1st Place: Jennifer Zhong, Grade 12
Teacher: Ms. Maria Zeitlin
School: Smithtown High School East
Location: Saint James, New York
“One humanity, many genomes” captures the essence of the human species. While we are all united under a shared genetic structure, our remarkably diverse genomes greatly impact our lives, allowing us to become phenotypically different as well as have different predispositions to disease. Genetically, all humans are approximately 99.9% the same. However, that small 0.1% difference in genome makes each of us so uniquely individual .
Human genetic variation can occur in many different ways. One of the most common are single nucleotide polymorphisms (SNPs), variations in DNA sequences that involve a change in only a single nucleotide . With approximately 11 million SNPs in the human genome, over 7 million occur with a minor allele frequency, a percentage based on the occurrence in a population of the second most common allele, of more than 5% . SNPs can cause great changes to our overall genetic makeup with approximately 1 nucleotide change occurring for every 400 . Additionally, copy number variants (CNVs), alterations in wider DNA regions, can change genes both at DNA transcription levels and through the translation of RNA, allowing for more diverse phenotypes. However, these genomic changes may cause simple monogenic diseases and contribute to polygenic diseases .
Human genetic information can also be encoded by epigenetic changes to chromatin structure such as DNA methylation, changes to proteins that bind DNA together, and modification of molecules that affect chromatin [2, 3]. In order to understand how human genetic variation contributes to phenotype, it is necessary to consider geneenvironment interactions that also regulate gene expression. For example, folate deficiency has been shown to affect placental development and DNA methylation in the fetus leading to growth deficits and neural tube defects cementing the importance of prenatal nutrition . Epigenetics has also been linked to microRNAs, non-coding RNA molecules that are involved in gene expression regulation, which have been expressed in certain cancers .
In recent years, well over 3000 genome-wide association studies (GWAS) have been published. This has widened the understanding of the human genome leading to new insight into the genetic etiology of complex diseases. By combining genetic and phenotypic data with gene-based designer drug availability, diseases can be more easily predicted [1, 9]. GWAS has helped identify approximately 10,000 strong associations between genes and complex traits which helps to explain the role of certain genes as well as environmental factors which can aid in risk prediction and personalized medicine, a field in which therapeutics are specifically targeted toward an individual’s genomic needs [8, 10]. By estimating the effects of SNPs at many different loci, a polygenic risk score can be formulated to make disease predictions . This has allowed for the discovery of more than 100 risk loci for schizophrenia, autism, and other conditions where the DRD2 locus has been shown to contain genes relevant to the etiology of schizophrenia . Hundreds of additional genomic areas have been statistically associated with complex traits which have increased the knowledge of molecular mechanisms and pathways associated with diseases . Specifically, in order to further understand cardiovascular disease, it is crucial to correlate symptoms and phenotypes that are important indicators such as heart failure, myocardial infarction, and stroke with specific genetic variations .
To translate genomic knowledge from GWAS to future research and treatment, it is important to identify shared genetic variants that are deleterious . Currently, due to increases in genomic research, many therapeutic targets have been identified and associated with cardiovascular disease . Pharmaceuticals including Warfarin, a common anticoagulant, and Statin, a preventative medication, have been closely associated with certain genes to better prescribe medications and dosages catered to an individual’s genome . Nucleic acid-based therapies have also been widely developed. Patients who received the siRNA drug Inclisiran were found to have lower low-density lipoprotein cholesterol (LDL-C) levels by targeting PCSK9, a gene important for bloodstream cholesterol levels, indicating that these treatments have been highly effective . In addition, genomic studies have allowed for the development of other RNA-targeted therapies, microRNA and epigenetic therapy, and genome editing with CRISPR which hold the potential to further advance personalized medicine .
As human genomic research continues, advances in understanding genomes have allowed us to research disease pathologies and develop better treatments. Although humans have many genomic differences, we are all united to further our understanding of how these differences can impact our lives. By learning more about genetic variation and epigenetics, we can advance personalized healthcare and medicine for people across the world.
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2nd Place: Bolin Miao, Grade 10
Teacher: Ms. Mary Frances Hanover
School: Dana Hall School
Location: Wellesley, Massachusetts
Between 200,000 and 60,000 years ago, humans dispersed from Africa to the rest of the world (1). Adapting to various environments, human genomes, the complete set of genetic instructions that make us who we are, have been shaped over time by a complex interplay of biological and environmental factors. In a study of 929 genomes from 54 geographically diverse human populations, 67.3 million single-nucleotide polymorphisms (SNPs) , 8.8 million small insertions or deletions (indels), and 40,736 copy number variants (CNVs) were identified (2). Compared to the 3 billion nucleotides present in the human genome, these variations are only a few. Statistically, due to common ancestry, only 0.1% of DNA varies between individuals (3). However, these differences, which arise from mutations over the course of human evolution, contribute to our distinct individual features and lineage.
Certain genomic variations became prevalent in particular populations due to the evolutionary advantage they offered. In regions of Africa where malaria was common, the sickle hemoglobin mutation became widely present, as people with sickle cell anemia are more likely to survive and reproduce. People living in high altitudes – Tibetans, along with Andeans and Ethiopians – have been found to possess the HIF2A gene and PHD2 gene, which orchestrates the transcriptional response to hypoxia (4). Skin color is another typical example: lighter complexion facilitates the production of more vitamin D, which prevents diseases like rickets in climates further away from the sun; by contrast, pigments in the skin can protect the skin from sun damage and skin cancer in areas exposed to sunshine (5). Considering this, race has no biological basis and its role as a justification for persecution and discrimination is flawed (1). In parts of the Middle East and Europe where animal husbandry is developed, changes in the lactase gene (LCT) allow people to continue producing lactase after entering adulthood, enabling them to drink milk without diarrhea and flatulence, which many East Asians experience (6). These changes in genomes were passed down through generations, contributing to distinct genomes in different regions.
Besides passive environmental selection, individual habits, including nutrient intake and exercise, also make our genome unique by altering gene expression through epigenetics. A recent analysis showed that endurance exercise training can lead to differentially expressed genes by regulating transcription factors, resulting in the transcriptional activation of specific genes related to phenotypic changes, including body weight loss and aerobic capacity increase (7). A mother’s diet can also shape the epigenome of the offspring: diets with different methyl dosages during pregnancy can lead to distinct DNA methylation in the fetus’s genome (8). Due to the uniqueness of personal habits, our epigenomes are also special.
The benefit of understanding our genome is immense. Genomes influence our appearance, susceptibility to disease, metabolism of drugs, and even our cognitive abilities (9). Through addressing these differences, we can explore the full potential of genomics since everyone can benefit from it. Prior research about the human genome was mainly based on European lineage, and it appears limited as people start to recognize the importance of human genome diversity in understanding ourselves. Scientists thus carried out various projects, including the Human Genome Diversity Program (HGDP), the 1000 Genomes Project, and the HapMap Project. Genome-Wide Association Studies (GWAS) relate genomes to disease susceptibility, which enables us to predict individual disease risk (10). These personal identifications of susceptibility could be expected to result in the uptake of more effective monitoring and preventive actions, decreasing the chance of illness. Moreover, the booming industry of precision medicine is made possible by the understanding of our genome and offers innovative, targeted solutions for disease treatment. Clinicians already started using whole-genome analysis to identify causative genes for rare diseases and to determine the most appropriate treatment approaches for some cancers (11). In the future, tailoring medications with people’s genomes will revolutionize the healthcare industry by replacing conventional symptomatic treatment (12). In addition to medical treatments, genomics has large-scale applicability to other areas, including but not limited to ancestry testing and personalizing healthy diets.
It is crucial for people to keep the idea of “One Humanity, Different Genomes” in mind. Our differences are derived from common humanity and should serve the development of the whole. This idea is a call to celebrate our commonalities as human beings while also embracing our differences. Genomic studies should bring us closer, allowing us to pay more attention to every member of the community and commit to our common future.
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- Jorde, Lynn B., and Stephen P. Wooding. “Genetic Variation, Classification and ‘race.'” PubMed, Nov. 2004, pubmed.ncbi.nlm.nih.gov/15508000/. Accessed 5 Mar. 2023.
