Common Ancestry-specific Ion Channel Variants Predispose to Drug-induced Arrhythmias

Background: Multiple reports associate the cardiac sodium channel gene ( SCN5A ) variants S1103Y and R1193Q with type 3 congenital long QT syndrome (LQTS) and drug-induced LQTS. These variants are, however, too common in ancestral populations to be highly arrhythmogenic at baseline: S1103Y allele frequency is 8.1% in Africans and R1193Q 6.1% in East Asians. R1193Q is known to increase late sodium current (I Na-L ) in cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) but the role of these variants in modulating repolarization remains poorly-understood. Methods: We determined the effect of S1103Y on QT intervals among Africans in a large electronic health record. Using iPSC-CMs carrying naturally occurring or genome-edited variants, we studied action potential durations (APDs) at baseline and after challenge with the repolarizing potassium current (I Kr ) blocker dofetilide, and I Na-L and I Kr at baseline. Results: In 1479 African subjects with no confounding medications or diagnoses of heart disease, QT in S1103Y carriers was no different from that in non-carriers. Similarly, baseline APD was no different in cells expressing the Y allele (SY, YY cells) compared to isogenic cells with the reference allele (SS cells). However, I Na-L was increased in SY and YY cells and the I Na-L blocker GS967 shortened APD in SY/YY but not SS cells (p<0.001). I Kr was increased almost 2-fold in SY/YY cells compared to SS cells (tail current: 0.66±0.1 vs 1.2±0.1 pA/pF, p<0.001). Dofetilide challenge prolonged APD at much lower concentrations in SY (4.1 nM [IQR 1.5-9.3], n=11) and YY (4.2 nM [1.7- 5.0], n=5) than in SS cells (249 nM [22.3-2905], n=14, p<0.001 and p<0.01, respectively) and elicited afterdepolarizations in 8/16 SY/YY cells but only in 1/14 SS cells. R1193Q cells similarly displayed no difference in baseline APD but increased I Kr and increased dofetilide sensitivity. Conclusions: These common ancestry-specific variants do not affect baseline repolarization, despite generating increased I Na-L . We propose that increased I Kr serves to maintain normal repolarization but increases the risk of manifest QT prolongation with I Kr block in variant carriers. Our findings further emphasize the need for inclusion of diverse populations in the study of adverse drug reactions.

Mutational cascade of SARS-CoV-2 leading to evolution and emergence of omicron variant

Background: Emergence of new variant of SARS-CoV-2, namely omicron, has posed a global concern because of its high rate of transmissibility and mutations in its genome. Researchers worldwide are trying to understand the evolution and emergence of such variants to understand the mutational cascade events. Methods: We have considered all omicron genomes (n = 302 genomes) available till 2nd December 2021 in the public repository of GISAID along with representatives of variants of concern (VOC), i.e., alpha, beta, gamma, delta, and omicron; variant of interest (VOI) mu and lambda; and variant under monitoring (VUM). Whole genome-based phylogeny and mutational analysis were performed to understand the evolution of SARS CoV-2 leading to emergence of omicron variant. Results: Whole genome-based phylogeny depicted two phylogroups (PG-I and PG-II) forming variant specific clades except for gamma and VUM GH. Mutational analysis detected 18,261 mutations in the omicron variant, majority of which were non-synonymous mutations in spike (A67, T547K, D614G, H655Y, N679K, P681H, D796Y, N856K, Q954H), followed by RNA dependent RNA polymerase (rdrp) (A1892T, I189V, P314L, K38R, T492I, V57V), ORF6 (M19M) and nucleocapsid protein (RG203KR). Conclusion: Delta and omicron have evolutionary diverged into distinct phylogroups and do not share a common ancestry. While, omicron shares common ancestry with VOI lambda and its evolution is mainly derived by the non-synonymous mutations.

