Each person is born with a unique genome - even identical twins! That means we had 8 billion different genomes in the world as the population reached the milestone at the end of 2022. Although human genomes are vastly diverse, we have made enormous progress in revealing their secrets and using what we have learned to improve human health. 

A 2021 whole-genome sequencing (WGS) study of 381 pairs of identical twins amazed scientists who have long assumed that they share 100% of their DNA code because they are formed from the exact same zygote. The study uncovered >100 differences in the genomes of 39 identical twins and an average of 5 sequence differences between each pair [1]. The genetic diversity among unrelated people is far more enormous, as shown by the hundreds of millions of differences identified by the 1000 genome project, in which more than 2,500 distinct genomes from 26 populations were sequenced [2-4]. 

So what are these differences between genomes, and how do they occur? The most common genetic differences observed in these studies involve a single nucleotide mistakenly swapped for a different one, called single nucleotide polymorphisms (SNPs). The most recent estimate of the number of SNPs per genome is 3.5 million and more than 600 million SNPs have been documented in dbSNP, a free public database of SNPs [5]. Half of the known SNPs that are associated with genetic diseases such as cancer, diabetes and obesity are a result of spontaneous conversion of one nucleotide to another that is catalyzed by a class of enzymes called deaminases [6]. Usefully, scientists have found ways to hijack these nucleotide “editors” to perform single nucleotide substitution in human cells as a new promising genetic tool for biomedical research and gene therapy [7]. 

Structural variants (SVs), the second type of commonly observed genetic differences, involve changes to a region of DNA> 1000 nucleotides in size, and include deletions, insertions, duplications, and inversions. A recent WGS study of 602 father-mother-child trios discovered >173,000 SVs [8], while another much larger study using the sequences of 150,119 genomes in the UK Biobank documented >895,000 SVs [9]. These SVs occur due to faulty repair during DNA replication [10]. SVs can influence cancer cell fitness by affecting the 3D folding of the DNA, with consequences that are much greater than those of SNPs [11]. 

The more we learn about the variations in human genomes, the more we could benefit humanity using this knowledge. One of the most important advances in genome research is the identification of thousands of genetic variants linked to the risk of human diseases using genome-wide association studies (GWAS). Using WGS data of 392,814 UK Biobank participants, scientists recently identified 975 associations between genetic variations and 744 diseases [12] . These associations can help explain disease mechanisms, identify genetic predictors of disease, select effective treatments, and find individuals at risk for more severe forms of a disease.  

Let me give you two examples. Many research studies have shown that genetic sequencing is a powerful tool to identify cancer patients who benefit from new “targeted therapies'' designed to combat cancer cells that have certain genetic mutations. This new treatment paradigm, known as precision oncology, makes it possible to “deliver the right drug, to the right patient and at the right time" [13]. More and more, genetic sequencing of cancer tissues, and even cancer DNA found in the blood, are becoming standard medical tests, especially with the significant decline of WGS cost and turnaround time [14]. In cases when genetic changes predict the severity of the disease, scientists could apply that information to choose treatments that are tailored to the patients. For example, variations in genes on chromosome 3 lead to a nearly 2-fold higher risk of respiratory failure in COVID-19 patients, while genetic differences on chromosome 12 confer a 22% reduction in the risk of becoming severely ill with COVID-19 [15]. Discoveries like these could help doctors select which patients need more aggressive treatments depending on their risk of developing severe symptoms. 

New applications of genetic sequencing are constantly being developed. For example, the success of precision oncology has encouraged a similar paradigm shift for treating other diseases such as Alzheimer’s [16]. Researchers are also exploring the utility of WGS in precision nutrition, that is, to inform personally tailored nutritional recommendations [17]. It is safe to say, genome research will continue to make a positive impact on our lives in many years to come.

1. Jonsson, H. et al. Differences between germline genomes of monozygotic twins. Nature Genetics 53, 27-34 (2021).

2. Genomes Project, C. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061-1073 (2010).

3. Genomes Project, C. et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56-65 (2012).

4. Sudmant, P.H. et al. An integrated map of structural variation in 2,504 human genomes. Nature 526, 75-81 (2015).

5. Lappalainen, T., Scott, A.J., Brandt, M. & Hall, I.M. Genomic Analysis in the Age of Human Genome Sequencing. Cell 177, 70-84 (2019).

6. Gaudelli, N.M. et al. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature 551, 464-471 (2017).

7. Tang, J., Lee, T. & Sun, T. Single-nucleotide editing: From principle, optimization to application. Human mutation 40, 2171-2183 (2019).

8. Byrska-Bishop, M. et al. High-coverage whole-genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios. Cell 185, 3426-3440.e19 (2022).

9. Halldorsson, B.V. et al. The sequences of 150,119 genomes in the UK Biobank. Nature 607, 732-740 (2022).

10. Beck, C.R. et al. Megabase Length Hypermutation Accompanies Human Structural Variation at 17p11.2. Cell 176, 1310-1324.e10 (2019).

11. Dubois, F., Sidiropoulos, N., Weischenfeldt, J. & Beroukhim, R. Structural variations in cancer and the 3D genome. Nat Rev Cancer 22, 533-546 (2022).

12. Sun, B.B. et al. Genetic associations of protein-coding variants in human disease. Nature 603, 95-102 (2022).

13. DasGupta, R., Yap, A., Yaqing, E.Y. & Chia, S. Evolution of precision oncology-guided treatment paradigms. WIREs Mech Dis 15, e1585 (2023).

14. Meggendorfer, M. et al. Analytical demands to use whole-genome sequencing in precision oncology. Semin Cancer Biol 84, 16-22 (2022).

15. Ellinghaus, D. et al. Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N Engl J Med 383, 1522-1534 (2020).

16. Hampel, H. et al. The foundation and architecture of precision medicine in neurology and psychiatry. Trends Neurosci 46, 176-198 (2023).

17. Mullins, V.A., Bresette, W., Johnstone, L., Hallmark, B. & Chilton, F.H. Genomics in Personalized Nutrition: Can You "Eat for Your Genes"? Nutrients 12(2020).