- Bigham, Abigail W., and Frank S. Lee. “Human High-altitude Adaptation: Forward Genetics Meets the HIF Pathway.” Genes Dev. Pubmed, https://doi.org/10.1101/gad.250167.114.
- Feng, Yuanqing, et al. “Evolutionary Genetics of Skin Pigmentation in African Populations.” Human Molecular Genetics, vol. 30, no. R1, 1 Mar. 2021. Oxford Academic, https://doi.org/10.1093/hmg/ddab007.
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- Smith, Gregory R. “Multiomic Identification of Key Transcriptional Regulatory Programs during Endurance Exercise Training.” Pubmed, 12 Jan. 2023, pubmed.ncbi.nlm.nih.gov/36711841/.
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- Ahmed, Zeeshan, et al. “Human Gene and Disease Associations for Clinical‐Genomics and Precision Medicine Research.” Clin Transl Med., winter 2020. Pubmed, https://doi.org/10.1002/ctm2.28.
3rd Place: Olivia Park, Grade 12
Teacher: Ms. Cindy Law
School: William Lyon Mackenzie C.I.
Location: Toronto, Canada
Have you ever stopped to consider just how unique your genetic makeup is? While we may share a genome that is 99.9% identical at base-pair, that 0.1% holds a vast array of differences that make each of us truly one of a kind (National Human Genome Research Institute, 2018). From our unique physical and biological traits, our genomes are a complex tapestry that plays a crucial role in determining who we are. This highlights the significance of the theme “One Humanity, Many Genomes.” Additionally, this essay will explore traits that make our genomes unique and explain how further advances in understanding our genomes will impact our lives in current and future research in medical treatments.
The first trait that determines the uniqueness of our genomes is single nucleotide polymorphisms (SNPs). SNPs are the most common type of genetic variation among people and occur when another nucleotide in the DNA sequence replaces a single nucleotide. These variations happen within coding and non-coding regions of our DNA, resulting in gene expressions and functions being affected. Studies have shown that SNPs impact our susceptibility to diseases, response to drugs, and physical traits. This is evident in the ongoing research of identifying SNPs association with medical conditions such as heart diseases (National Library of Medicine, 2022).
The second trait that determines the uniqueness of our genomes is copy number variations (CNVs). CNVs have a varying number of specific segment DNA copies among individuals’ genomes and these variations can involve a deletion or duplication of genetic material that can differ from hundreds to millions of base pairs. They play a crucial role in the uniqueness of our genomes because they contribute to variations in gene expression, which in turn influence our traits and predispositions to certain diseases and are associated with several genetic disorders, including autism, schizophrenia, and intellectual disabilities (National Human Genome Research Institute, 2023). For instance, a deletion of a segment of DNA containing the lactase gene leads to lactose intolerance. In contrast, duplications of the amylase gene that produce more amylase enzymes increase the ability to digest starchy foods (Gao et al., 2017).
The profound impact of understanding our genomes can be observed in various aspects of our lives, one of the most significant advances being the development of personalized medicine. Since personalized medicine is the process of tailoring medical treatment to suit an individual’s genetic information, it leads to greater health outcomes with reduced side effects. As an example, genetic research on the CYP2C19 gene metabolizes certain medications after analyzing specific SNPs: allowing physicians to determine the most effective treatment for individuals (Lee, 2012). Cancer research has also been influenced by an advanced understanding of genome sequences. Cancer is a disease caused by genetic mutations, and understanding these mutations is essential for developing personalized treatments that target specific genetic mutations that have been identified from genome sequencing (National Cancer Institute, 2021). For example, drugs like Herceptin and Gleevec target specific genetic mutations found in certain types of breast and blood cancer, resulting in improved survival rates (National Cancer Institute, 2018). A final example of an area where understanding our genomes has had a significant impact is in the field of genetic testing. Genetic testing involves analyzing an individual’s DNA to identify genetic variations that may be associated with certain diseases or conditions. Furthermore, this information can help individuals make informed decisions about their health. For example, if there is a family history of breast cancer, an individual may choose to undergo genetic testing to determine if they have inherited the mutation that increases their risk of developing breast cancer. With the given information, the individual can proceed to take the measures they see fit to reduce the risk of developing breast cancer (Centers for Disease Control and Prevention, 2022).
Overall, “One Humanity, Many Genomes” emphasizes the diversity and uniqueness of our genetic information. Traits such as SNP and CNV are used to convey the immense difference 0.1% has on our genomes and how it is reflected in our physical traits, gene structure, and gene regulation. Furthermore, an advanced understanding of our genomes has the potential to help improve health outcomes and effective medical treatments while highlighting the importance of continuous research on the human genome.
Centers for Disease Control and Prevention. (2022, June 24). Genetic Testing | CDC. Genomics & Precision Health. Retrieved February 24, 2023, from https://www.cdc.gov/genomics/gtesting/genetic_testing.htm
Gao, Y., Jiang, J., Yang, S., Hou, Y., Liu, G. E., Zhang, S., Zhang, Q., & Sun, D. (2017, March 29). CNV discovery for milk composition traits in dairy cattle using whole genome resequencing – BMC Genomics. BMC Genomics. Retrieved February 24, 2023, from https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-017-3636-3
Lee, J. (2012, December 20). Clinical Application of CYP2C19 Pharmacogenetics Toward More Personalized Medicine. Frontiers. Retrieved February 24, 2023, from https://www.frontiersin.org/articles/10.3389/fgene.2012.00318/full
National Cancer Institute. (2018, April 11). How Gleevec Transformed Leukemia Treatment – NCI. National Cancer Institute. Retrieved February 24, 2023, from https://www.cancer.gov/research/progress/discovery/gleevec
National Cancer Institute. (2021, October 11). What Is Cancer? – NCI. National Cancer Institute. Retrieved February 24, 2023, from https://www.cancer.gov/about-cancer/understanding/what-is-cancer
National Human Genome Research Institute. (2018, April 6). Human Genomic Variation. National Human Genome Research Institute. Retrieved February 24, 2023, from https://www.genome.gov/dna-day/15-ways/human-genomicvariation
National Human Genome Research Institute. (2023, February 23). Copy Number Variation (CNV). National Human Genome Research Institute. Retrieved February 24, 2023, from https://www.genome.gov/genetics-glossary/CopyNumber-Variation
National Library of Medicine. (2022, March 22). What are single nucleotide polymorphisms (SNPs)? MedlinePlus. Retrieved February 24, 2023, from https://medlineplus.gov/genetics/understanding/genomicresearch/snp/
Teacher: Ms. Dameli Oralovna
Humanity is incredibly diverse, and our genomes reflect that diversity. Although we share many similarities in our genetic code, there are also significant differences that make each of us unique. In this essay, we will look at what makes our genomes unique, and how advances in understanding our genomes affect our lives.
The first example of what makes our genomes unique is genetic variations. There are many types of genetic variations, including single nucleotide polymorphisms (SNPs), insertions, deletions, and structural variants. These variations can occur throughout the genome and can affect many aspects of human biology, including how we respond to drugs, our susceptibility to diseases, and even our physical traits . For example, the gene encoding the protein beta-globin is located on chromosome 11, and mutations in this gene can cause sickle cell disease. One of the most well-known mutations that cause sickle cell disease is a single nucleotide substitution in the beta-globin gene, resulting in the production of an abnormal form of hemoglobin. This abnormal hemoglobin leads to the characteristic sickle-shaped red blood cells, which can cause a wide range of health problems, including severe pain, organ damage, and increased risk of infections.
Another example of genetic variation is the HLA genes, which play a crucial role in the immune system. There are many different versions of the HLA genes, and these versions can affect how well the immune system can recognize and respond to pathogens. Сertain versions of the HLA genes are associated with an increased risk of developing autoimmune diseases like type 1 diabetes, while other versions may confer protection against certain infections .
The second example of what makes our genomes unique is epigenetics. Epigenetic modifications are chemical changes to the DNA molecule or the proteins that interact with DNA, which can affect how genes are expressed. These modifications can occur in response to environmental factors such as diet, stress, and exposure to toxins, and can be passed down from one generation to the next. One well-known example of epigenetic modifications is DNA methylation. DNA methylation involves the addition of a methyl group to a cytosine nucleotide, which can silence gene expression. DNA methylation patterns can be influenced by environmental factors such as diet, and changes in DNA methylation have been associated with a wide range of diseases, including cancer and neurodegenerative disorders .
