans from a separate helper.29PubMed Central. A short cis-acting sequence is required for hepatitis B virus pregenome encapsidation and sufficient for packaging of foreign RNA Gene therapy vectors take advantage of this by splitting viral parts across separate pieces of DNA.30PubMed. Lentiviral vectors: optimization of packaging, transduction and gene expression The helper DNA in the packaging cells lacks most cis sequences, which makes the system safer because the helper genes can’t be packaged themselves.31PubMed. Regulated lentiviral packaging cell line devoid of most viral cis-acting sequences The finished particle carries the therapeutic gene and cannot make more virus, because the genes for building it were left behind.
CRISPR diagnostic enzymes cut their target in cis.32PubMed Central. Signal Amplification by the trans-Cleavage Activity of CRISPR-Cas Systems: Kinetics and Performance. Once activated, they also chop nearby unrelated RNA or DNA, called trans-cleavage, which powers rapid tests.33PubMed Central. Signal Amplification by the trans-Cleavage Activity of CRISPR-Cas Systems: Kinetics and Performance.
In proteins, cis and trans describe two shapes the amino acid proline can take, a different chemistry meaning.34Nature Chemical Biology. Prolyl cis-trans isomerization as a molecular timer Flipping between the shapes can set the pace of protein folding.35PubMed. Proline cis-trans isomerization and protein folding
Three-dimensional folding of the genome fits the same pattern. DNA spots close together along a chromosome touch far more often than spots on different chromosomes, and each chromosome occupies its own territory in the nucleus. This helps explain why cis contacts dominate.