Copy number and loss of heterozygosity (LOH)

In one sentence

Copy number counts copies of a genetic region, while loss of heterozygosity means a cell population no longer retains both previously distinguishable sequence versions.

The intuition

Imagine a shelf containing two editions of a book. Counting books tells you how many copies exist; checking editions tells you whether both versions remain. Two books can be two different editions or two copies of one edition. The analogy cannot tell you whether either edition works: DNA count and sequence-version identity are separate from biological function.

How it works

An allele is a sequence version. At an informative location, a normal sample might carry distinguishable versions A and B. Total copy number counts the region's copies; allele-specific copy number estimates the contributions of its distinguishable versions.

The following states describe an idealized, uniform cancer-cell population at that region. A and B are arbitrary version labels, not known functional states.

Copies of A and B	Total copies	Interpretation
1 + 1	2	Both versions retained, ordinary diploid state
1 + 0	1	Deletion with loss of heterozygosity (LOH)
2 + 0	2	Copy-neutral LOH: two copies, but only one original version
2 + 1	3	Copy gain with both versions retained

Thus LOH is not synonymous with deletion. Copy-neutral LOH can follow loss of one version and duplication of the other, or recombination-related events. Conversely, a total-copy gain does not necessarily erase either version. Allele-aware primary methods distinguish these states. Shen and Seshan 2016.

Reports often use major and minor copy counts: the larger and smaller estimated allelic contributions. A minor count of zero supports an LOH state under that model. Those labels do not automatically identify maternal or paternal origin, or assign a particular mutation to a copy. Phasing asks which sequence changes lie on the same chromosome copy and needs suitable evidence.

Local copy count differs from ploidy, the average genome-copy context. Tumor and normal cells also mix. Relative signal alone can fit different purity-and-ploidy combinations; apparent fractional counts may reflect mixture or subclonal states rather than a fraction of a chromosome in every cell. Carter 2012.

How it is measured

Allele-aware methods combine relative DNA (deoxyribonucleic acid) coverage with the balance at informative heterozygous sites, group the genome into segments and fit copy states. A suitable matched normal helps identify original versions and control measurement biases. A total-copy profile alone cannot distinguish 1 + 1 from 2 + 0. If both normal copies have the same sequence at a site, that site alone is uninformative for version loss.

Why it matters in cancer

Copy changes can influence gene dosage and the variant allele fraction. LOH can remove a functional version while retaining an altered one, but the copy call does not establish which version remains or whether useful ribonucleic acid (RNA) or protein survives. Copy gain is not automatically increased expression, dependency or a drug-response prediction.

Assay card

Field	What to retain
Measures and method	Relative coverage and allelic balance, segmented and modeled into copy states
Input and tissue cost	Tumor DNA and, where required, suitable normal DNA; extraction consumes an aliquot. Adequate existing data can be reanalyzed without new tissue
Output and units	Total/major/minor copies, segments, LOH calls, purity/ploidy fits and uncertainty
Thresholds	Caller-specific informative-site, depth, segmentation and fit criteria; no universal amplification or functional-loss cutoff
Failure modes	Low tumor content, few informative sites, mapping or capture biases and multiple plausible copy fits
Limits and validation	Research-method validation does not automatically validate every clinical assay. Copy states do not establish phase, current protein function or treatment benefit

Common confusions

Two copies versus two versions: copy-neutral LOH retains the count while losing diversity.
LOH versus gene shutdown: the retained version may still function; sequence and downstream evidence matter.
One segment versus every cell: a bulk-sample fit can conceal subpopulations and unsampled lesions.

Try it

A fictional normal sample has A and B. An adequate allele-aware tumor model supports two A copies and no B copies. Has the gene been deleted or proven inactive?

Answer: Neither. This is copy-neutral LOH under the model. The region still has two copies. Identify the retained sequence and test any proposed functional consequence separately.

Explain it back

“Total copies tell me ______; allele-specific copies add ______; function still requires ______.”

One answer: “how many; which versions remain; appropriate sequence, expression or functional evidence.”

Takeaway

Count copies, identify versions and test function as three distinct questions.

Alleles and zygosity: version identity and combinations.
Genomic scars: historical chromosome patterns and method-specific scores.
Human leukocyte antigen (HLA) loss of heterozygosity: a specialized antigen-presentation locus question.

Sources and scope

Source check: October 10, 2026. General copy-state education; examples are fictional. Expert and learner review remain pending. No gene-function or treatment-sensitivity conclusion is inferred.