Advances in understanding our genomes have already had a significant impact on our lives, and they will continue to do so in the future. One area where genomic research has had a profound impact is in personalized medicine. Personalized medicine involves tailoring medical treatments to the individual based on their unique genetic makeup. Сertain genetic variations can affect how well a patient responds to a particular drug. By identifying these genetic variations, doctors can prescribe the most effective treatment for each patient, potentially reducing side effects and improving outcomes.
Genomic research has also led to the development of new treatments for diseases. For example, targeted therapies that specifically target the genetic mutations driving cancer growth have revolutionized cancer treatment in recent years. By targeting specific genetic mutations, these therapies can be more effective and have fewer side effects than traditional chemotherapy .
In the future, advances in understanding our genomes are likely to lead to even more personalized and effective treatments. Gene editing technologies like CRISPR/Cas9 have the potential to correct genetic mutations that cause diseases. While this technology is still in its early stages, it has already shown promise in treating genetic disorders like sickle cell disease.
In conclusion, while we are all part of the same humanity, our genomes reflect the incredible diversity of our species. Genetic variations and epigenetic modifications make each of us unique, and advances in genomic research are providing new insights into the ways in which our genomes influence our health and wellbeing. From personalized medicine to gene editing, these advances offer exciting possibilities for improving our lives and tackling some of the most challenging diseases we face .
- “The Human Genome Project: A Brief Overview” by Francis S. Collins and Eric D. Green (Nature, 2001) https://www.nature.com/articles/35057062
- “Genetic Variations and Their Role in Human Disease” by Daniel J. Rader and Sekar Kathiresan (Nature, 2008) https://www.nature.com/articles/nature06801
- “Genome-Wide Association Studies and Human Disease,” by Mark I. McCarthy and Andrew P. Morris (Nature Reviews Genetics, 2011) https://www.nature.com/articles/nrg2882
- “The Human Genome in Health and Disease” by David B. Goldstein (Annual Review of Medicine, 2012) https://www.annualreviews.org/doi/abs/10.1146/annurev-med-041010-162003
- “The Genomic Landscape of Human Diversity” by Carlos D. Bustamante et al. (Nature, 2011) https://www.nature.com/articles/nature10644
Teacher: Mr. Jesse Klingebiel
With the complete sequencing of the human genome in 2022, modern science established an extensive basis for the genetics of human biology . Our genetic similarities and differences give rise to both the collective features of humankind and the unique attributes of each individual, creating the biological foundation of a diverse yet unified humanity. This invites human biology research to treat different genetic backgrounds unbiasedly while still taking genetic variations into account.
Certain portions of the human genome are distinct to humankind and may account for Homo sapiens’ ability to thrive compared to our ancestral relatives. These sequences shed light on arguably our most salient organ—the brain—and the medical implications of its complexity. Recent research revealed that only 1.5 to 7 percent of our genome distinguishes us from archaic hominins most closely related to H. sapiens. These regions are highly enriched for genes associated with neurodevelopment and brain functions , consistent with the human-specific genes’ involvement in neocortex expansion . One notable locus in the human genome is chromosome 1q21.1, which contains abundant human-specific segmental duplications [4, 5]. Intriguingly, deletions of duplications occurring at 1q21.1 have been associated with language impairment and schizophrenia, which are rarely, if ever, diagnosed in non-human species [4, 6].
Another signature component of the human genome is the human accelerated regions (HARs)—evolutionarily conserved sequences that exhibit elevated frequency of nucleotide changes in humans . Most HARs are regulatory enhancers enriched for neurodevelopment; therefore, these sequences may contribute to the human brain’s complex architecture by producing differential transcriptional patterns. Albeit limited, the knowledge about chromosome 1q21.1, HARs, and other uniquely human genomic features indicates that human-specific genes may underlie the cognitive capabilities that enable humanity to flourish. Furthermore, the study of these genomic regions provides key psychiatric insights. Through enrichment analyses of HARs in schizophrenia-related loci, researchers are uncovering the genetic roots and evolutionary trajectories of schizophrenia . Current discoveries support the hypothesis that certain human-specific mental disorders arose as byproducts of a more intricate brain structure, allowing researchers to better understand the intricate pathogenesis of psychiatric disorders unique to humankind .
While the shared portions of the human genome outline a collective humanity, variations in DNA and transcriptomic profiles define each person’s individuality. On a grand scheme, humans exhibit relatively low intraspecific genetic diversity: about 99.6 percent of the human genome is identical . Nonetheless, 0.4 percent of genetic variations still have significant medical and social implications.
The inclusion of human genetic variations is pivotal for pathological studies. Presently, over 80 percent of datasets used for biomedical research are from individuals of European descent . The heterogeneity of human genomes frequently results in varying manifestations of and susceptibility toward certain genetic diseases; therefore, selection bias prohibits scholars from drawing valid inferences applicable to other populations. Furthermore, since research primarily characterizes disease-causing genetic variants in Europeans, causative mutations in other populations may be overshadowed. This lack of genetic diversity fails to address allelic heterogeneity in Mendelian diseases. For instance, the prevalent allele that causes cystic fibrosis (CF) varies between Europeans and African Americans [12, 13]. Since research refers to the pathogenic allele in Europeans when examining the treatments and diagnostics of CF, it overlooks the underserved African American patients.
The problem likewise exists on the broader genomic level. Genome-wide association study (GWAS)—a common approach for identifying genetic markers associated with diseases—has serious flaws in its current implementation. As of 2018, individuals of African and Hispanic ancestry were featured in only nine percent and five percent of studies, respectively; meanwhile, 52 percent of studies include those of European ancestry . Since genetic associations may not be transethnic, differences in genetic background can affect the efficacy and safety of certain drugs considerably . Hence, inadequate information and deficient representation in biomedical research result in health inequality, wherein understudied groups do not receive appropriate diagnosis and treatment. Despite the homogeneity in individual human genomes, biomedical research must heed genetic diversity in order to advance in an inclusive, holistic manner.
The uniquely human genomic segments shared by humankind endow us with the cognitive power to raise humanity to its present robustness. Simultaneously, genetic variations among individuals build a diverse array of human characteristics, creating a rich mosaic of our society. New research enhances our understanding of psychiatric disorders and accentuates the importance of diversity and inclusion in genetic research for biomedical treatments. While one collective humanity connects us all, genetic diversity characterizes our individuality, both in the social and biological context.
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- Schaefer, N. K., Shapiro, B., & Green, R. E. (2021). An ancestral recombination graph of human, Neanderthal, and Denisovan genomes. Science advances, 7(29), eabc0776. https://doi.org/10.1126/sciadv.abc0776
- Florio, M., Heide, M., Pinson, A., Brandl, H., Albert, M., Winkler, S., Wimberger, P., Huttner, W. B., & Hiller, M. (2018). Evolution and cell-type specificity of human-specific genes preferentially expressed in progenitors of fetal neocortex. eLife, 7, e32332. https://doi.org/10.7554/eLife.32332
- Benítez-Burraco, A., Barcos-Martínez, M., Espejo-Portero, I., Fernández-Urquiza, M., Torres-Ruiz, R., RodríguezPerales, S., & Jiménez-Romero, M. S. (2018). Narrowing the Genetic Causes of Language Dysfunction in the 1q21.1 Microduplication Syndrome. Frontiers in Pediatrics, 6, 163. https://doi.org/10.3389/fped.2018.00163
- Dougherty, M. L., Nuttle, X., Penn, O., Nelson, B. J., Huddleston, J., Baker, C., Harshman, L., Duyzend, M. H., Ventura, M., Antonacci, F., Sandstrom, R., Dennis, M. Y., & Eichler, E. E. (2017). The birth of a human-specific neural gene by incomplete duplication and gene fusion. Genome biology, 18(1), 49. https://doi.org/10.1186/s13059-017-1163-9
- Pang, H., Yu, X., Kim, Y. M., Wang, X., Jinkins, J. K., Yin, J., Li, S., & Gu, H. (2020). Disorders Associated With Diverse, Recurrent Deletions and Duplications at 1q21.1. Frontiers in genetics, 11, 577. https://doi.org/10.3389/fgene.2020.00577
- Whalen, S., & Pollard, K. S. (2022). Enhancer Function and Evolutionary Roles of Human Accelerated Regions. Annual review of genetics, 56, 423–439. https://doi.org/10.1146/annurev-genet-071819-103933
- Guardiola-Ripoll, M., & Fatjó-Vilas, M. (2023). A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge. International Journal of Molecular Sciences, 24(4), 3597. https://doi.org/10.3390/ijms24043597
- Bhattacharyya, U., Deshpande, S. N., Bhatia, T., & Thelma, B. K. (2021). Revisiting Schizophrenia from an Evolutionary Perspective: An Association Study of Recent Evolutionary Markers and Schizophrenia. Schizophrenia bulletin, 47(3), 827–836. https://doi.org/10.1093/schbul/sbaa179
- Toledo, C., & Saltsman, K. (2022, May 6). Genetics by the Numbers. National Institute of General Medical Sciences. https://nigms.nih.gov/education/Inside-Life-Science/Pages/Genetics-by-the-Numbers.aspx
- Lee, S. S., Fullerton, S. M., McMahon, C. E., Bentz, M., Saperstein, A., Jeske, M., Vasquez, E., Foti, N., Saco, L., & Shim, J. K. (2022). Targeting Representation: Interpreting Calls for Diversity in Precision Medicine Research. The Yale Journal of Biology and Medicine, 95(3), 317–326.
