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Maintenance of the heterozygous connexin 26 mutation within human population

Paper Type: Free Essay Subject: Sciences
Wordcount: 2349 words Published: 31st Mar 2021

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Maintenance of the heterozygous connexin 26 mutation within human populations affords potential epithelial and gastrointestinal advantages associated with increased rates of survival via a heterozygote advantage


 Connexin 26, or the GJB2 mutation, is a critical factor leading to human deafness and dermatological disorders worldwide. Connexins, which are the functional components of gap junctions, form six-member rings to shape hemichannels. These cellular structures are fundamental to cellular communication as they allow the passage of ions, cAMP, cGMP, and ATP. The epithelial lining of the inner ear, gastrointestinal tract, and skin are all comprised of connexins, therefore mutations in these proteins lead to fundamental disorders of the auto sensory and immune systems. Increasing numbers of individuals are heterozygous for the GJB2 deletion, leading to studies on the efficacy and maintenance of a heterozygous advantage within the population. A heterozygote advantage would infer some adaption which would provide an advantage over others within the population, and would explain how a high frequency of an allele exists within the population with only low phenotypic disadvantages. Several physiological advantages are associated with the GJB2 mutation, including a thickened ‘protective’ epithelium, antimicrobial resistance in the gut microbiome, heightened wound healing, and a decrease in cell death of laboratory cell lines. Although deafness would normally be considered a disadvantage to early human populations, would the physiological advantages outweigh the lack of hearing associated with the C-26 mutation? This paper seeks to examine the proliferation of the C-26 mutation and whether it carries an evolutionary advantage to the heterozygous population affected. 

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The role of connexin gap junctions (GJB2) are paramount to the functionality of cell to cell communication and intracellular transportation of ionic compounds, potassium, monosaccharides, and ATP. Molecules, such as cAMP, cGAMP, amino acids, and glutathionine, are transported through gap junctions. By allowing the passage of molecules, cations, and ATP, connectins are vital in regulating cellular replication, differentiation, and homeostatic conditions within epithelial tissues. Additionally, once these molecules are transported through connexins, they may function as a paracrine or autocrine signal (Garcia, et al., 2016). The connexin-26 (C-26) polypeptide is comprised of four transmembrane domains, including an intracellular loop, a cytosolic N and C terminus, two extracellular loops, and the N-terminal domain, which may catalyze and incite channel gating and voltage action potential (Press et al., 2017). The formation of connexins are critical, as each component of the six-member ring must bind with one another to form the hemi-channel, or the channel pore. Gap junctions serve another important purpose within the framework of cellular communication by synchronizing the firing of neurons and in a rapid, timed manner, as these gap junctions regulate metabolic processes between adjacent neurons and astrocytes (Anselmi, et al., 2008). Many cellular processes could not function without properly functioning connexin gap junction proteins, and mutations in these proteins often prove detrimental to the individual.

Deafness of a biological or pathological origin, such as profound deafness, is statistically rare within the population, as the most common cause of deafness is injury, illness, or age. Worldwide, approximately 17.3% of hearing loss is attributed to allelic connexin gap junction mutations (Press et al., 2017), and one in 1,000 children are born deaf due to GJB2 mutations (Martin, et al., 2014). Mutations in the C-26 lead to two primary phenotypes resulting from homeostatic imbalance of calcium and water in the inner ear and permanent potassium deficiency of the epithelium, degeneration of the cochlea, and mass apoptosis (Garcia, et al., 2016). Once homeostasis of ions is lost in the cochlea and inner ear, permeant hearing loss ensues. Individuals of the first phenotype experience non-syndromic deafness with a moderate to severe deafness of a single origin. Other than a lack of hearing, these individuals experience no other symptoms associated with the GJB2 mutation. The second phenotype, syndromic deafness, additionally experiences one or more forms of epithelial tissue involvement, such as keratitis ichthyosis deafness syndrome (KID), Bart-Pumphrey syndrome, or Vohwinkel syndrome (Garcia, et al., 2016). These individuals experience a range of epithelial involvement due to the homozygous allele. Heterozygotes do not experience epithelial tissue involvement, and their level of hearing loss can vary.

