Written and maintained by CASRAI Editorial Board
Last updated
Positional cloning is a laboratory approach used to locate a disease-associated gene by its position on a chromosome, rather than by what its protein does. The NHGRI glossary notes that the strategy can succeed even when nothing is known about the role of the gene’s encoded protein in the disease.
Definition and scope
The National Human Genome Research Institute (NHGRI) Talking Glossary defines positional cloning as a laboratory approach used to locate the position of a disease-associated gene on a chromosome. The term dates to the late 1980s and was developed for diseases such as cystic fibrosis, where the function of the gene was unknown when the search began (NHGRI Talking Glossary, checked 2026-10-29).
The idea is a change of starting point. Instead of asking which protein is abnormal and then finding its gene, the investigator asks where in the genome the disease travels with the inheritance of a known landmark, and then works inward to the gene at that location. Related background on how genes and inheritance are studied is in what is genetics, and the bench basics of isolating and propagating DNA fragments are covered in gene cloning.
How it is used in practice
According to NHGRI, positional cloning typically relies on known polymorphic markers whose inheritance can be traced through members of affected families. Two ingredients therefore matter at the outset:
- Polymorphic markers: known DNA variants at defined positions that differ between individuals, which can serve as landmarks along a chromosome.
- Affected families: pedigrees in which the marker alleles that members inherit can be compared with who has the disease.
The position narrows from a chromosome region toward a candidate gene, and the candidate is then examined for differences in affected people. The cystic fibrosis example below shows what that looked like in a real, published study.
Positional cloning vs functional cloning
NHGRI contrasts positional cloning with functional cloning, in which a gene is found by understanding something about its function. The practical difference is the starting knowledge.
| Question to ask | Positional cloning | Functional cloning |
|---|---|---|
| What do you start from? | The chromosomal position of the disease, inferred from marker inheritance in families | Something known about the gene’s function |
| Must the protein’s role be known? | No. It can succeed when nothing is known about the encoded protein’s role | Yes, some understanding of function is the entry point |
| What evidence leads to the gene? | Polymorphic markers traced through affected family members | Knowledge of the gene’s function |
NHGRI’s example of functional cloning is the hemophilia gene, found by knowing there was a problem with a blood clotting factor and then working out which gene must encode it. For most diseases that kind of functional clue is missing, which is why positional cloning came into being, with cystic fibrosis as the motivating case.
Worked example: the cystic fibrosis gene (1989)
The gene mutated in cystic fibrosis is the classic case. Riordan, Rommens, Kerem and colleagues reported its identification in Science on 8 September 1989 (volume 245, issue 4922, pages 1066-1073; DOI 10.1126/science.2475911; PubMed 2475911, checked 2026-10-29). What the abstract reports:
- Overlapping complementary DNA (cDNA) clones were isolated from epithelial cell libraries, starting from a genomic segment from the putative cystic fibrosis locus on chromosome 7.
- The transcripts were about 6,500 nucleotides long and were detectable in tissues affected in cystic fibrosis.
- The predicted protein has two motifs, each with a membrane-associated domain and an ATP-binding domain.
- A three-base-pair deletion that removes a phenylalanine in the first nucleotide-binding domain was found in patients.
The sequence of the work runs from a chromosomal locus, to cDNA clones from that region, to a difference found in affected people. That order is the signature of the positional approach.
Where it matters for labs and clinics
Positional cloning is a part of how the field reached disease genes before function was understood, and it explains the vocabulary found in older genetics literature. For laboratory staff, the practical connection is to routine molecular biology work such as DNA extraction and plasmid design, and to the wider molecular biology toolkit. This page does not give procedural instructions.
Common misunderstandings
- It is not the same as gene cloning in a vector. The name refers to finding a gene by its location; making copies of a DNA fragment is a separate laboratory topic.
- It does not require knowing the protein. That is its defining advantage according to NHGRI, as opposed to functional cloning.
- It is not tied to a single disease. Cystic fibrosis is the example NHGRI cites for why it was developed, not a limit on its use.
FAQ
What is positional cloning?
A laboratory approach used to locate the position of a disease-associated gene on a chromosome, often using polymorphic markers traced through affected families.
When was the term introduced?
NHGRI places the term in the late 1980s.
How is it different from functional cloning?
Functional cloning finds a gene by understanding something about its function; positional cloning works from chromosomal location and does not need the protein’s role to be known.
Sources
- NHGRI Talking Glossary, Positional Cloning: https://www.genome.gov/genetics-glossary/Positional-Cloning (checked 2026-10-29)
- Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245(4922):1066-1073. https://pubmed.ncbi.nlm.nih.gov/2475911/ (checked 2026-10-29)
