Research Paper Sample: Origins of MHC and Its Ancestral Organization

The B7 family of genes is primarily essential in regulating the adaptive immune system. Bot variable constant (C)- and variable (V)- type domains constitute most of the B7 family members of the immunoglobulin superfamily (IgSF). According to Flajnik, Tlapakova, Criscitiello, Krylov, and Ohta (2012), the chromosomal distribution of the B7 family members into the paralogous regions within the human genome is consistent with the genome-wide duplication (WGD) primarily early in the history of the vertebrates as shown in the right and middle columns of Figure 1 below:

Figure 1: B7 family members evolution. Source: Flajnik et al. (2012, p28).

Essentially, as Figure 1 shows, all B7 members are distributed into the MHC paralogous regions, chromosome 9 (B7H1, B7DC) and chromosome 1 (B7H4) as major paralogs, and 15 (B7H3) and 11 (B7H6) as minor paralogs. Additionally, Flanik et al. (2012) also articulated that IgSF genes within the Ciona genome, and chromosomes 21 (B7H2) and 3 (B7.1, B7.2, B7H7) were identified in connection to the MHC paralogous regions on chromosome q and 19q as shown in the left column of Figure 7. In essence, this suggested that these chromosomal regions were associated with the proto-MHC and translocated out prior to WGD. As the B7 family members were found in the MHC paralogous regions, this provides evidence that the precursor of B7 should have arisen before the emergence of the vertebrates as shown in proto-MHC in Figure 7 above. Also, as Flajnik et al. (2012) revealed, the B7H4 genes may have been silenced from a differential perspective in Xenopus and human, which consequently resulted in two paralogous regions. Besides, the Xenopus B7H4 gene is categorically linked to genes that are found in chromosome 3q13 in humans, closely to the B7.1, and human B7H4 is located on chromosome 1 as shown in Figure 1. The similarity of B7 V domains found in MHC-linked MOG and BTN is consistent with the B7 family presence in proto MHC. There was also a close linkage of B2M to B7HXen and XMIV mapping to MHC, as well as NKp30 mapping to similar chromosome as B7H6. Besides, Flajnik et al. (2012) claimed B7 precursor was encoded in B2M and proto MHC, NKRs, and antigen receptors, which play a primary role in adaptive immunity.

Contrasting Neandertal and Modern Human MHC

According to Sullivan, de Manuel, Marques-Bonet, and Perry (2017), there are various hypothesis that contrast Neandertals to modern human, and which are likely to explain their extinction and why human survived. Sullivan et al. (2012) recognized the differential pathogen resistance hypothesis that supports that Neandertals were disproportionately affected owing to the exposure to novel infectious diseases that were transmitted during the spatiotemporal sympatry period with modern humans. Golovanova et al. (2010) hypothesized that climate fluctuations between 40-30 million years ago played a massive role in Neandertal extinction, but this hypothesis was discounted on the simultaneous Eurasian presence of anatomically modern humans for most of the 40-30 kya period in combination with the established environmental resilience of Neandertals (Lowe et al., 2012). Other extinction hypothesis focus on modern human-Neandertal competition, as well as the language capabilities and intelligence of current humans, and a recent proposal about the benefits that resulted from the domestication of dogs, which may have aided human sin hunting for food hence a rapid population growth (Shipman, 2015).

Besides, in their hypothesis, Sullivan et al. (2017) also pointed out that there was a direct genetic admixture of Neandertals with humans but the genetic diversity was considerably lower diversity. In effect, this left Neandertals more susceptible to pathogens. As such, the best hypothesis was that pathogen defense made humans survive. Sullivan et al. (2017) supported, asserting that Neandertals had 31-39% as many nonsynonymous polymorphisms in 73 innate immune system genes in comparison to modern humans, which when coupled by less genetic diversity contributed to their extinction. Humans survived because of greater pathogen defense and more genetic diversity.

Selection at MHC genes that supports Adaptive Evolution

According to Civetta (2015), there is a positive selection of genes associated with pregnancy and MHC. This selection lends to a complete story of MHC evolution. In essence, the researcher surveyed patterns of molecular evolution at genes with a role in embryo implantation and early pregnancy and identified two genes that evolved under positive selection in the phylogenic branch to the evolution of embryo in the maternal uterine layers among primates. Notably, the genes were KIR2DL4, and Human Leukocyte Antigens-E (HLA-E) were detected under positive selection as members of the immune system, and thus, played a huge role in the evolution of the immune system. In essence, the Natural Killer (NK) cells fight pathogen-infected cells by surveying the expression of MHC such as the HLA in infected cells. Even so, some of the positively selected sites involved amino acid substitution coupled with predicted damaging effects on the function of proteins, and this highlighted the possibility of antagonistic pleiotropic effects. Therefore the selection of gene coding for receptors expressed in uterine cells (KIR) that interacts with HLA genes suggested a main role for immunological adaptations in embryo invasion in the maternal endometrium.