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Smithtown High School East
Saint James, New York
Teacher: Ms. Maria Zeitlin
Our Unique Genomes: STRs, CNVs, and the Microbiome
When I was in fourth grade, my grandmother passed away from pancreatic cancer. Why her? Why are some people predisposed to diseases while others are not? The answer goes far beyond just the sequences of base-pairs in our DNA, but ultimately has to do with the factors that contribute to the variation in the expression of our genes.
The genomic variations that may predispose some people, like my grandmother, to cancer are also what makes each person unique. Forensic scientists exploit this genetic uniqueness when examining DNA left at a crime scene. To identify a criminal, they examine areas of short tandem repeats, or STRs, which are segments of DNA up to ~100 nucleotides long, consisting of repeating patterns that are 1-6 bp long (1). Forensic scientists analyze 15 different STRs in a given DNA sample, giving them a high power of discrimination, which allows them to identify a single person as the perpetrator (2). When analyzing a series of STR’s, the chances of two DNA samples from two different people having 15 identical STRs is 1 in 1 billion (3). STRs exhibit such uniqueness due to their high mutation rates caused by the prevalence of strand-slippage. Strand slippage occurs during the replication of DNA when the template strand fails to properly align with the sense strand, causing mutations in the STRs produced (1). As forensics has shown, STRs in the human genome identify each person as unique due to their high mutation rate.
This genetic uniqueness extends even to monozygotic twins. Although they might seem to be identical, phenotypic differences among monozygotic twins may occur due to copy number variations (CNVs) with high mutation rates (5). Copy number variations occur when an individual possesses more than two copies of a segment of DNA, and they account for more genetic individuality between people than single nucleotide variations and indels combined (4, 6). CNVs are formed through structural changes in the actual DNA backbone (6). One way this could happen is via homologous recombination, in which crossing over occurs between homologous regions of homologous chromosomes. CNVs can also arise from non-homologous recombination, in which crossing over occurs between two homologous regions of non-homologous chromosomes (7).
In concert with STRs and CNVs, which make everyone’s DNA unique, there is the internal ecosystem, collectively referred to as the microbiome, which affects both DNA and gene expression, further contributing to the distinctiveness of everyone’s genomes. Recent studies have found that our internal microbes distinctly impact a plethora of biochemical processes including DNA methylation, DNA damage, non-coding RNA expression and cell proliferation (8). Microbes can indirectly affect the epigenome by producing compounds, such as butyrate and short-chain fatty acids, that cause downregulation of proinflammatory cytokines (8). Microbes’ production of compounds such as butyrate additionally inhibit histone deacetylase, causing DNA to become more loosely wrapped around histones, making more DNA accessible for transcription (9). Furthermore, different species of microbes can change chromatin accessibility, and therefore alter gene expression in that way (11). Our microbiomes play a tremendous role in making each person’s DNA, and DNA expression, different. We are not only “One Humanity, Many Genomes,” but we are also “One Humanity, Many Species’ Genomes.”
Heightened knowledge of our unique genomes has implications for a variety of state-of-the-art medical advancements. By identifying genetic mechanisms underlying diseases, treatments are developed that target diseases on a genetic level (12). Individualized gene therapy has proven to have great potential. One method by which this may be used is through the use of antisense oligonucleotides (ASOs) (13). These strands of DNA work to block segments of RNA from transcription, thus, disabling its function (14). Further promising gene therapy methods include adeno-associated viral (AAV) vectors (15). These modified viral cells can be used to deliver desired DNA fragments to patients to treat any number of ailments (16). Though the scalability and cost-effectiveness of some of these personalized gene therapies remain a limitation, this novel medicine, aided by our understanding of our genomes, shows enormous potential.
Increased knowledge of unique genomes, and the things that cause the individuality of genomes increases, will pave the way for the development of more personalized treatments to various cancers and diseases, previously thought to be incurable. Perhaps, with this advancement in knowledge of STRs, CNVs, and the microbiome, others who have been diagnosed with pancreatic cancer, as my grandma was, will be able to receive treatments and will not have to share the same fate as my grandma.
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- Abdellaoui, Abdel, et al. “CNV Concordance in 1,097 MZ Twin Pairs” Twin Res Hum Genet. 18 (2015): 1-12.
- Shaikh, Tamim H. “Copy Number Variation Disorders” Curr Genet Med Rep. 5 (2017): 183-190.
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- Miro-Blanch, Joan, et al. “Epigenetic Regulation at the Interplay Between Gut Microbiota and Host Metabolism.” Frontiers Genetics 10 (2019)
- Richards, Allison L., et al. “Gut Microbiota Has a Widespread and Modifiable Effect on Host Gene Regulation.” ASM Journals 4 (2019)
- Marks, Peter, et al. “Toward a New Framework for the Development of Individualized Therapies.” Gene Therapy 28 (2021): 615-617.
- Naso, Michael F., et al. “Adeno-Associated Virus (AAV) as a Vector for Gene Therapy.” BioDrugs 31 (2017): 317- 334.
Research Laboratory Academy Seoul
Seoul, Republic of Korea
Teacher: Ms. Deborah Lee
The past two decades have ushered in a new era of genetic research. Since the completion of the Human Genome Project  in 2003, efforts to more fully understand the human genome have advanced research rapidly, with projects like The BabySeq Project  and the 100,000 Genomes Project  at the fore. Genomes, or the complete set of genes in an organism, hold the blueprint of our physical and biological characteristics, and variations in our genes can influence our susceptibility to diseases, response to medications, and overall health . So far, genetic research has been limited by the underrepresentation in the data of genetic variations from non-European populations . Projects like the All of Us Research Program aim to address this, by collecting more diverse genetic data for use in medical studies . Going forward, genetic research should focus on exploring the full diversity of human genomes, including how this can influence susceptibility to disease, and the possibilities of genetic therapies for improved patient outcomes.
It is commonly stated that 99.9 percent of what comprises the human genome is shared across the species. However, given the vast number of base pairs in our DNA, this 0.1 percent difference leaves approximately three million base pairs to vary between any two humans . Some of these differences can lead to increased risk factors for disease. For example, researchers have found a region of chromosome three, thought to be inherited from Neanderthals, linked with a higher propensity for severe illness from COVID-19. This genomic segment was found in 50 percent of people from South Asia, and 16 percent of people of European descent . Neanderthal DNA is known to be more common in humans of European or Asian descent more generally, and this variation across ethnic groups should guide researchers when designing genetic treatments . Neanderthal DNA present in the human genome has also been associated with some autoimmune disorders .
