by Letizia Desiata
Credit: James King-Holmes/Science Photo Library
The PanGenome is described as containing 47 phased, diploid assemblies from a cohort of genetically diverse individuals [1]. Naturally this differs from the genome, the Pangenome takes into account a wider range of different genomes thus crucial in considering the variation within the population of species that occurs over time. Throughout time, evolution is inevitable and as Charles Darwin states in the origin of species “The shield may be as important for victory, as the sword or spear.”[1] The whole human population will have a diverse gene pool, and this is due to environmental factors and genetic factors that have a polygenic effect producing continuous variation (for example heights) and genetic factors solely, introducing discontinuous variation ( for example blood groups). As a whole, variation can give us genetically unique alleles within the same human species, the genes are same but the alleles differ, and this is the basis of phylogeny. Comparing base sequences (using DNA, Cytochrome C, or protein primary sequences like Albumin) between our ancestors, concludes that humans are constantly diverging from their ancestors, due to the process of natural selection which drives evolution over time. If we were to compare my DNA with my oldest ancestor we may still have some similarities in our alleles, but there would be a larger number of differences as a greater number of mutations over generations, natural selection of alleles that are more beneficial for that environment will have produced a more evolved human species, me.
Thus, only sequencing the current genome would be futile, because for the future of ecology, and microbiology the greatest necessity would be to explore types of variation that could never be examined before, such as large chunks of duplicated, lost or rearranged DNA, that could reveal more about genetic underpinnings of heart diseases, schizophrenia and various other diseases and disorders [2]. Even Though, I have undermined the sequencing of the genome, this process was nevertheless an essential prototype, as the primary sequence gives a mosaic representation of individual haplotypes containing one representative scaffold sequence for each chromosome[3].In other words, the generic genome that has been sequenced is still evidently important in propelling the production of the pangenome.
T2T-CHM13 is a complete 3.055 billion-base pair sequence of a human genome[3] removing a 20-year-old barrier that has hidden 8% of the genome from sequence-based analysis, including all centromeric regions and the entire short arms of five human chromosomes [4]. This significant milestone opened the world of biotechnology, specifically genotype-phenotype correlation, and an understanding of genetic diseases (for example, Cystic Fibrosis ,caused by a mutated faulty recessive gene that has been passed along generations) but there are still rather eminent limitation in the sector of pharmacogenomics and in personalized medicine, because a large number of individuals need to be sequenced in quick time and at an astronomically lower cost. The prohibitively high cost and time of sequencing genomes in 2001 led researchers to explore alternate scale up technologies to Sanger Sequencing, so as to bring down the cost of sequencing to an affordable one thousand dollars [5] .Essentially, the cost and time of sequencing a person's genome everytime was problematic especially when now more than ever, newly developing treatment concepts were beginning to be used globally.
For instance, the production of new organs using the same genetic information as the patient to reduce the use of immunosuppressants as the risk of rejections would be reduced to almost zero percent. Nanocarrier drug delivery (for example for the treatment of Cardiogenic Pulmonary Edema) would give us the ability of only targeting the diseased tissues therefore not compromising healthy cells, affecting the patient the least. The use of monoclonal antibodies in the role of diagnosing diseases using specific trackers , as well as also being used in radiography to deliver contrast (for example, a radioactive isotope of iodine with a short half-life is ingested and is used to monitor the efficiency of the kidneys in deamination and diagnosing the blockage of kidneys). This is where the necessity of the PanGenome becomes apparent.