Epilogue

Briefly drawing together the main themes of the book in a roundup of ‘lessons learned’, the epilogue sketches out a vision for new forms of group alignment that transcend the parochialism of ancient imagistic worlds and the forms of outgroup derogation and intolerance that doctrinal systems foment, replacing them with new forms of extended fusion. These are required to address all the major challenges of the Anthropocene, including the need to recognize a shared set of human obligations, alongside our much-vaunted rights. As we strive to combat racism and fuel instead the recognition that we are all members of one species, we may also seek to extend that intuition of shared biological essence to all other outgrowths on the tree of life, with which we share a common ancestry. Joining in new rituals that emphasize these sorts of shared experiences and shared bodies will be vital because, in the end, our fates are entwined and the ritual animal is, well, just another animal.

Colonial Roots of the Aryan Invasion/Migration Theory and the Contemporary Archaeological Evidence in Western Sources

William Jones, famously, by identifying close linkages between Sanskrit and European languages, gave birth to research into the common ancestry between Indians and Europeans. In the earlier years of contention on the matter, India was considered the cradle of civilisation and Sanskrit as the mother of all Indo-European languages. With the rise in the imperial power of Europe over India, the cradle of civilisation began to shift outside India and ultimately landed in Europe. Simultaneously, the idea of invasion of India by the ‘Aryan race’, or the Aryan invasion theory (AIT), was promoted. Since then, however, one archaeological find over another have consistently refuted the AIT, proving it as false. As flawed as it remains, this theory has, nonetheless, persisted and morphed in its current form as the Aryan migration theory (AMT) and continues to find mention and favour in contemporary academic discourse. In mainstream academia, today, whether in grade-school texts or in texts meant for undergraduate and graduate study, whenever India and Hinduism are mentioned, the coming of Aryans from outside of India and establishing Hinduism and civilisation in India are discussed as veritable facts. By examining the theory in anticolonial and postcolonial contexts, we show that despite considerable archaeological evidence refuting the theories of the invasion or migration of Aryans into India, its colonial embeddedness in the notion of the racial superiority of the Europeans or people with European ancestry that the theory does not fade into oblivion.

Quantifying bacterial evolution in the wild: A birthday problem for Campylobacter lineages

Measuring molecular evolution in bacteria typically requires estimation of the rate at which nucleotide changes accumulate in strains sampled at different times that share a common ancestor. This approach has been useful for dating ecological and evolutionary events that coincide with the emergence of important lineages, such as outbreak strains and obligate human pathogens. However, in multi-host (niche) transmission scenarios, where the pathogen is essentially an opportunistic environmental organism, sampling is often sporadic and rarely reflects the overall population, particularly when concentrated on clinical isolates. This means that approaches that assume recent common ancestry are not applicable. Here we present a new approach to estimate the molecular clock rate in Campylobacter that draws on the popular probability conundrum known as the ‘birthday problem’. Using large genomic datasets and comparative genomic approaches, we use isolate pairs that share recent common ancestry to estimate the rate of nucleotide change for the population. Identifying synonymous and non-synonymous nucleotide changes, both within and outside of recombined regions of the genome, we quantify clock-like diversification to estimate synonymous rates of nucleotide change for the common pathogenic bacteria Campylobacter coli (2.4 x 10−6 s/s/y) and Campylobacter jejuni (3.4 x 10−6 s/s/y). Finally, using estimated total rates of nucleotide change, we infer the number of effective lineages within the sample time-frame–analogous to a shared birthday–and assess the rate of turnover of lineages in our sample set over short evolutionary timescales. This provides a generalizable approach to calibrating rates in populations of environmental bacteria and shows that multiple lineages are maintained, implying that large-scale clonal sweeps may take hundreds of years or more in these species.

A histological investigation of dental crown characters used in mosasaur phylogenetic analyses