Autoimmune disorders are diseases in which the immune system mistakenly attacks healthy cells and tissues in the body, leading to inflammation and damage. They are believed to have a polygenic inheritance pattern , meaning that they are caused by the combined effect of multiple genetic variations rather than a single gene mutation. For instance, human leukocyte antigen (HLA) gene variations are strongly associated with autoimmune disorders such as type 1 diabetes, rheumatoid arthritis, and multiple sclerosis . HLA genes encode proteins that help the immune system distinguish between self and non-self cells . Variations in these genes can cause the immune system to attack the body cells and tissues. Given that autoimmune disorders disproportionately affect women, more contextdriven research into treatment options is necessary, with an understanding of the complexity of the genetic risk factors present .
Gene therapy and genetic screening for medical treatment and disease prevention is a relatively new area of research and should be developed with the diversity of the human genome in mind. Some genetic variants that are common in one population may be rare or absent in another, as illustrated by the differences in genomes of white and nonwhite patients with cystic fibrosis (CF). Nonwhite CF patients have genomes containing variations that are not reported in CF patients of European descent , rendering gene therapies designed to target a specific genetic mutation ineffective for nonwhite populations. A disease currently being heavily researched by geneticists is early-onset Alzheimer’s disease (EOAD). The rise of EOAD is predicted in Western countries by observing already identified genes . However, a study in Korea identified several other genes that were not previously linked to EOAD, such as the UNC5C and NOS1 genes . The authors suggested that these findings may have implications for treating EOAD in the Korean population. As genetic screening for disease risk becomes more common, we must ensure that we take genetic variations across ethnic groups into account to prevent overlooking the presence of key genes. Genetic research must center on the importance of recognizing and valuing the diversity of human genomes while acknowledging the shared genetic heritage that unites us as a species. The lack of diversity in study populations can limit the generalizability of findings and lead to inaccurate conclusions about genetic differences and disease risks. Addressing these biases requires a concerted effort to develop more inclusive research practices that account for population differences in genetic variation and ancestry. Only with this concerted effort will we unlock the full potential of genomes to continue humanity’s great escape from disease.
- Gibbs, Richard A. “The human genome project changed everything.” Nature Reviews Genetics 21.10 (2020): 575-576.
- Holm, Ingrid A., et al. “The BabySeq project: implementing genomic sequencing in newborns.” BMC pediatrics 18.1 (2018): 1-10.
- Wheway, Gabrielle, Genomics England Research Consortium, and Hannah M. Mitchison. “Opportunities and challenges for molecular understanding of ciliopathies–the 100,000 genomes project.” Frontiers in genetics 10 (2019): 127.
- Ahmed, Zeeshan et al. “Human gene and disease associations for clinical-genomics and precision medicine research.” Clinical and translational medicine vol. 10,1 (2020): 297-318. doi:10.1002/ctm2.28
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- Crow, James F. “Unequal by nature: A geneticist’s perspective on human differences.” Daedalus 131.1 (2002): 81-88.
- Zeberg, Hugo, and Svante Pääbo. “The major genetic risk factor for severe COVID-19 is inherited from Neanderthals.” Nature 587.7835 (2020): 610-612.
- Wall, Jeffrey D et al. “Higher levels of neanderthal ancestry in East Asians than in Europeans.” Genetics vol. 194,1 (2013): 199-209. doi:10.1534/genetics.112.148213
- Kerner, Gaspard et al. “New insights into human immunity from ancient genomics.” Current opinion in immunology vol. 72 (2021): 116-125. doi:10.1016/j.coi.2021.04.006
- Grimbacher, Bodo et al. “The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects.” The Journal of allergy and clinical immunology vol. 137,1 (2016): 3-17. doi:10.1016/j.jaci.2015.11.004
- Muñiz-Castrillo, Sergio, Alberto Vogrig, and Jérôme Honnorat. “Associations between HLA and autoimmune neurological diseases with autoantibodies.” Autoimmunity Highlights 11 (2020): 1-13.
- Crux, Nicole B., and Shokrollah Elahi. “Human leukocyte antigen (HLA) and immune regulation: how do classical and non-classical HLA alleles modulate immune response to human immunodeficiency virus and hepatitis C virus infections?.” Frontiers in immunology 8 (2017): 832.
- Angum, Fariha et al. “The Prevalence of Autoimmune Disorders in Women: A Narrative Review.” Cureus vol. 12,5 e8094. 13 May. 2020, doi:10.7759/cureus.8094
- Kim, Jong-Won. “Pathogenic Variants Spectrum and Allele Frequency of the CFTR Gene in Asians.” Allergy, asthma & immunology research vol. 14,5 (2022): 444-446. doi:10.4168/aair.2022.14.5.444
- Bellenguez, Céline, et al. “New insights into the genetic etiology of Alzheimer’s disease and related dementias.” Nature genetics 54.4 (2022): 412-436.
- An, Seong Soo et al. “A genetic screen of the mutations in the Korean patients with early-onset Alzheimer’s disease.” Clinical interventions in aging vol. 11 1817-1822. 15 Dec. 2016, doi:10.2147/CIA.S116724Harmony
Harmony Heming LI
Shanghai High School International Division
Teacher: Dr. Feifan Zhang
One humanity, many genomes
A momentous achievement in human genomics was the generation of the first complete human genome sequence called the T2T-CHM13 assembly in 2022 (Nurk et al. 44). Although the Human Genome Project was launched in 1990 and the International Human Genome Sequencing Consortium was published in 2004 (Lincoln et al. 931), technological limitations left some regions of the human genome unresolved. The landmark resource of the T2TCHM13 assembly along with state-of-the-art technologies for its construction not only opens up a path to the generation of many complete human genomes but also will enable important biological discoveries based on human genomics.
In order to understand human uniqueness from the aspect of human genomes, paleontologists including Dr. Svante Pääbo, 2022 Nobel Laureate in Physiology or Medicine, have compared them with genomes of our closest extinct relatives, archaic hominins. Archaic hominins including Neandertals and Denisovans lived in Eurasia and were mysteriously replaced by Homo sapiens migrating from Africa to the Middle East and spreading to the rest of the world about 70,000 years ago (Pääbo et al. 216). Sequencing genomic DNA recovered from archaic specimens seemed impossible until Dr. Svante Pääbo and his team improved the methods to isolate and analyze DNA from bone remains and published the first Neanderthal genome sequence in 2010 (Green et al. 710). Dr. Svante Pääbo also made the sensational discovery of a previously unknown hominin, Denisova (Krause et al. 894).
One fascinating finding in 2022 based on genomic comparison sheds light on what gives humans an evolutionary advantage and uniqueness over other hominins. Transketolase-like 1 (TKTL1), an enzyme in the glucose metabolic pathway, is one of the few proteins with a single amino acid substitution found in present-day humans but absent from extinct archaic humans, the Neanderthals, and Denisovans (Pinson et al. 6422). The lysine-to-arginine amino acid substitution of TKTL1 might increase neocortical neurogenesis and the number of brain cells in the hominins that preceded modern humans, probably giving them a cognitive advantage over archaic humans, allowing them to take in information about the environment, organize, form social alliances, and raise the probability of survival in difficult times (Reardon 665). This might be one explanation for the big mystery of why modern humans were so successful in their expansion whereas the Neanderthals and Denisovans went extinct after having adapted to a Eurasian environment for many years.
Homo sapiens had mixed with Neanderthals and Denisovans during periods of co-existence, resulting in unique human genomes with introgression of archaic DNA. For example, the Denisovan version of the gene Endothelial PAS Domain Protein 1 (EPAS1), which confers an advantage for survival at high altitudes, is common among present-day Tibetans (Huerta-Sánchez et al. 194). The Tibetan-EPAS1 haplotype came from the East Asian-specific Denisovan introgression event and remained selectively neutral for a long time in the population before positive selection occurred, which might be concurrent with the permanent inhabitation of the Tibetan Plateau (Zhang et al. 1).
Human genomic and paleontology discoveries have greatly impacted our lives. Archaic gene sequences from our extinct relatives influence the physiology of present-day humans. For example, archaic alleles on human chromosomes 3 and 12 can either increase or decrease the risk for respiratory failure during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (Zeberg, “The major genetic risk” 610; “A genomic region” 1). Specifically, a genomic segment of around 50 kilobases on chromosome 3 is the major genetic risk factor for severe symptoms after SARS-CoV-2 infection and hospitalization. The gene cluster is inherited from Neanderthals and carried by around 50% of people in south Asia and around 16% of people in Europe (“The major genetic risk” 610). Therefore, advances in understanding human genomes make it possible to speculate about the susceptibility of people carrying the gene cluster to relevant pathogens and plan for timely medical treatments.
