Evaluation of the relationship between CD36 and MARCO single-nucleotide polymorphisms and susceptibility to carotid atherosclerosis in a Chinese Han population.

OBJECTIVE: This study analyzed the genetic association between two scavenger receptors single nucleotide polymorphisms (CD36 rs1761667, MARCO rs12998782) and carotid atherosclerosis in a Chinese Han population. METHODS: Samples of genomic DNA collected from patients (n=215) and healthy control subjects (n=252) were analyzed by the polymerase chain reaction with high-resolution melting analysis. Odds ratios and 95% confidence intervals were used to evaluate the association between the two SNPs and carotid atherosclerosis. RESULTS: There was no difference between the SNPs regarding their association with the frequency of carotid atherosclerosis in the case and control groups or in the male case group and control group. Female patients of genotype GA for CD36 rs1761667 and CT for MARCO rs12998782 were at an increased risk for carotid atherosclerosis. The presence of rs1761667 GA and rs12998782 CT may increase the risk for carotid atherosclerosis among postmenopausal females. CONCLUSIONS: CD36 and MARCO are associated with the susceptibility of Chinese Han females to carotid atherosclerosis. Menopausal status may affect the association between gene polymorphisms and carotid atherosclerosis in the female Chinese Han population.

Penetrance and the Healthy Elderly.

The variable penetrance of pathogenic variants (PVs) represents a major challenge to the field of human genetics, often complicating clinical decision-making and risk management. Nonpenetrance, the detection of PVs in the absence of disease manifestation, is a common phenomenon, yet, we know very little about the underlying factors, which may protect some individuals and not others. Placing a new focus on the genomic study of the healthy elderly may be pivotal for advancing our understanding of penetrance. Studying those who remain unaffected late into life, despite harboring known genetic risk variants, could provide important insights into disease mechanisms and ultimately inform clinical care, yet, it has received relatively little attention as a research strategy. The ever increasing use of sequencing technology is further driving the requirement to understand the penetrance of ascertained variants. The ASPREE Biobank of Healthy Ageing provides a unique opportunity to address this area of need. DNA has been collected from a cohort of over 14,000 healthy elderly individuals aged 70 years or older enrolled in an aspirin clinical trial. The ASPREE cohort represents a healthy reference population ascertained without the typical biases of a genetic study. The cohort is depleted of expressed monogenetic disease, yet will contain hundreds of elderly individuals with known PVs in clinically actionable genes. Investigating this population along with other cohorts of the healthy elderly will provide critical new knowledge into the penetrance of actionable variants as a foundation for informing clinical care.

Isoform Evolution in Primates through Independent Combination of Alternative RNA Processing Events.

Recent RNA-seq technology revealed thousands of splicing events that are under rapid evolution in primates, whereas the reliability of these events, as well as their combination on the isoform level, have not been adequately addressed due to its limited sequencing length. Here, we performed comparative transcriptome analyses in human and rhesus macaque cerebellum using single molecule long-read sequencing (Iso-seq) and matched RNA-seq. Besides 359 million RNA-seq reads, 4,165,527 Iso-seq reads were generated with a mean length of 14,875 bp, covering 11,466 human genes, and 10,159 macaque genes. With Iso-seq data, we substantially expanded the repertoire of alternative RNA processing events in primates, and found that intron retention and alternative polyadenylation are surprisingly more prevalent in primates than previously estimated. We then investigated the combinatorial mode of these alternative events at the whole-transcript level, and found that the combination of these events is largely independent along the transcript, leading to thousands of novel isoforms missed by current annotations. Notably, these novel isoforms are selectively constrained in general, and 1,119 isoforms have even higher expression than the previously annotated major isoforms in human, indicating that the complexity of the human transcriptome is still significantly underestimated. Comparative transcriptome analysis further revealed 502 genes encoding selectively constrained, lineage-specific isoforms in human but not in rhesus macaque, linking them to some lineage-specific functions. Overall, we propose that the independent combination of alternative RNA processing events has contributed to complex isoform evolution in primates, which provides a new foundation for the study of phenotypic difference among primates.