Selection at MHC genes that show Host-pathogen Evolution

Barber, Lee, Griffin, and Elde (2017) also provided another example that shows positive selection. Barber et al. (2017) explained other selection factors that show MHCs evolution. The researchers tied MHC evolution to type 2 immune responses that have varying ties to old/new world primates. Barber et al. (2017) also highlighted some MHC similarities between primate species and humans and tied these MHC similarities with shared pathogenicity. In essence, Barber et al. (2017) posited that host immunity pathways evolved rapidly, usually in response to antagonism by pathogens. Also, Barber et al. (2017) asserted that microbial infections could also- contribute to the triggering of excessive inflammation that can lead to autoimmune disorders such as arthritis, lupus, asthma, and diabetes. Even though they pointed out that definitive links between human autoimmune diseases and immune system evolution were unclear, they provided evidence that several components of type 2 immune response pathways are subject to recurring positive selection in the primate lineage. In fact, the substitutions in the central immune regulator IL13 corresponds to a polymorphism that is linked to the susceptibility of asthma among humans. They also provided evidence of accelerated amino acids substitutions along with gene loss and gain events in eosinophil granule proteins, which are toxic antimicrobial effectors that are attributed to promoting asthma pathology through the damage of airway tissues. Therefore, the results supported the hypothesis on evolutionary conflicts with pathogens, which promotes tradeoffs for increasingly robust immune responses in animal evolution. The findings were also consistent with the view that natural selection led to the spread of autoimmune disease alleles among humans. As such, it can be derived that there are MHC similarities between primate species and humans and MHC similarities have shared pathogenicity, which implies positive selection in MHCs evolution.

Co-evolution found between Pathogenic Molecules and MHC.

Jiang and Fares (2010) also provided examples of positive selection that supports MHC/HLA evolution, and their article provided co-evolution of pathogen molecules as a source. According to Jiang and Fares (2010), the antigenic peptide, major histocompatibility complex molecule (MHC or HLA), coreceptor CD4 or CD8, and T-cell receptor (TCR) function as a complex to affect the mechanisms of the immune system. Necessarily, the tight physical and functional interaction among the molecules may have involved strong coevolution links in the protein domains. They performed a coevolution analysis and revealed the independencies, and hence provided evidence to understand the arms race of host-pathogen interaction. As they highlighted, the independencies play a considerable role in shaping the evolution and function of the molecules. Notably, Jiang and Fares (2010) identified intramolecular coevolution in HLA class I and II domains that are important for their immune activity. They also detected most of the amino acids sites identified to be coevolving in HLAI and attributed to undergo positive Darwinian selection highlighting, which reveals their adaptive value. The researchers identified coevolution among antigen-binding pockets (P1-P9) and these and the TCR binding sites. In converse to HlAI, as Jiang and Fares (2010) asserted, coevolution is weaker in HLAII. Therefore, the results supported that coevolutionary patterns are often attributed to selective pressures of host-pathogen coevolution, as well as cooperative binding of TCRs, CD8/CD4, and antigenic peptides to HLAI and HLAII. Besides, the results also revealed that indeed the disruption of the optimized interactions between and among coevolving residues could lead to various levels of disease susceptibility and resistance, for example, progression to AIDS.

Current Understanding of Sialic acid and Neu5Gc Evolutionary History

Springer, Diaz, and Gagneux (2014) highlighted the evolutionary difference between humans and primates. Springer et al. (2014) pointed out that human sialic acid biology is unusual and thought to be unique among mammals compared to the other primates. In essence, humans lack a functional Cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) protein, and thus, they cannot synthesize the sugar Neu5Gc, which is an innate mammalian signal of self. CMAH is the enzyme that enhances a hydroxyl group to CMP-Neu5Ac forming CMP-Neu5Gc (Springer et al., 2014). Inactivation of CMAH usually causes the absence of Neu5Gc in human tissues. Since humans loosed this sugar, it changed how we interact with some of the deadliest pathogens we are predisposed to, including influenza, malaria, and streptococcus. In fact, New World monkeys currently comprising of a third of all primate species contain a human-like sialic acid biology. They lost Neu5Gc primarily because of an independent CMAH inactivation, dates approximately 30 million years ago in comparison to 3 million years ago in hominids (Perez, Tejedor, Novo, & Aristide, 2013). Essentially, the parallel loss of the Neu5Gc opens sialic acid biology to comparative phylogenetic analysis and also showcases an unexpected conservation priority. For this reason, it can be derived that New World monkeys are currently at a risk of infection by human pathogens that cannot otherwise recognize cells in the absence of Neu5Gc.

For this reason, from Springer et al.s (2014) stud, it can be derived that the striking molecular convergence provided a mechanism that can explain the longstanding observation that monkeys are currently susceptible to human infections that cannot be transmittable to other primates. Therefore, human sialic acid biology has changed over the years extensively to compensate for the absence of Ne5Gc. In fact, sialic acid binding proteins, for example, Siglecs evolve by positive selection, and many have human mutations.

Contrasting the CD33rSiglec among Primates and Possible Red Queen Effects

Padler-Karavani et al. (2013) explain some of the genetic differences between humans and primates. More specifically, they focus on the differences at the CD33 receptor which is a major siglec family. Siglecs are sialic aci...