The exciting discoveries of the genomes of extinct hominins and human evolution have improved my understanding of “one humanity, many genomes”. Thanks to Dr. Svante Pääbo and other scientists’ work, there is now a rich resource of genome data from ancient human specimens found worldwide from different time periods. Comparing diverse genomes of humans and archaic hominins offers exciting new possibilities to identify critical genetic variants that distinguish us from archaic hominins. Elucidating functions of unique human genetic variants will further improve our understanding of humanity and open new windows for physiology and medicine.
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Huerta-Sánchez, Emilia et al. “Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA.”
Nature, vol. 512, no. 7513, 2014, pp. 194-7. doi:10.1038/nature13408
Krause, Johannes et al. “The complete mitochondrial DNA genome of an unknown hominin from southern Siberia.”
Nature, vol. 464, no. 7290, 2010, pp. 894-7. doi:10.1038/nature08976
Lincoln, Stein et al. “International Human Genome Sequencing Consortium.” Nature vol. 431, 2004, pp. 931–945. doi.org/10.1038/nature03001
Nurk, Sergey et al. “The complete sequence of a human genome.” Science, vol. 376, no. 6588, 2022, pp. 44-53. doi:10.1126/science.abj6987
Pääbo, Svante et al. “The human condition-a molecular approach.” Cell, vol. 157, no. 1, 2014, pp. 216-26. doi:10.1016/j.cell.2013.12.036
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Neanderthals.” Science, vol. 377, no. 6611, 2022, pp. 6422. eabl6422. doi:10.1126/science.abl6422
Reardon, Sara. “Did this gene give modern human brains their edge?.” Nature, vol. 609, no. 7928, 2022, pp. 665-666. doi:10.1038/d41586-022-02895-2
Zeberg, Hugo, and Svante Pääbo et al. “A genomic region associated with protection against severe COVID-19 is inherited from Neandertals.” Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 9, 2021, pp. 1-5. doi:10.1073/pnas.2026309118
Zeberg, Hugo, and Svante Pääbo et al. “The major genetic risk factor for severe COVID-19 is inherited from Neanderthals.” Nature, vol. 587, no. 7835, 2020, pp. 610-612. doi:10.1038/s41586-020-2818-3
Zhang, Xinjun et al. “The history and evolution of the Denisovan-EPAS1 haplotype in Tibetans.” Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 22, 2021, pp. 1-9. doi:10.1073/pnas.2020803118
Waterloo Collegiate Institute
Teacher: Ms. Lauren Crosby
‘One humanity, many genomes.’ This statement recognizes the diverse genomes amongst various ethnicities, responsible for differences in everything from hair colour to hemoglobin levels. This also holds implications for the future of medical treatment; recognizing the diversity of the human genome also includes implementing technologies and tailoring treatments to account for these genetic differences to improve outcomes.
The diversity of the human genome is best exemplified by the extreme traits that have arisen from different selective pressures. For instance, the Sama-Bajau, a Southeast Asian Austronesian ethnic group, have been documented to be proficient free-divers, being able to hold their breath for up to 13 minutes (1). This can be attributed to a variety of genes, including a variation on the PDE10A gene that causes them to have larger spleens, and therefore a larger bank of oxygenated red blood cells. Additionally, FAM178B encodes a protein that maintains the pH level of the blood, preventing carbon dioxide build up. As well, CACNA1A improves the physiological response to hypoxia (2).
The Amhara, an Ethiopian ethnic group, and Tibetan highlanders have adapted to high-altitude, low-oxygen environments using similar physiological mechanisms; however, they are influenced by different genes (3). Both groups have adapted to use oxygen more efficiently via lowered hemoglobin levels. This also reduces their risk of adverse hypoxia-related effects such as thickened blood, which increase risk of stroke and heart attack (4). However, genetic variations that contribute to lowered hemoglobin levels in Tibetan highlanders, such as EPAS1 and EGLN1, were found to be largely absent in the Amharan genome (5, 6). Instead, Amharan hemoglobin levels are controlled by a genetic variation known as rs10803083. In both groups, however, the effects are pronounced. The Amhara produce 10% less hemoglobin than their counterparts, the Omoro lowlanders. When Omoro reach high altitudes, their blood hemoglobin levels increase in the same manner reported in lowlander Tibetans attempting to climb the Himalayas.
Another example of diversity in the human genome is the sickle cell trait. Malaria is a disease where the liver and blood cells are attacked by the parasite Plasmodium falciparum and undergo lysis; it is prominent in South Asia, Africa, and parts of South America. These regions also have the highest incidence rates of the sickle cell trait, occurring in up to 40% of the population (7). The sickle cell trait is caused by a single substitution mutation, causing normal, biconcave red blood cells to form a sickle shape when dehydrated or exposed to low-oxygen levels. This decreases flexibility of infected cells, thereby removing them from circulation (8). This strategy is especially beneficial in the early stages of malaria; parasite densities are reported to be lower in those with the sickle cell trait (9).
Although all human genomes are 99.9% identical, the 0.1% that remains includes 3 billion nitrogenous bases that potentially differ (10). As of 2018, 78% of genome samples in genome-wide association studies were of European ancestry; the vast geographic region of Africa—which also has the greatest genetic diversity—contributes only 2% of total genome samples (11, 12). Diversity in human genome samples could help medical professionals better understand, diagnose and treat illnesses for diverse populations. For example, hypertrophic cardiomyopathy is a heart condition that is diagnosed via analyzing specific genetic variations. However, it has been discovered that 5 of the genetic markers previously associated with the condition were more common in African-Americans patients, despite them not being at risk for the disease, resulting in multiple false diagnoses (13). Analysis of non-European genomes has also revealed twenty-seven new genes that are related to conditions including diabetes and kidney disease. For example, a genetic variant associated with cigarette usage is common in Pacific Islanders, but rare in other ethnicities (14).
Diversity in genomics also aids progress in medical treatments. For example, gene therapy is an experimental technology that makes locus-specific modifications to an individual’s genome for therapeutic effect; it shows promise in curing otherwise untreatable conditions, such as cystic fibrosis or glioblastoma (15). Analyzing diverse genomes can help geneticists account for differences in gene varieties and their location in the genome. Analysis of genomes of highlanders and free-divers have helped medical professionals better understand the factors that influence human hypoxia tolerance; this can be extended to other geographically-localized genetic adaptations.
In conclusion, the many genetic variants found within humanity testify to the environments and conditions different humans have endured, and the adaptability of the human genome. In modern society, it is increasingly important to ensure that treatments and diagnoses account for differences in genomes.
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- Alkorta-Aranburu, G., Beall, C. M., Witonsky, D. B., Gebremedhin, A., Pritchard, J. K., & Di Rienzo, A. (2012). The genetic architecture of adaptations to high altitude in Ethiopia. PLoS Genetics, 8(12). https://doi.org/10.1371/journal.pgen.1003110
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- Peng, Y., Yang, Z., Zhang, H., Cui, C., Qi, X., Luo, X., Tao, X., Wu, T., Ouzhuluobu, Basang, Ciwangsangbu, Danzengduojie, Chen, H., Shi, H., & Su, B. (2010). Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas. Molecular Biology and Evolution, 28(2), 1075–1081. https://doi.org/10.1093/molbev/msq290
- Beall, C. M., Cavalleri, G. L., Deng, L., Elston, R. C., Gao, Y., Knight, J., Li, C., Li, J. C., Liang, Y., McCormack, M., Montgomery, H. E., Pan, H., Robbins, P. A., Shianna, K. V., Tam, S. C., Tsering, N., Veeramah, K. R., Wang, W., Wangdui, P., … Zheng, Y. T. (2010). Natural selection on EPAS1 ( HIF2α ) associated with low hemoglobin concentration in Tibetan Highlanders. Proceedings of the National Academy of Sciences, 107(25), 11459–11464. https://doi.org/10.1073/pnas.1002443107
- Serjeant, G. R. (2013). The natural history of sickle cell disease. Cold Spring Harbor Perspectives in Medicine, 3(10). https://doi.org/10.1101/cshperspect.a011783
- Archer, N. M., Petersen, N., Clark, M. A., Buckee, C. O., Childs, L. M., & Duraisingh, M. T. (2018). Resistance to plasmodium falciparum in sickle cell trait erythrocytes is driven by oxygen-dependent growth inhibition. Proceedings of the National Academy of Sciences, 115(28), 7350–7355. https://doi.org/10.1073/pnas.1804388115
- Uyoga, S., Macharia, A. W., Ndila, C. M., Nyutu, G., Shebe, M., Awuondo, K. O., Mturi, N., Peshu, N., Tsofa, B., Scott, J. A., Maitland, K., & Williams, T. N. (2019). The indirect health effects of malaria estimated from health advantages of the sickle cell trait. Nature Communications, 10(1). https://doi.org/10.1038/s41467-019-08775-0
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Southland Boys’ High School
Invercargill, New Zealand
Teacher: Mrs. Julia Shannon
Looking at the many different species living on our planet, it is often easy to forget that genomic variation is seen between humans themselves. Genome sequencing and genome analysis techniques have allowed scientists to detect these variations, which has proved useful in developing more accurate diagnosis techniques and effective medicines for diseases.