Context characterization of amino acid homorepeats using evolution, position, and order.

Amino acid repeats, or homorepeats, are low complexity protein motifs consisting of tandem repetitions of a single amino acid. Their presence and relative number vary in different proteomes, and some studies have tried to address this variation, proteome by proteome. In this work, we present a full characterization of amino acid homorepeats across evolution. We studied the presence and differential usage of each possible homorepeat in proteomes from various taxonomic groups, using clusters of very similar proteins to eliminate redundancy. The position of each amino acid repeat within proteins, and the order of co-occurring amino acid repeats were also addressed. As a result, we present evidence about the unevenly evolution of homorepeats, as well as the functional implications of their relative position in proteins. We discuss some of these cases in their taxonomic context. Collectively, our results show evolutionary and positional signals that suggest that homorepeats have biological function, likely creating unspecific protein interactions or modulating specific interactions in a context dependent manner. In conclusion, our work supports the functional importance of homorepeats and establishes a basis for the study of other low complexity repeats. Proteins 2017; 85:709-719. © 2016 Wiley Periodicals, Inc.

Natural Selection in the Great Apes.

Natural selection is crucial for the adaptation of populations to their environments. Here, we present the first global study of natural selection in the Hominidae (humans and great apes) based on genome-wide information from population samples representing all extant species (including most subspecies). Combining several neutrality tests we create a multi-species map of signatures of natural selection covering all major types of natural selection. We find that the estimated efficiency of both purifying and positive selection varies between species and is significantly correlated with their long-term effective population size. Thus, even the modest differences in population size among the closely related Hominidae lineages have resulted in differences in their ability to remove deleterious alleles and to adapt to changing environments. Most signatures of balancing and positive selection are species-specific, with signatures of balancing selection more often being shared among species. We also identify loci with evidence of positive selection across several lineages. Notably, we detect signatures of positive selection in several genes related to brain function, anatomy, diet and immune processes. Our results contribute to a better understanding of human evolution by putting the evidence of natural selection in humans within its larger evolutionary context. The global map of natural selection in our closest living relatives is available as an interactive browser at http://tinyurl.com/nf8qmzh.

Detection of human adaptation during the past 2000 years.

Detection of recent natural selection is a challenging problem in population genetics. Here we introduce the singleton density score (SDS), a method to infer very recent changes in allele frequencies from contemporary genome sequences. Applied to data from the UK10K Project, SDS reflects allele frequency changes in the ancestors of modern Britons during the past ~2000 to 3000 years. We see strong signals of selection at lactase and the major histocompatibility complex, and in favor of blond hair and blue eyes. For polygenic adaptation, we find that recent selection for increased height has driven allele frequency shifts across most of the genome. Moreover, we identify shifts associated with other complex traits, suggesting that polygenic adaptation has played a pervasive role in shaping genotypic and phenotypic variation in modern humans.

Antibiotic susceptibility profile of bacilli isolated from the skin of healthy humans

Abstract In the present work, twelve bacilli were isolated from four different regions of human skin from Bela population of Nagpur district, India. The isolated bacilli were identified by their morphological, cultural and biochemical characteristics. Seven isolates were Gram negative rods, out of which five were belong to genus Pseudomonas. Three among the five Gram positive isolates were identified as Dermabactor and the remaining two Bacillus. Their antimicrobial susceptibility profile was determined by Kirby-Bauer disc diffusion method. The isolates showed resistance to several currently used broad-spectrum antibiotics. The Dermabactor genus was resistant to vancomycin, although it was earlier reported to be susceptible. Imipenem was found to be the most effective antibiotic for Pseudomonas while nalidixic acid, ampicillin and tetracycline were ineffective. Isolates of Bacillus displayed resistance to the extended spectrum antibiotics cephalosporin and ceftazidime. Imipenem, carbenicillin and ticarcillin were found to be the most effective antibiotics as all the investigated isolates were susceptible to them. Antibiotic resistance may be due to the overuse or misuse of antibiotics during the treatment, or following constant exposure to antibiotic-containing cosmetic formulations.