Globally, a high carrier frequency of the C-26 mutation may suggest a heterozygous advantage to the population. The importance of a heterozygous advantage is to impart a genetic advantage onto offspring which better enables them to survive their environment. When an offspring receives one recessive and one dominant copy of the allele, the offspring may not express the full phenotypic variant of the C-26 mutation, which is syndromic or non-syndromic deafness, but may simply benefit from the epithelial barrier which is developed as a response to the allele. This high carrier frequency is found within various ethnic groups worldwide of varying prevalence, although highest in Africa (Man et al., 2007). The C-26 mutation has been detected in frequencies of one in seventy in northern Europe and one in thirty in the Mediterranean region (D’Adamo, et al., 2008). The Chinese population, which has previously been linked with having a predisposition locus to psoriasis, additionally has a high prevalence of the C-26 mutation with the population (Scott, et al., 2012). Varying selective pressures based on regional differences, such as climate, the availability and scarcity of food, climate, and differences in predation are potential reasons why the C-26 carrier frequencies vary so wildly. These selective pressures would have been stronger in seperate human populations before civilizations changed and advanced into more structured societies with different evolutionary pressures.

The predominant heterozygous mutation in Africa, R143W, coincides with the presentation of a thickening of the epidermis in the carriers within the population (Man et al., 2007). These individuals are heterozygous carriers and are not deaf, and do not experience epithelial tissue disease. In the study by Man et al., the researchers expressed either R143W or wild type cells in a migrating in vitro keratinocyte study to compare the thickness of epidermal layers grown. This study successfully demonstrated that R143W cells developed thicker epithelial layers, and additionally, were less vulnerable to S. flexneri gastrointestinal bacterial than wild type cells (Man et al., 2007). R143W cells benefitted from having an impenetrable epithelium in which bacteria could not infect, providing an evolutionary benefit to the cell line.

To further support the evidence for heterozygote advantage for C-26 mutations, Commons et al., studied GJB2 in vivo to examine cellular death in wild type cells versus the mutant cells after growth of epithelial layers (2004). GJB2 mutated cells demonstrated a decreased number of keratinocyte deaths than the wild type, which may provide evidence supporting a heterozygote advantage at a population level (Commons et al., 2004). This particular phenotype may be of enough advantage to warrant potential risk of deafness within the population. According to Martin, et al., not only can a recessive mutation, but a gene deletion, such as the C-26 deletion, produce deafness, and epithelial thickness, but no skin disease (2014). This equates to an evolutionary “cost-benefit analysis” in which there is a slight risk for a small percent of individuals out of the population as a whole of developing a small defect or disorder by incurring a greater survival benefit.

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Additionally, gastrointestinal protection has been demonstrated by the protection via supplementary goblet cells to ward off invading Shigella Flexneri bacteria(D’Adamo, et al., 2008). A solid selective effect may be caused by S. flexneri and Escherichia coli as the primary causes of diarrheal diseases in the human population (Woods, et al., 2014). Protection from bacterial pathogens such as these would provide individuals with an evolutionary adaptation that would enable them to live longer and produce more healthy, viable offspring who would not succumb to gastrointestinal infections if heterozygous for C-26. Even today, diarrheal diseases remain one of the deadliest diseases to developing nations, so a heterozygous advantageous could save hundreds of thousands of lives per year.  

 The necessitation for a heterozygote advantage for the human population cannot be overstated as its’ importance has neither lost its value over time nor importance. Since the beginning of time, various phenotypic variances have arisen over time and were maintained within the population as they provided evolutionary advantages to survival. Those which were most successful were heterozygous, such as the connexin 26 mutation. Despite much evidence to support the theory of the C-26 mutation providing the human population with a heterozygous advantage, another possibility could also explain why the mutation continues to be found in a steady prevalence. The founder effect additionally explains why Africa demonstrates the highest carrier frequency in the world with radiating frequencies in the Mediterranean region, Europe, and Asia. The highest concentration of mutations would remain in the original population, being the African population, and due to international travel and cross-cultural reproduction, the C-26 heterozygous mutation has traveled worldwide, in lower carrier frequencies, to protect the population at large.

 Gap junction proteins such as connexin-26 are vital to the communication which occurs intracellularly between epithelial cells which line the inner ear, cochlea, gastrointestinal tract, and surface epithelium. Disorders of the C-26 connexin range from singularly deafness to deafness associated with a range of epithelial tissue involvement, such as keratitis ichthyosis deafness syndrome (KID). Interestingly, individuals who are heterozygous for the C-26 mutation do not experience any epithelial disorders and only a small percentage are deaf. As demonstrated by the discussed research outlined in this paper, a heterozygous advantage could afford the population which carries one copy of the mutated allele an advantage over the homozygous subset of the population, thus providing an evolutionary edge. Although these studies provide evidence which support a theory, a second explanation for the maintenance of the heterozygote within the human still exists, which is the founder effect. Although the actual evolutionary pressure has yet to be determined conclusively as of yet, of one thing researchers are certain, that C-26 heterozygotes do demonstrate a biological and evolutionary advantage over homozygotes for health and survival in today’s times.


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