The PanGenome is made up of a number of genetically diverse individuals, this is of significant importance, as to form a global representation we need a genetic representation of the world. Anonymous donors were used, making up the “1000 genome project”. Interestingly, a large number of the donors that were chosen were of African and Asian ancestry because compared to the reference genome contain the most diversity (surprisingly, the African PanGenome is 10% larger than the reference human genome). Evan Eichler proposes that because all africans hold so much diversity “all humans are descendants of
African populations, in Africa we have to do much deeper sampling before we have a true human PanGenome reference”[6]
The major goal would be to map every variation, not to map the whole 8 billion genomes. This is because we know that our genes can be split into two separate groups; the base sequence, which everyone of the human species has to obtain to be classified as a Homosapien and the polygenic parts genes where different alleles can arise, causing variation. Therefore, we would only need to sequence the parts of the genome that are uncommon, where polymorphic genes play a key role. The small differences contribute to each person’s uniqueness and can provide insights about their health, helping to diagnose disease, predict outcomes and guide medical treatments [7], which are about 1% of the actual human genome. As well as including variation, the PanGenome is advantageous due to the fact that it uses “long-read DNA sequencing”. The generic genome is created by many small parts , which create many gaps, and uncertainties, therefore, there is a great incompleteness. It is estimated that the use of short reads and reference based assembly may have resulted in non-reporting of more than 70% of the structural variations [8]
The ability to remove this genetic bias is not only the key to the future, but could also propose the ability of prediction of the genotype of future generations, so diagnosis of disease can be performed as early as possible, perhaps even before the birth of the offspring.
Citations
(1)Charles Darwin, The Origin Of Species
(2) 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 526, 68–74 (2015).[internet] [cited 19th of may 2024} available at https://www.nature.com/articles/nature15393
(3)the complete sequence of the human genome. Nurk, Sergey & Koren, Sergey & Rhie, Arang & Rautiainen, Mikko & Bzikadze, Andrey & Mikheenko, Alla & Vollger, Mitchell & Altemose, Nicolas & Uralsky, Lev & Gershman, Ariel & Aganezov, Sergey & Hoyt, Savannah & Diekhans, Mark & Logsdon, Glennis & Alonge, Michael & Antonarakis, Stylianos & Borchers, Matthew & Bouffard, Gerry & Brooks, Shelise & Phillippy, Adam. (2022). The complete sequence of a human genome. Science (New York, N.Y.). 376. 44-53. 10.1126/science.abj6987. https://www.researchgate.net/figure/Summary-of-the-complete-T2T-CHM13-human-genome-assembly_fig1_359661443
(4) Tina Hesman Saey. The new human pangenome could help unveil the biology of everyone. Science news. 9-12 (May 10, 2023)[internet][cited 19th of may 2024} available at https://www.sciencenews.org/article/new-human-pangenome-biology-dna-diversity
(4) Nurk, S. et al. The complete sequence of a human genome. Science 376, 44–53 (2022).[internet][cited 19th of may 2024} available at https://www.science.org/doi/10.1126/science.abj6987
(5) The complete sequence of a human genome. science .Vol 376, Issue 6588. pp. 44-53. (31 Mar, 2022)[internet][cited 19th of may 2024} available at https://www.science.org/doi/10.1126/science.abj6987
(6) Singh V, Pandey S, Bhardwaj A. From the reference human genome to human pangenome: Premise, promise and
challenge. Front Genet. 2022 Nov 10;13:1042550. doi: 10.3389/fgene.2022.1042550. PMID: 36437921; PMCID: PMC9684177.[internet][cited 19th of may 2024} available at https://pubmed.ncbi.nlm.nih.gov/36437921/
(7) Micheal Le Page.What is the human pangenome and why do we need it? 32-34 (10 may 2023)[internet] available at https://www.newscientist.com/article/2372915-what-is-the-human-pangenome-and-why-do-we-need-it/
(8) NIH.Scientists release a new human “pangenome” reference.14-16 (10 may 2023)[internet][cited 19th of may 2024} available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10161434/
(9) Singh V, Pandey S, Bhardwaj A. From the reference human genome to human pangenome: Premise, promise and
challenge. Front Genet. 2022 Nov 10;13:1042550. doi: 10.3389/fgene.2022.1042550. PMID: 36437921; PMCID: PMC9684177. [internet][cited 19th of may 2024} available at https://pubmed.ncbi.nlm.nih.gov/36437921/
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