HOW DOES ONE PERSON’S GENOME DIFFER FROM ANOTHER PERSON’S GENOME?
People differ from one another by several types of DNA sequence changes or “variants” (Figure a and b). Approximately 3.8 to 4 million variants, or one in every 1,200 bases, are single letter or base changes (termed single nucleotide variants, or “SNVs”). There are also about 500,000 to 850,000 small insertions and deletions of 1–100 bases (“indels”). Finally, there are also thousands of large insertions, deletions, inversions, and other types of chromosome rearrangements, some as large as several hundred kilobases (1 kilobase = 1,000 bases) in length. These are called structural variants and although fewer in number than single nucleotide variants, they affect many bases and are an important contributor to genetic diversity among individuals.
Figure . (a) Changes in our DNA called “variants” make us different from one another genetically. These differences can lead to the production of different RNAs and proteins, which make us each unique. (Note the DNA sequence is hypothetical and does not correspond to the individuals shown.) (b) There are three general types of genetic variants among people: (1) Single letter or Nucleotide Variants (SNVs), (2) Short Insertions and Deletions (Indels), and (3) Larger and more complex rearrangements called Structural Variants (SVs). These SVs can be Deletions, Insertions (I), Duplications, and Inversions. Left photo: Right image: National Institute of Human Genome Research.
Many variants appear in the genes that encode proteins. A variety of evidence suggests, however, that most differences that make people differ from one another actually occur in the sequences that regulate gene expression, rather than occurring in the actual protein-coding sequences. These variants contribute to differences among individuals in physical, personality, and disease-susceptibility traits.
With all the variation among genomes, you may be wondering why there are not more dramatic differences among individuals and not more individuals afflicted with genetic diseases. At the DNA level, the average difference between two unrelated individuals is believed to be approximately 0.1%. In a 6 billion base pair genome, this represents a substantial amount of DNA. However, not all differences in DNA sequence are functionally relevant. A variant may occur in a region of the genome that does not contain genes and does not have any critical function. Even if a variant occurs in a protein-coding gene, it may not necessarily affect the expression of that gene or the form of the protein that is produced. Furthermore, because individuals inherit DNA from both parents, for many genes there is a backup system—if the gene from the mother contains a deleterious variant, it may not have a discernible effect if the corresponding gene inherited from the father is fully functional. This backup system may not work in all cases; for example, if the product of the gene with the deleterious variant actually interferes with the activity of the “normal” gene or if proper expression of both maternal and paternal genes is required to achieve adequate gene product for normal function. Finally, if a variant has a profound adverse effect, it may interfere so severely with development that it causes fetal death and that variant, therefore, is not found in living human populations.