There is ~99.9% similarity between the genomes of each human, as result of single nucleotide variations (SNVs) . When SNVs, insertions/deletions and structural variants, this percentage decreases to ~99.6% . This means that the average human genome is affected by 5.5 million variants spreading over 27 million nucleotides . These variants are present in both coding and non-coding regions of our genome and makes each person unique. While these figures show just how unique each individual is, it is likely that more variants will be found as genome sequencing technologies improve.
The history of genome sequencing goes back to the 1970s when Maxam Gilbert and Sanger sequencing were introduced . When next generation sequencing methods were developed in the early 2000s, they increased the speed, cost and accuracy of genome sequencing . However, these still displayed flaws in detecting structural variants and repetitive elements . Further developments led to PacBio’s HiFi sequencing method that reads 20,000 bases with near perfect accuracy and Oxford Nanopore’s sequencing technology that reads 1 million with reasonable accuracy, both of which allow for real-time long-read sequencing . The level of accuracy and efficiency achieved by new sequencing technologies has allowed for a more robust analysis of genomes and continue to improve our understanding of genomic variation within the human population.
Eye color and race are prominent examples in showing how our knowledge has changed with improved understanding of genomic variation. In the past, eye color was thought to be inherited monogenetically by a dominant brown allele and a recessive blue allele . Recent research has shown there are at least ten separate genes associated with determining eye color, which explains why two blue-eyed parents could have brown-eyed children . Similarly, genome sequencing has revealed that there is more genetic variation within self-identified racial groups than between them, showing that race cannot be used as a valid biological category .
Understanding variations within human genomes is facilitating the development of new treatments for diseases. One such example includes the search for better drugs against heart diseases. With the help of genome sequencing and rare-variant analysis, researchers were able to identify that a loss-of-function mutation in the PCSK9 gene led to certain individuals having an unusually low amount of LDL cholesterol, a factor that increases heart disease risk [6,7]. Research around this resulted in the development of PCSK9 inhibitors to reduce LDL cholesterol levels in individuals with unmutated PCSK9 genes, with two PCSK9 inhibitor drugs being currently approved by the FDA [7,8]. Using PCSK9 inhibitors to reduce heart disease risk shows how genome sequencing has formed the base in developing novel treatments for diseases.
Due to genomic variation between humans, the same medicine can have different impacts on different people, even if they are diagnosed with the same disease. For instance, the response of Alzheimer’s patients to certain medications depends on which variant of the Apolipoprotein E gene is present in that person’s genome . Genome sequencing has allowed a more personalized approach that will consider each person’s individual genome. Due to this reason, genome analysis is involved in both diagnosis and treatment of diseases. Checking for specific variants of BRCA1
and BRCA2 genes associated with increased risk has proved to be an effective tool in the early diagnosis of breast cancer . Similarly, the development of precision medicine that targets cancer-specific pathways has gained traction, due to chemotherapy’s low efficacy rates and unfavorable effects on surrounding tissue. Precision medicine, which considers the genetic profile of both the tumor and patient, has shown promise in cancer treatment research . For example, BCR-ABL inhibitor drugs, given to chronic myeloid leukemia patients with BCR-ABL gene fusion, have increased survival rates to 90% over 5 years . As a rapidly evolving field, precision medicine is facilitating the development of medicines better suited to patients by considering their individual genomic information. Genome sequencing and analysis has been a valuable tool in not only for understanding, but also diagnosing, treating and developing new drugs for diseases. As we develop more efficient, accurate and cost-effective sequencing and analysis methods, it is likely that the concept of human genomic variation will continue to play an important role in the field of medicine.
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DeBakey High School for Health Professions
Teacher: Mrs. Marla Maharaj
Homo sapiens defines humanity as we know it today. We all belong to a single species, but we all have diverse genetic makeups that make us unique individuals. While we all share a common ancestry and morphological structures, there are differences in our genome that give rise to the observable differences between us.
Our DNA sequences consist of nucleotides that code for genes, which, when expressed, affect our phenotypic features and behaviors. Even a single minute difference in the nucleotide sequence can result in a gene expressing an entirely different phenotype, and this phenomenon is called Single Nucleotide Polymorphisms (SNPs). SNPs are predicted to be responsible for 40-50% of the variation in human height  and could be responsible for other observable phenotypes, such as facial structure . Today, hundreds of thousands of SNPs are available for genomewide association study (GWAS), and they are often examined to determine the genotypic causes of genetic diseases . For example, studies on SNPs indicate a polygenic influence of Brugada syndrome, a cardiac arrhythmia disorder . Crohn’s disease, an inflammatory condition of the digestive tract, has also been associated with SNPs, specifically the promoter region of the IL-10 gene . Just one nucleotide discrepancy is not the only genotypic difference that can cause genetic variation, though; Copy Number Variations (CNVs) involve differences in the number of copies of specific DNA segments and can have significant effects on gene expression. Some individuals may have extra copies of a gene that allow them to metabolize drugs faster ; CNVs can even be associated with certain diseases. For example, CNVs contribute 10-15% of congenital heart disease cases  and are associated with renal disease . Certain CNVs are also commonly implicated as the genetic cause of neurodevelopmental disorders, such as bipolar disorder, schizophrenia, and autism .
Modifications of genes outside of the nucleotide sequence can also cause genetic variation. Epigenetics studies how gene expression and resultant phenotypes are affected without altering the underlying DNA. Processes of epigenetics include DNA methylation, which adds methyl groups to the histone tails of nucleosomes, effectively forming tightly coiled heterochromatin and repressing gene expression, and DNA acetylation, which adds acetyl groups to the histone tails of nucleosomes, effectively loosening the chromatin to create euchromatin that can be more easily transcribed. Methylation and acetylation are implicated in observable phenotypic variations, such as aging , and they are also critical factors in genetic diseases. Because methylation makes the chromatin more coiled, it is harder to transcribe specific genes, which can lead to complications such as cancer [11,12], autoimmune thyroid disease , pulmonary fibrosis , and more. Acetylation makes the chromatin looser and can be transcribed easier, which can over-transcribe genes and contribute to tumor progressions . Other epigenetic processes, such as diet and nutrition, can also contribute to differences in the genome. Recent research has suggested that the Mediterranean Diet, specifically olive oil, can have vital roles in how susceptible individuals are to hypertension and cardiovascular disease . Diet and nutrition are also important during pregnancy, as the epigenetic processes can affect prenatal life and offspring’s neurodevelopment [16,17]. High-fat diets of pregnant women have been implicated in their offspring’s behavioral phenotypic deficits .
In attempts to understand the vast differentiation in the human genome and its impact, genomic research has been focused on developing methods to understand the variations and discovering novel medical treatments. To determine the effects of SNPs and their interactions with each other, researchers often employ machine learning and statistical techniques, creating new models and frameworks that can give insight into how genomic differences affect susceptibility to diseases [18, 19, 20]. These techniques also study the effects of other differences in nucleotide sequences and epigenetics. By understanding the human genome and its various interactions, treatments like precision oncology and gene therapy become more viable. Precision oncology aims to tailor cancer treatment specific to a patient’s genome based on the genetic alterations that contribute to the development and progression of cancer. For example, targeted therapies for certain lung cancers have shown great promise and have better outcomes than standard chemotherapy . Gene therapies alternatively aim to repair defective genes or introduce new genes to treat diseases. This is made possible by understanding the underlying interactions between nucleotides and genes, and it has shown promise in combating various genetic disorders and cancers .
