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Blessing and Curse of Genetic Variations

Blessing and Curse of Genetic Variations

19-05-2024
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10 mins Read
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Our Lord wrote the fate of every human in a holy book that will hardly be changed. As a biologist, I assume that human fate is partly written in a unique format that scientists term “gene/DNA,” located in the nucleus of individual cells. A gene is a special arrangement of particular types (out of four) of deoxyribonucleic acid (DNA) that produce the respective protein.

Whether a given person is tall or short in size, white or black in skin colour, male or female in gender, they are written in a DNA sequence or gene. A gene is translated into a respective protein, such as an enzyme, which is the key player in our cell or body, performing all the cellular functions. Therefore, any variation in the arrangement of DNA sequences or genes modulates corresponding protein structure, function, and ultimately our lives. The human genome contains approximately 20,000 protein-coding genes. A subset of this gene is essential for life, which means that without these genes, a human embryo will die in the mother’s womb. A subset of genes is not essential for life but plays an important physiological function; therefore, any functional abnormalities or variations lead to complications in our daily lives.

There are a number of genetic disorders, such as cystic fibrosis (CF) and sickle cell anaemia, that are derived from a minor variation in DNA sequences (called mutations) but cause a life-threatening disorder. DNA is double-stranded; father and mother contribute a single stand. Double-stranded DNA contains two copies or forms of a gene, called alleles, each derived from an individual parent. Therefore, to develop a disease characteristic such as chronic coughing in the case of CF, the given individual must receive a copy of the mutated allele or gene from each parent during fertilization. If one parent provides a normal gene and another parent provides a mutated gene, the disease symptoms will not appear strongly. Therefore, most of the genetic disorders are developed after receiving the mutated genes from each parent, and this feature is called “autosomal recessive disorder.” By nature, the majority of the disorders derived from genetic variation are deleterious and result in complete or partial loss of function of the respective gene. In contrast, in a few cases, genetic alteration leads to a novel type of deleterious feature termed “gain-of-function.”.

HIV (human immunodeficiency virus), the causative agent of AIDS (acquired immunodeficiency syndrome), targets and destroys the body’s immune cells, called T cells, more specifically helper T cells (CD4+ T cells). The helper T cells are the key players that protect our body against infection. Therefore, the infected person died due to immunodeficiency. There are two parts on the T cell’s surface called CD4 and CCR5. They work together to help HIV find and enter the CD4+ T cell. The CCR5 receptor is crucial for HIV infection. At the end of the nineteenth century, several researchers identified a partial deletion in the CCR5 gene (CCR5Δ32), which resulted in the production of functionally inactive receptors. This genetic alteration is remarkable because individuals with this mutation in both copies of the gene (allele) are completely resistant to HIV infection even with repeated exposure. European and Caucasian populations have been found to contain a high frequency of this function-altering allele. Roughly 10% of the European population contains these function-altering genes; thereby, the European population showed comparative resistance against HIV. While the allele is virtually absent in African, Asian, Middle Eastern, and American Indian populations, this finding is remarkable and has incited scientists to further research.

The pathogenic bacterial species Yersinia pestis, which causes bubonic plague, has had a significant impact on human civilization, particularly in Europe. The bubonic plague killed an estimated 25–40% of Europeans from 1346 to 1352. A few centuries later, the European population experienced a second pandemic, known as the ‘‘Great Plague,’’ that killed 15–20%. Researchers hypothesise that the enormous and consistent selection pressure against bubonic plague acts as the driving factor in genetically reshaping the European population for CCR5. The person who survived the bubonic plague and the great plague was subjected to great selection pressure for CCR5Δ32. A part of the population that already had CCR5”32 survived and grew during the bubonic plague, which lasted for several years. Also, repeated infections with the same type of bacteria were what caused CCR5”32 to appear in the European population.

However, the relationship between the CCR5Δ32 mutation and the survival of bubonic plague has been controversial. Both research works were published in prestigious “Nature” journals. One group claimed that mice containing the CCR5Δ32 mutation were protected from Yersinia pestis (a causal agent of bubonic plague) infection, while another group did not recapitulate this result in their laboratory. However, it is hard to tell from experiments whether the CCR5·32 evolves de novo (from scratch) because of the pressure to protect against plague or if it already existed in the past at a similar frequency. To show that there is a link between the selection pressure caused by the plague and the establishment of CCR5 32, researchers need to do gene sequence analyses on an equal number of samples from people who died before the bubonic plague and people who died after it. This will be very difficult to do.

In the United States, over 0.6 million people are suffering from end-stage kidney disease (ESKD), requiring some form of kidney replacement therapy to survive. African Americans, constituting 12% of the US population, develop kidney disease at fourfold higher rates than European Americans. There are few, if any, other common diseases that show such a noticeable racial disparity. The black American revealed chronic kidney disease (CKD), including hypertension-associated ESKD, focal segmental glomerulosclerosis (FSGS), and pathogen-triggered HIV-associated nephropathy. In 2008, two remarkable studies identified genetic variations of Apolipoprotein L1 (APOL1) as the causative factor of high-frequency kidney disease in African-Americans. APOL1, located in 22 chromosomes, has three variants: G0 (reference), G1, and G2. The risk variants (G1 and G2) responsible for kidney disease are exclusively identified in the sub-Saharan African population.

APOL1, circulating in the blood, confers protection against Trypanosoma brucei,a parasite responsible for acute African sleeping sickness prevalent in East Africa. APOL1 attracts Trypanosoma brucei as a food and energy source inside the human body, and the parasite engulfs APOL1. APOL1 inside the parasite body destroys its organelles and finally kills the parasite, thereby conferring host (human) protection. However, two sub-species of this parasite have emerged as a human pathogen because of the evolving APOL1-neutralising factor “serum resistance antigen (SRA)” that binds to and inactivates APOL1. Therefore, humans show susceptibility to these sub-species. Interestingly, G1 and G2 risk variants of APOL1 still show anti-parricidal activity against these two sub-species that cause the APLO1G0 variant to be inactive. It seems like a race to make molecular arms to defeat the opponent by altering a small change in the respective DNA.

Disgracefully, the risk variants that protect the African population from parasitic infection are also deleterious to humans and cause the above-mentioned kidney diseases. APOL1 risk variants affect various cellular organelles, physiological processes, and finally, cell death. Why and how APOL1 risk variants exclusively destroy the filtering unit of the kidney are yet to be resolved.

The origin of genetic variations or DNA sequence alteration has controversy, but their effect is a great reality, affecting human civilization, changing culture, society, the economy, and most importantly, human health. In spite of their deleterious effects on human health, there are some God-gifted variations in our DNA that serve human existence. However, whether the variations are created spontaneously in nature requires tremendous work, involving large-scale DNA sequencing of populations that passed away thousands or even millions of years ago, which is beyond our capacity.
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author
Dr. Md. Abdulla Al Mamun
The author of this article is a Postdoctoral Fellow at Harvard Medical School, Boston
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