Draft genome sequence of Inquilinus limosus strain MP06, a multidrug-resistant clinical isolate

The bacterium, Inquilinus limosus, with its remarkable antimicrobial multiresistant profile, has increasingly been isolated in cystic fibrosis patients. We report draft genome sequence of a strain MP06, which is of considerable interest in elucidating the associated mechanisms of antibiotic resistance in this bacterium and for an insight about its persistence in airways of these patients.

Nicotinic receptors in non-human primates: Analysis of genetic and functional conservation with humans.

Nicotinic acetylcholine receptors (nAChRs) are highly conserved between humans and non-human primates. Conservation exists at the level of genomic structure, protein structure and epigenetics. Overall homology of nAChRs at the protein level is 98% in macaques versus 89% in mice, which is highly relevant for evaluating subtype-specific ligands that have different affinities in humans versus rodents. In addition to conservation at the protein level, there is high conservation of genomic structure in terms of intron and exon size and placement of CpG sites that play a key role in epigenetic regulation. Analysis of single nucleotide polymorphisms (SNPs) shows that while the majority of SNPs are not conserved between humans and macaques, some functional polymorphisms are. Most significantly, cynomolgus monkeys express a similar α5 nAChR Asp398Asn polymorphism to the human α5 Asp398Asn polymorphism that has been linked to greater nicotine addiction and smoking related disease. Monkeys can be trained to readily self-administer nicotine, and in an initial study we have demonstrated that cynomolgus monkeys bearing the α5 D398N polymorphism show a reduced behavioral sensitivity to oral nicotine and tend to consume it in a different pattern when compared to wild-type monkeys. Thus the combination of highly homologous nAChR, higher cortical functions and capacity for complex training makes non-human primates a unique model to study in vivo functions of nicotinic receptors. In particular, primate studies on nicotine addiction and evaluation of therapies to prevent or overcome nicotine addiction are likely to be highly predictive of treatment outcomes in humans. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.

Core promoter short tandem repeats as evolutionary switch codes for primate speciation.

Alteration in gene expression levels underlies many of the phenotypic differences across species. Because of their highly mutable nature, proximity to the +1 transcription start site (TSS), and the emerging evidence of functional impact on gene expression, core promoter short tandem repeats (STRs) may be considered an ideal source of variation across species. In a genome-scale analysis of the entire Homo sapiens protein-coding genes, we have previously identified core promoters with at least one STR of ≥ 6-repeats, with possible selective advantage in this species. In the current study, we performed reverse analysis of the entire Homo sapiens orthologous genes in mouse in the Ensembl database, in order to identify conserved STRs that have shrunk as an evolutionary advantage to humans. Two protocols were used to minimize ascertainment bias. Firstly, two species sharing a more recent ancestor with Homo sapiens (i.e. Pan troglodytes and Gorilla gorilla gorilla) were also included in the study. Secondly, four non-primate species encompassing the major orders across Mammals, including Scandentia, Laurasiatheria, Afrotheria, and Xenarthra were analyzed as out-groups. We introduce STR evolutionary events specifically identical in primates (i.e. Homo sapiens, Pan troglodytes, and Gorilla gorilla gorilla) vs. non-primate out-groups. The average frequency of the identically shared STR motifs across those primates ranged between 0.00005 and 0.06. The identified genes are involved in important evolutionary and developmental processes, such as normal craniofacial development (TFAP2B), regulation of cell shape (PALMD), learning and long-term memory (RGS14), nervous system development (GFRA2), embryonic limb morphogenesis (PBX2), and forebrain development (APAF1). We provide evidence of core promoter STRs as evolutionary switch codes for primate speciation, and the first instance of identity-by-descent for those motifs at the interspecies level.