Mosasaur researchers have used varieties of tooth crown ornamentation as diagnostic and phylogenetic characters for decades. Such tooth crown features include facets, flutes, striations, serrated carinae, and coarse anastomosing texture. This study investigates the relative contribution of dentine and enamel to the development of these dental characters and assesses possible homologies between these structures. Histological analysis of isolated mosasaur teeth revealed that flutes and facets develop initially from the dentine, and the external enamel morphology we observe macroscopically mirrors the shape the underlying dentine. Striations combine underlying contributions from the dentine with additional and irregular enamel deposition that results strictly from amelogenesis. In both serrated carinae and anastomosing texture the border between the dentine and the enamel is smooth, and these external ornamentations form through variations in enamel development. Based on these observations, we infer that flutes and facets are part of a morphological spectrum and should not be treated as separate phylogenetic characters. Conversely, striations develop differently than flutes and facets, and should therefore be treated as a distinct character. We recommend referring to the “serrations” on mosasaur carinae as crenulations to differentiate these enamel-only structures from true denticles possessing a dentine core. Anastomosing texture can also coincide with significant apical thickening, both of which could be adaptations for processing hard-shelled prey. Care must be taken when using tooth crown features as diagnostic or phylogenetic characters because seemingly different morphologies can have similar developmental origins, and tooth morphology can be more closely tied to diet than to common ancestry.

Human norovirus GII.4 Hong Kong variant shares common ancestry with GII.4 Osaka and emerged in Thailand in 2016

Human norovirus is a leading cause of non-bacterial acute gastroenteritis, which affects all age groups and are found globally. Infections are highly contagious and often occur as outbreaks. Periodic emergence of new strains are not uncommon and novel variants are named after the place of first reported nucleotide sequence. Here, we identified human norovirus GII.4 Hong Kong variant in stool samples from Thai patients presented with acute gastroenteritis. Comparison of amino acid residues deduced from the viral nucleotide sequence with those of historical and contemporary norovirus GII.4 strains revealed notable differences, which mapped to the defined antigenic sites of the viral major capsid protein. Time-scaled phylogenetic analysis suggests that GII.4 Hong Kong shared common ancestry with GII.4 Osaka first reported in 2007, and more importantly, did not evolve from the now-prevalent GII.4 Sydney lineage. As circulation of norovirus minor variants can lead to eventual widespread transmission in susceptible population, this study underscores the potential emergence of the GII.4 Hong Kong variant, which warrants vigilant molecular epidemiological surveillance.

Exploring the Origin and Relatedness of Maternal Lineages Through Analysis of Mitochondrial DNA in the Holstein Horse

Maternal lineages are important for the breeding decision in the Holstein horse breed. To investigate the genetic diversity of the maternal lineages and the relationships between founder mares, the maternal inherited mitochondrial genome (except the repetitive part of the non-coding region) of 271 mares representing 75 lineages was sequenced. The sequencing predominantly revealed complete homology in the nucleotide sequences between mares from one lineage with exceptions in 13 lineages, where differences in one to three positions are probably caused by de novo mutations or alternate fixation of heteroplasmy. We found 78 distinct haplotypes that have not yet been described in other breeds. Six of these occurred in two or three different lineages indicating a common ancestry. Haplotypes can be divided into eight clusters with all mares from one lineage belonging to the same cluster. Within a cluster, the average number of pairwise differences ranged from zero to 16.49 suggesting close maternal relationships between these mares. The results showed that the current breeding population originated from at least eight ancestral founder mares.

The Lamprey Forebrain – Evolutionary Implications

The forebrain plays a critical role in a broad range of neural processes encompassing sensory integration and initiation/selection of behaviour. The forebrain functions through an interaction between different cortical areas, the thalamus, the basal ganglia with the dopamine system, and the habenulae. The ambition here is to compare the mammalian forebrain with that of the lamprey representing the oldest now living group of vertebrates, by a review of earlier studies. We show that the lamprey dorsal pallium has a motor, a somatosensory, and a visual area with retinotopic representation. The lamprey pallium was previously thought to be largely olfactory. There is also a detailed similarity between the lamprey and mammals with regard to other forebrain structures like the basal ganglia in which the general organisation, connectivity, transmitters and their receptors, neuropeptides, and expression of ion channels are virtually identical. These initially unexpected results allow for the possibility that many aspects of the basic design of the vertebrate forebrain had evolved before the lamprey diverged from the evolutionary line leading to mammals. Based on a detailed comparison between the mammalian forebrain and that of the lamprey and with due consideration of data from other vertebrate groups, we propose a compelling account of a pan-vertebrate schema for basic forebrain structures, suggesting a common ancestry of over half a billion years of vertebrate evolution.