Relación genotipo‐fenotipo: un universo a ser descubierto

Las características morfológicas resultan de procesos complejos que involucran expresión espacial y temporal de varios genes que interactúan durante el desarrollo. Sin embargo, aún se sabe poco acerca del exacto conjunto de genes que estaría relacionado con la diversidad morfológica normal dentro y entre especies de mamíferos, incluyendo al Homo sapiens sapiens. En este trabajo se investigaron varios genes (PAX9, PAX1, PAS4, MSX1, MSX2, BMP2, BMP4, FGFR1 e TCOF1) todos con posibles implicancias en la variabilidad craneofacial y dental en mamíferos. Datos preliminares relativos al SNP -346C>T del gen TCOF1 (el alelo T reduce en un 38% los niveles de transcripción in vitro), por ejemplo, muestran que el alelo T está presente en Amerindios y Esquimales, y ausente en Europeos.Asociación de Antropología Biológica de la República Argentin

Arms Race: Coevolução vírus-hospedeiro com foco na família Coronaviridae

Em 1973, o biólogo evolutivo Leigh Van Valen propôs a hipótese da Rainha Vermelha para explicar a condição evolutiva dada particularmente aos conflitos bióticos entre espécies antagonistas. Essetermo é inspiradonafrase "It takes all the running you can do, to keep in the same place." Numa tradução livre para o português, seria "É preciso correr o máximo possível para permanecer no mesmo lugar" dita pela Rainha Vermelha, personagem obra literária de Lewis Carrol (Alice Através do Espelho). Essa frase aplicada ao que ocorre na natureza significa que o aumento do valor adaptativo de uma espécie, pode levar à diminuição do valor adaptativo de outra, que estaria sendo predada ou parasitada, tornando esse processo coevolutivo numa espécie de corrida evolucionaria armamentista (arms race do inglês) travada ao longo do tempo e que encerraria somente se uma das espécies envolvidas se extinguisse. Um exemplo bastante representativo de arms race é a complexa interação coevolutiva entre hospedeiro e patógeno. Em um período pandêmico, como não lembrar do SARS-COV-2, agente causador da COVID-19. Assim, apresentamos nesse artigo tópicos de taxonomia, morfologia, estrutura viral, e uma revisão da origem e patogênese dos coronavírus e a suas relações com a arms race travada com seus hospedeiros, incluindo o Homo sapiens. In 1973, evolutionary biologist Leigh Van Valen proposed the Red Queen hypothesis to explain the evolutionary condition, particularly to biotic conflicts between antagonistic species. This term is inspired by the phrase "It takes all the running you can do, to keep in the same place", said by the Red Queen character in Lewis Carroll's literary work (Alice Through the Looking Glass). This phrase applied to what happens in nature means that the increase in the adaptive value of one species can lead to the decrease in the adaptive value of another, which would be being preyed upon or parasitized, turning this coevolutionary process into a kind of evolutionary arms race waged over time and which would end if one of the species involved became extinct. A representative example of an arms race is the complex coevolutionary interaction between host and pathogen. How can we not remember, in this context, SARS-COV-2, the responsible agent for COVID-19. In this article, we present information on the taxonomy, morphology and viral structure of coronaviruses, together with a review of the origin and pathogenesis of coronaviruses and their relationships with the arms race fought with their hosts, including Homo sapiens

Gallstones, body mass index, C-reactive protein, and gallbladder cancer: mendelian randomization analysis of chilean and european genotype data

Background and Aims: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C-reactive protein (CRP) level as a marker of chronic inflammation. Approach and Results: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 × 10−5) and Europeans (P = 9 × 10−5). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 × 10−6). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. Conclusions: Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk

Native American ancestry significantly contributes to neuromyelitis optica susceptibility in the admixed Mexican population

Neuromyelitis Optica (NMO) is an autoimmune disease with a higher prevalence in non-European populations. Because the Mexican population resulted from the admixture between mainly Native American and European populations, we used genome-wide microarray, HLA high-resolution typing and AQP4 gene sequencing data to analyze genetic ancestry and to seek genetic variants conferring NMO susceptibility in admixed Mexican patients. A total of 164 Mexican NMO patients and 1,208 controls were included. On average, NMO patients had a higher proportion of Native American ancestry than controls (68.1% vs 58.6%; p = 5 × 10⁻⁶). GWAS identified a HLA region associated with NMO, led by rs9272219 (OR = 2.48, P = 8 × 10⁻¹⁰). Class II HLA alleles HLA-DQB1*03:01, -DRB1*08:02, -DRB1*16:02, -DRB1*14:06 and -DQB1*04:02 showed the most significant associations with NMO risk. Local ancestry estimates suggest that all the NMO-associated alleles within the HLA region are of Native American origin. No novel or missense variants in the AQP4 gene were found in Mexican patients with NMO or multiple sclerosis. To our knowledge, this is the first study supporting the notion that Native American ancestry significantly contributes to NMO susceptibility in an admixed population, and is consistent with differences in NMO epidemiology in Mexico and Latin America

Identification of circulating lncRNAs associated with gallbladder cancer risk by tissue-based preselection, cis-eQTL validation, and analysis of association with genotype-based expression

Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candi dates for cancer risk prediction. Few studies have investigated the association between individual genotypes and lncRNA expression. Here we integrate three separate datasets with information on lncRNA expression only, both lncRNA expression and genotype, and genotype information only to identify circulating lncRNAs associated with the risk of gallbladder cancer (GBC) using robust linear and logistic regression techniques. In the first dataset, we preselect lncRNAs based on ex pression changes along the sequence “gallstones → dysplasia → GBC”. In the second dataset, we validate associations between genetic variants and serum expression levels of the preselected lncR NAs (cis-lncRNA-eQTLs) and build lncRNA expression prediction models. In the third dataset, we predict serum lncRNA expression based on individual genotypes and assess the association between genotype-based expression and GBC risk. AC084082.3 and LINC00662 showed increasing expression levels (p-value = 0.009), while C22orf34 expression decreased in the sequence from gallstones to GBC (p-value = 0.04). We identified and validated two cis-LINC00662-eQTLs (r2 = 0.26) and three cis-C22orf34-eQTLs (r2 = 0.24). Only LINC00662 showed a genotyped-based serum expression associ ated with GBC risk (OR = 1.25 per log2 expression unit, 95% CI 1.04–1.52, p-value = 0.02). Our results suggest that preselection of lncRNAs based on tissue samples and exploitation of cis-lncRNA-eQTLs may facilitate the identification of circulating noncoding RNAs linked to cancer risk

Differing evolutionary histories of the ACT3*R577X polymorphism among the major human geographic groups

It has been proposed that the functional ACTN3*R577X polymorphism might have evolved due to selection in Eurasian human populations. To test this possibility we surveyed all available population-based data for this polymorphism and performed a comprehensive evolutionary analysis of its genetic diversity, in order to assess the action of adaptive and random mechanisms on its variation across human geographical distribution. The derived 577X allele increases in frequency with distance from Africa, reaching the highest frequencies on the American continent. Positive selection, detected by an extended haplotype homozygosisty test, was consistent only with the Eurasian data, but simulations with neutral models could not fully explain the results found in the American continent. It is possible that particularities of Native American population structure could be responsible for the observed allele frequencies, which would have resulted from a complex interaction between selective and random factors

ACE2 diversity in placental mammals reveals the evolutionary strategy of SARS-CoV-2

The recent emergence of SARS-CoV-2 is responsible for the current pandemic of COVID-19, which uses the human membrane protein ACE2 as a gateway to the host-cell infection. We perform comparative genomic analysis of 70 ACE2 placental mammal orthologues to identify variations and contribute to the understanding of evolutionary dynamics behind this successful adaptation to infect humans. Our results reveal that 4% of the ACE2 sites are under positive selection, all located in the catalytic domain, suggesting possibly taxon-specific adaptations related to the ACE2 function, such as cardiovascular physiology. Considering all variable sites, we selected 30 of them located at the critical ACE2 binding sites to the SARS-CoV-like viruses to analyze in more detail. Our results reveal a relatively high diversity of ACE2 between placental mammal species while showing no polymorphism within human populations, at least considering the 30 inter-species variable sites. A perfect scenario for natural selection favored this opportunistic new coronavirus in its trajectory of infecting humans. We suggest that SARS-CoV-2 became a specialist coronavirus for human hosts. Differences in the rate of infection and mortality could be related to the innate immune responses, other unknown genetic factors, as well as non-biological factors

Genome-wide association studies and CRISPR/Cas9-mediated gene editing identify regulatory variants influencing eyebrow thickness in humans

Hair plays an important role in primates and is clearly subject to adaptive selection. While humans have lost most facial hair, eyebrows are a notable exception. Eyebrow thickness is heritable and widely believed to be subject to sexual selection. Nevertheless, few genomic studies have explored its genetic basis. Here, we performed a genome-wide scan for eyebrow thickness in 2961 Han Chinese. We identified two new loci of genome-wide significance, at 3q26.33 near SOX2 (rs1345417: P = 6.51×10−10) and at 5q13.2 near FOXD1 (rs12651896: P = 1.73×10−8 ). We further replicated our findings in the Uyghurs, a population from China characterized by East Asian-European admixture (N = 721), the CANDELA cohort from five Latin American countries (N = 2301), and the Rotterdam Study cohort of Dutch Europeans (N = 4411). A meta-analysis combining the full GWAS results from the three cohorts of full or partial Asian descent (Han Chinese, Uyghur and Latin Americans, N = 5983) highlighted a third signal of genome-wide significance at 2q12.3 (rs1866188: P = 5.81×10−11) near EDAR. We performed fine-mapping and prioritized four variants for further experimental verification. CRISPR/Cas9-mediated gene editing provided evidence that rs1345417 and rs12651896 affect the transcriptional activity of the nearby SOX2 and FOXD1 genes, which are both involved in hair development. Finally, suitable statistical analyses revealed that none of the associated variants showed clear signals of selection in any of the populations tested. Contrary to popular speculation, we found no evidence that eyebrow thickness is subject to strong selective pressure

ACE2 diversity in placental mammals reveals the evolutionary strategy of SARS-CoV-2

The recent emergence of SARS-CoV-2 is responsible for the current pandemic of COVID-19, which uses the human membrane protein ACE2 as a gateway to host-cell infection. We performed a comparative genomic analysis of 70 ACE2 placental mammal orthologues to identify variations and contribute to the understanding of evolutionary dynamics behind this successful adaptation to infect humans. Our results reveal that 4% of the ACE2 sites are under positive selection, all located in the catalytic domain, suggesting possibly taxon-specific adaptations related to the ACE2 function, such as cardiovascular physiology. Considering all variable sites, we selected 30 of them located at the critical ACE2 binding sites to the SARS-CoV-like viruses for analysis in more detail. Our results reveal a relatively high diversity of ACE2 between placental mammal species, while showing no polymorphism within human populations, at least considering the 30 inter-species variable sites. A perfect scenario for natural selection favored this opportunistic new coronavirus in its trajectory of infecting humans. We suggest that SARS-CoV-2 became a specialist coronavirus for human hosts. Differences in the rate of infection and mortality could be related to the innate immune responses, other unknown genetic factors, as well as non-biological factors