While we may be far from revolutionizing standard medicine with genetic treatments, understanding the uniqueness of our genomes is a stepping stone to reaching that achievement.
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Smithtown High School East
Saint James, New York
Teacher: Ms. Maria Zeitlin
Despite striking visual and behavioral differences between people from different parts of the world, the vast majority of our genomes are identical to each other. The 0.1% difference in our genomes is what makes us unique. Our genomes are affected by individual differences and large scale differences from early in our evolutionary history. Small differences in our genomes have significant impacts on the treatment of incurable diseases and on personalized medicine.
There are many types of genetic differences, ranging from point mutations in our DNA to changes during meiosis that create new unique genomes. One of the most prominent examples of genetic variation is the single nucleotide polymorphism (SNP), where a single DNA base pair is altered. SNPs represent the most common type of genetic variation, yet there is an enormous level of variation in the number of SNPs expressed across the human genome, . There is a significant potential for SNPs as tools for genetic studies. Because of their abundance and relatively predictable mutation rate, SNPs are a potential marker for linkage disequilibrium scans that aim to measure the relationship between two genes. Another prominent cause of genetic variation is copy number variations (CNV), or variations in the number of times a repeating DNA sequence is copied. CNVs are linked to many traits. In a study by Wong, et al, 68% of 800 CNV variations with a frequency of 3% or more in the test population overlapped with important coding regions that affected the senses, metabolism, and vulnerability to disease. For example, the heterozygous phenotype for PARK2 CNVs leads to increased risk for developing the Mendelian form of Parkinson’s disease.
One of the causes of large scale genetic differences, such as those between different racial groups, is the amount of DNA inherited from ancient hominids. Modern humans and early hominids are closely related. We share 99.5% of our genome with Neanderthals. However, not all ethnic groups have the same share of ancient DNA. On average, East Asians have 20% more Neanderthal DNA than Western Europeans. Although people from New Guinea and Australia are the closest ancestors to Denisovans, genes from Denisovans are present throughout Southeast Asia and Oceania. The difference between the amount of DNA inherited is responsible for multiple physical, behavioral, and neurological differences in cultures.
Understanding the variation in our genomes may hold the key to advancing medical treatment for all. For example, rare mutations in the human genome may hold the key to treating previously incurable diseases, like HIV. Stephen Crohn was the first documented case of HIV immunity. In 1994, Crohn responded to a request from William Paxton for individuals that had been in contact with HIV but were not infected. Paxton and his colleagues eventually discovered a mutation that altered the CCR5 receptors on Crohn’s cells that granted him immunity to HIV. The CCR5 receptor is one of the main co-receptors involved in HIV cell entry. Crohn had a mutation known as “delta 32” in which 32 base pairs were deleted from his CCR5 gene. The resulting protein is not exhibited on the surface of HIV target cells, which prevents HIV from entering the cell. The discovery of CCR5 polymorphisms in individuals like Crohn has led to the development of inhibitor drugs and antibodies that can prevent HIV from entering cells. Another disease that benefits from an increased understanding of our genomes is cancer prevention and treatment. Genetic Cancer Risk Assessment (GCRA) uses genetic testing or family pedigrees to assist individuals in cancer risk management or treatment.[14,9] If doctors suspect that a mutation may be present in an individual, they can use one of many models to predict whether an individual has a mutation. GCRA testing for BRCA, a gene which can cause breast cancer, helped doctors perform risk-reducing surgeries that lowered breast cancer risk and breast cancer mortality rates. Furthermore, new discoveries on the role of BRCA genes in DNA repair have led to the development of PARP inhibitors, which inhibit the DNA damage response and prevent DNA repair.
Our genetic variation is influenced by small scale differences between individuals and large scale differences caused by differences early in our evolutionary history. Our unique genomes contain mutations that can lead to immunity to normally fatal diseases. The differences in our genomes also help us identify risk factors for diseases like cancer. Understanding our genomes will help us treat diseases on a personal basis.
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St. Paul’s Co-educational College
Hong Kong, China
Teacher: Ms. Pui Lan Wong
Evolution, the concept of descent with modification, accounts for the remarkable unity and diversity of life . Humans emerged as a separate species, Homo sapiens, after branching off from the last common ancestor of humans and chimpanzees. Henceforth, “one humanity” became the basis from which “many genomes” arose. While we are all humans, our genomes are unique. Zooming in, our genetic diversity is a result of multiple factors. Novel alleles are generated during mutation events. The number of genetic combinations is increased drastically by random fertilization during sexual reproduction, crossing over of non-sister chromatids in prophase I, as well as the independent assortment of homologous chromosomes in metaphase I. From a macroscopic perspective, natural selection and genetic drift give rise to genetic variation across different human populations, while gene flow creates new genetic combinations with the advent of globalization.
Among the “many genomes”, there are two main types of genetic variants that make individuals unique, namely single nucleotide polymorphisms (SNPs) and structural variations (SVs). Firstly, SNPs are point mutations in which a single nucleotide pair is substituted at a given locus with frequency not less than 1% in a community . As the most common form of genetic variation, SNPs scatter throughout a person’s DNA, occurring once in about 300-2000 nucleotides on average . There are 84.7 million SNPs identified . They can be silent if they occur on a wobble base pair, but they can also affect phenotypes. As an example, there is an accumulating body of evidence that skin colour is associated with SNPs on genes like TYR and IRF4 . Secondly, SVs are also an important source of genetic variation. These include deletions, insertions, duplications, inversions, translocations and copy number variations (CNVs), which are DNA segments with a varying number of repeats in different individuals. It is estimated that there are 2100-2500 SVs, among which 160 are CNVs . Both types of genetic variants are found in coding and non-coding sequences, and both may cause genetic conditions. For instance, sickle cell anaemia is caused by a SNP in the HBB gene , while Huntington’s disease is caused by a CNV in the HTT gene .
Apart from the uniqueness of individual genomes, the human genome is also distinctive in that it has a few genes involved in neurodevelopment and brain function that are uniquely human , such as the ARHGAP11B gene, which contributes to the evolutionary expansion of the neocortex . Moreover, there are human accelerated regions that regulate human-specific social and behavioural traits . Altogether, these sequences make up merely 1.5%-7% of the human genome , but they define our important features. Our common identity as humans is reinforced by the remarkable similarity in our genetic makeup. Up to 99.9% of our genes are identical , despite our high level of genetic diversity. Our “many genomes” are united by “one humanity”.
Understanding the similarities and differences of our genomes have significant applications in medicine. Currently, it helps unravel molecular pathways behind genetic disorders and it facilitates drug development targeting gene expression, protein production, etc. For example, in acute promyelocytic leukaemia, understanding the expression patterns of the PML-RARA fusion gene led to the development of ATRA-ATO therapy, turning a highly fatal disease into a highly curable one with a complete remission rate of 90-95% . With the rapid development of gene editing technology like CRISPR-Cas9, understanding on our genomes will be further enhanced, and more gene therapies are expected to complete their clinical trials and be brought into commercial use.
Recent advancements in the understanding of our genomes have been rapid as biologists from various backgrounds have diverse opinions and unite in a concerted effort for this task. The success of the scientific endeavour illustrates the power of unity in diversity, which is made possible by “one humanity, many genomes”. To utilize this power, we should embrace our diversity and respect differences between us. Human civilization will thrive if we can build an inclusive, harmonious and united society. This is the deeper meaning behind “one humanity, many genomes”.
To encapsulate the essence of “one humanity, many genomes”, we are united by a shared human identity, upon which genetic variations flourished and gave rise to billions of unique human genomes that we are striving to understand. As a single species with remarkable diversity, we must learn to embrace our differences and live in harmony. Just as descent with modification drove evolution, unity in diversity can be a powerful driving force for human civilization to unleash its full potential.
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