Any two people differ at millions of places in their DNA. The two commonest kinds of difference, single nucleotide polymorphisms and copy number variations, compared side by side, with the other variant types and how they are used to find disease genes.
- SNPs: single-base differences, almost always biallelic, the commonest variation; only about 1% fall in coding sequence
- CNVs: segments from about 1 kb to several megabases present in different numbers of copies; about half involve coding sequence
- Scale: CNVs account for roughly 5–24 million base pairs of difference between any two people
- Use: SNPs mark disease loci through linkage disequilibrium in genome-wide association studies
- Most variants: are harmless; a few alter genes or their regulation and cause or predispose to disease
SNPs versus CNVs
| Feature | Single nucleotide polymorphisms (SNPs) | Copy number variations (CNVs) |
|---|---|---|
| What varies | One base at a single position | Number of copies of a stretch of DNA, about 1 kb to several Mb |
| Alleles | Almost always biallelic | Some biallelic (simply duplicated or deleted); others multiallelic with complex rearrangements |
| Frequency | Several million per genome; the commonest variation | Fewer events but cover more total sequence |
| Coding sequence | About 1% in coding regions | About 50% involve coding sequence |
| Sequence difference between two people | Spread across single bases | Roughly 5–24 million base pairs |
| Disease link | Mostly markers of risk; some alter protein or regulation | Linked to autism, schizophrenia and developmental disorders; gene dosage effects |
| Main detection method | SNP arrays, sequencing | Chromosomal microarray, sequencing |
Other types of variation
- Insertions and deletions (indels): a few bases added or lost; frameshifts in coding regions.
- Short tandem repeats (microsatellites): repeats of 1–6 bases used in forensic DNA profiling, chimerism testing after transplantation and microsatellite instability testing.
- Structural variants: inversions, translocations and large insertions.
- Epigenetic changes: methylation and histone modification change gene expression without changing the DNA sequence, so they are not true sequence variants.
Linkage disequilibrium and GWAS
A SNP is useful as a marker when it is inherited together with a nearby disease-causing variant more often than chance would predict: the two are in linkage disequilibrium. Genome-wide association studies (GWAS) compare SNP frequencies across hundreds of thousands of positions in people with and without a disease to find such risk regions.
A GWAS-associated SNP is usually a signpost, not the cause. It points to a region of the genome in which the causal variant, often regulatory, lies.
Practice questions
What proportion of SNPs lie in coding regions?
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A SNP that is inherited together with a nearby disease variant more often than expected by chance is said to be in:
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Which test is best for detecting copy number variations in a child with developmental delay?
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- SNPs: single-base, biallelic, commonest, about 1% coding.
- CNVs: 1 kb to Mb, biallelic or multiallelic, about 50% coding, 5–24 Mb difference between two people.
- SNPs mark disease loci through linkage disequilibrium in GWAS.
- Microarray detects CNVs; STRs are used in forensic and chimerism testing.
Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 10th ed. Elsevier; 2020 · Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine, 8th ed. Elsevier; 2016
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