Advances and limits of using population genetics to understand local adaptation.

Local adaptation shapes species diversity, can be a stepping stone to ecological speciation, and can facilitate species range expansion. Population genetic analyses, which complement organismal approaches in advancing our understanding of local adaptation, have become widespread in recent years. We focus here on using population genetics to address some key questions in local adaptation: what traits are involved? What environmental variables are the most important? Does local adaptation target the same genes in related species? Do loci responsible for local adaptation exhibit trade-offs across environments? After discussing these questions we highlight important limitations to population genetic analyses including challenges with obtaining high-quality data, deciding which loci are targets of selection, and limits to identifying the genetic basis of local adaptation.

Why we are not all multiregionalists now.

Recent revelations that human genomes contain DNA introgressed through interbreeding with archaic populations outside of Africa have led to reassessments of models for the origins of our species. The fact that small portions of the DNA of recent Homo sapiens derive from ancient populations in more than one region of the world makes our origins 'multiregional', but does that mean that the multiregional model of modern human origins has been proved correct? The extent of archaic assimilation in living humans remains modest, and fossil evidence outside of Africa shows little sign of the long-term morphological continuity through to recent humans expected from the multiregional model. Thus, rather than multiregionalism, a recent African origin (RAO) model for modern humans is still supported by the data.

Exceptional expansion and conservation of a CT-repeat complex in the core promoter of PAXBP1 in primates.

Adaptive evolution may be linked with the genomic distribution and function of short tandem repeats (STRs). Proximity of the core promoter STRs to the +1 transcription start site (TSS), and their mutable nature are characteristics that highlight those STRs as a novel source of interspecies variation. The PAXBP1 gene (alternatively known as GCFC1) core promoter contains the longest STR identified in a Homo sapiens gene core promoter. Indeed, this core promoter is a stretch of four consecutive CT-STRs. In the current study, we used the Ensembl, NCBI, and UCSC databases to analyze the evolutionary trend and functional implication of this CT-STR complex in six major lineages across vertebrates, including primates, non-primate mammals, birds, reptiles, amphibians, and fish. We observed exceptional expansion (≥4-repeats) and conservation of this CT-STR complex across primates, except prosimians, Microcebus murinus and Otolemur garnettii (Fisher exact P<4.1×10(-7)). H. sapiens has the most complex STR formula, and longest repeats. Macaca mulatta and Callithrix jacchus monkeys have the simplest STR formulas, and shortest repeat numbers. CT≥4-repeats were not detected in non-primate lineages. Different length alleles across the PAXBP1 core promoter CT-STRs significantly altered gene expression in vitro (P<0.001, t-test). PAXBP1 has a crucial role in craniofacial development, myogenesis, and spine morphogenesis, properties that have been diverged between primates and non-primates. To our knowledge, this is the first instance of expansion and conservation of a STR complex co-occurring specifically with the primate lineage.

Homo sapiens as physician and patient: a view from Darwinian medicine.

Medicine's cardinal diagnostic and therapeutic resource is the clinical encounter. Over the last two centuries and particularly over the last five decades the function of the clinical encounter has been eroded to the point of near irrelevance because of the atomized and atomizing influence of technology and microspecialization. Meanwhile, over the past five decades the exceptionalist view of Homo sapiens inherent in the social and religious traditions of the West has similarly undergone radical changes. H. sapiens is now best understood as a microecosystem integrated into a much broader ecosystem: the biosphere. That human microecosystem is composed of constituents derived from the archaeal, bacterial, and eukaryan domains via endosymbiotic, commensalistic and mutualistic interactions. This amalgamation of 100 trillion cells and viral elements is regulated by a composite genome aggregated over the 3.8 billion years of evolutionary history of organic life. No component of H. sapiens or its genome can be identified as irreducibly and exclusively human. H. sapiens' humanity is an emergent property of the microecosystem. Ironically as H. sapiens is viewed by evolutionary science in a highly integrated manner medicine approaches it as a balkanized, deaggregated entity through the eye of 150 different specialties. To effectively address the needs of H sapiens in its role as patient by the same species in its role as physician the disparate views must be harmonized. Here I review some conceptual elements that would assist a physician in addressing the needs of the patient in integrum, as a microecosystem, by the former address the latter as a historical gestalt being. The optimal way to recover the harmony between patient and physician is through a revitalization of the clinical encounter via an ecological and Darwinian epistemology.

