Gene Variants and Polymorphisms: What Makes Each Person's DNA Unique

No two people—except identical twins—have exactly the same DNA sequence. Human genetic variation underlies differences in appearance, disease susceptibility, drug responses, and countless other traits. Understanding the types of genetic variants and how they are catalogued is fundamental to modern genetics and genomics.

Single Nucleotide Polymorphisms (SNPs)

Single nucleotide polymorphisms (SNPs, pronounced 'snips') are the most common type of genetic variation—a single base change at a specific position in the genome. SNPs occur approximately every 300 base pairs across the genome, and there are over 650 million known human SNPs catalogued in public databases. The vast majority of SNPs occur outside of protein-coding regions and have no known functional significance.

However, coding SNPs can alter amino acid sequences (missense variants) or introduce premature stop codons (nonsense variants). Synonymous SNPs change the DNA sequence without changing the amino acid. Regulatory SNPs in promoters or enhancers can affect gene expression levels. SNPs in splicing signals can alter mRNA processing.

Insertions and Deletions (Indels)

Insertions and deletions (indels) involve the addition or removal of one or more bases. Small indels (1-50 base pairs) in coding regions can cause frameshift mutations—shifting the reading frame so that all downstream codons are altered, typically producing a non-functional protein. Larger indels can delete entire exons or disrupt regulatory regions. Microsatellites (short tandem repeats) are highly polymorphic repeat sequences used in forensic DNA profiling and genetic linkage studies.

Copy Number Variations (CNVs)

Copy number variations involve segments of the genome (typically 1 kilobase to several megabases) that are present in different copy numbers in different individuals. CNVs affect more base pairs of the genome than SNPs in aggregate and can have significant functional consequences when they affect gene dosage. CNV databases catalog thousands of known variants, distinguishing those of uncertain significance from those associated with specific diseases or syndromes.

Structural Variations

Large-scale structural variations include inversions (segments reversed in orientation), translocations (segments moved between chromosomes), and complex rearrangements. Chromosomal structural variants can cause disease by disrupting genes at breakpoints, altering gene dosage, or disrupting regulatory element-gene interactions. Population genomics studies using long-read sequencing technologies are revealing the full extent of structural variation in the human genome.

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