Proximal metatarsal articular surface shape and the evolution of a rigid lateral foot in hominins.

This study quantifies the proximal articular surface shape of metatarsal (MT) 4 and MT 5 using three-dimensional morphometrics. Humans and apes are compared to test whether they have significantly different shapes that are skeletal correlates to comparative lateral foot function. In addition, shod and unshod humans are compared to test for significant differences in surface shape. The MT 4 fossils OH 8, Stw 628, and AL 333-160, and the MT 5 fossils AL 333-13, AL 333-78, OH 8, and Stw 114/115 are compared with humans and apes to assess whether they bear greater similarities to humans, which would imply a relatively stable lateral foot, or to apes, which would imply a flexible foot with a midfoot break. Apes have a convex curved MT 4 surface, and humans have a flat surface. The MT 4 fossils show greater similarity to unshod humans, suggesting a stable lateral foot. Unshod humans have a relatively flatter MT 4 surface compared with shod humans. There is much overlap in MT 5 shape between humans and apes, with more similarity between humans and Gorilla. The fossil MT 5 surfaces are generally flat, most similar to humans and Gorilla. Because of the high degree of shape overlap between humans and apes, one must use caution in interpreting lateral foot function from the proximal MT 5 surface alone.

[The genetics and the dignity of the human being]. / La genética y la dignidad del ser humano.

The biological elements of man are not sufficient to confront the bioethical questions around the person concept, but are necessary to accurately define the properties of the human beings and the theological, philosophical and legal aspects that are attributable to each person. The human being is a singular being. Indeed, the coexistence of two dimensions of different nature, material and spiritual, is the most important difference between the man and the rest of living beings. Moreover, in man appears a new characteristic, unique between the living beings, the ethical component. The values and guidelines of the moral and ethical behavior of the human being must be considered of natural origin since they have contributed to the success and survival of the species. The man is not only Homo sapiens but also Homo moralis. The recognition of fault, self-control, solidarity, love, generosity, altruism and honesty, among others, are innate qualities in the human beings. The unit of the human species demands the respect and the consideration of the same dignity for all its members, but only for its members. The philosophical anthropology emphasizes the singularity of each human being, each person. This agrees totally with the data of the science, which emphasize the individual and singular genetic identity of each human being.

Evolutionary genetic analyses of MEF2C gene: implications for learning and memory in Homo sapiens.

MEF2C facilitates context-dependent fear conditioning (CFC) which is a salient aspect of hippocampus-dependent learning and memory. CFC might have played a crucial role in human evolution because of its advantageous influence on survival of species. In this study, we analyzed 23 orthologous mammalian gene sequences of MEF2C gene to examine the evidence for positive selection on this gene in Homo sapiens using Phylogenetic Analysis by Maximum Likelihood (PAML) and HyPhy software. Both PAML Bayes Empirical Bayes (BEB) and HyPhy Fixed Effects Likelihood (FEL) analyses supported significant positive selection on 4 codon sites in H. sapiens. Also, haplotter analysis revealed significant ongoing positive selection on this gene in Central European population. The study findings suggest that adaptive selective pressure on this gene might have influenced human evolution. Further research on this gene might unravel the potential role of this gene in learning and memory as well as its pathogenetic effect in certain hippocampal disorders with evolutionary basis like schizophrenia.