Autopoiesis and natural drift: genetic information, reproduction, and evolution revisited

The contribution of the theory of autopoiesis to the definition of life and biological theory affirms biological autonomy as a central notion of scientific and philosophical inquiry, and opposes other biological approaches, based on the notion of genetic information, that consider reproduction and evolution to be the central aspects of life and living phenomenology. This article reviews the autopoietic criticisms of genetic information, reproduction, and evolution in the light of a biology that can solve the problem of living organization.     

Evolution of the mammalian MHC: natural selection, recombination, and convergent evolution

Summary: The genes that encode molecules involved in antigen presentation within the class I and class II regions of the mammalian major histocompatibility complex (MHC) include several that are highly polymorphic. There is evidence that this polymorphism is maintained by positive selection, most likely overdominant selection, relating to their role in presenting foreign peptides to T cells. This selection can maintain allelic lineages for much longer periods of time than neutral polymorphisms are expected to last, but sharing of polymorphic amino acid motifs among species of different mammalian orders is due to independent (or convergent) evolution rather than common ancestry. It has been suggested that interallelic recombination (gene conversion) plays a role in enhancing polymorphism, but there is evidence of striking differences among loci with respect to the rate at which such recombination has contributed to current polymorphism. Recent attempts to interpret linkage relationships in the MHC region as evidence of ancient genomic duplications are not supported by phylogenetic analysis. Rather, natural selection may have played a role in the linkage of other genes to those of the MHC.     

Impact of selection, mutation rate and genetic drift on human genetic variation

The accumulation of genome-wide information on single nucleotide polymorphisms in humans provides an unprecedented opportunity to detect the evolutionary forces responsible for heterogeneity of the level of genetic variability across loci. Previous studies have shown that history of recombination events has produced long haplotype blocks in the human genome, which contribute to this heterogeneity. Other factors, however, such as natural selection or the heterogeneity of mutation rates across loci, may also lead to heterogeneity of genetic variability. We compared synonymous and non-synonymous variability within human genes with their divergence from murine orthologs. We separately analyzed the non-synonymous variants predicted to damage protein structure or function and the variants predicted to be functionally benign. The predictions were based on comparative sequence analysis and, in some cases, on the analysis of protein structure. A strong correlation between non-synonymous, benign variability and non-synonymous human-mouse divergence suggests that selection played an important role in shaping the pattern of variability in coding regions of human genes. However, the lack of correlation between deleterious variability and evolutionary divergence shows that a substantial proportion of the observed non-synonymous single-nucleotide polymorphisms reduces fitness and never reaches fixation. Evolutionary and medical implications of the impact of selection on human polymorphisms are discussed.     

Inhalation exposure to low levels of ethyl tertiary butyl ether: Its genetic effects were significantly modified by ALDH2 activity

Previous experiments showed that high concentrations of ethyl tertiary butyl ether (ETBE) exposure (500–5,000 ppm) significantly resulted in DNA damages in aldehyde dehydrogenase 2 (Aldh2) knockout (KO) mice. This study was aimed to verify the genotoxic effects in three genetic types, Aldh2 KO, heterogeneous (HT), and wild type (WT), of mice exposed to lower concentrations of ETBE (50–500 ppm) by inhalation. Histopathology assessments in the livers, measurements of genotoxic biomarkers in blood and livers, and urinary 8-hydroxydeoxyguanosion (8-OH-dG) for the oxidative DNA damage of whole body were performed. Significant histopathological changes and DNA strand breaks both in hepatocytes and leukocytes were found in HT and KO male mice exposed to ≥200 ppm ETBE, but not in 50 ppm ETBE. 8-OH-dG levels either in liver or urine were higher in the HT and KO male mice exposed to ≥200 ppm ETBE. The pathological and genetic effects of ETBE were almost at the same extents for HT and KO mice. Thus, 50 ppm could be the no observed adverse effect level for ETBE in HT and KO male mice, which was far lower than the 500 ppm in WT mice. These results suggested that decrease and deficiency of ALDH2 activity would significantly increase the sensitivity to ETBE-induced genotoxicity as well as hepatotoxic effects after exposure even to low concentrations of ETBE. Environ. Mol. Mutagen. 60: 145–153, 2019. © 2018 Wiley Periodicals, Inc.     

Contributions of genetic drift and negative selection on the evolution of three strains of wheat streak mosaic tritimovirus

Summary.  Genome sequences of three Wheat streak mosaic virus (WSMV) strains were compared. The Type and Sidney 81 strains of WSMV from the American Great Plains were closely related, with sequence identities of 97.6% (nucleotide) and 98.7% (amino acid). In contrast, the El Batán 3 strain from central Mexico was divergent, and shared only 79.2–79.3% (nucleotide) and 90.3–90.5% (amino acid) sequence identity with Type and Sidney 81. All three WSMV strains were serologically related, however the El Batán 3 capsid protein (CP) had 15 fewer amino acid residues. Phylogenetic analysis of the CP cistron indicated that Type, Sidney 81, and nine other American isolates of WSMV were closely related and distinct from the El Batán 3 sequence. Nucleotide substitutions among the WSMV strains were not randomly distributed across the genome with more variation within P1, HC-Pro, and CP, and less within P3. One 400-nucleotide region of the genome, corresponding to the 3′-end of P3, was strikingly deficient in silent substitutions. Nonetheless, the ratio of synonymous to non-synonymous substitutions throughout the genome was essentially the same for all three WSMV strains. Collectively, our data indicate that both genetic drift and negative selection have contributed to the evolution of WSMV strains. Received April 10, 2000 Accepted August 2, 2000     

High frequencies of human genetic diseases: Founder effect with genetic drift or selection?

Rare genetic diseases have been reported with high frequency in some populations. The mechanisms which were proposed to explain most of these observations include founder effect, genetic drift or selective advantage. In recent years, many genes have been sequenced and mutations causing some of these disorders were characterized. According to the analysis of haplotypes and/or mutations, it may be possible to distinguish 3 groups of disorders frequent in isolated populations. In the first group, all the affected patients have only one frequent mutation, suggesting a founder effect with genetic drift. In the second group, more than one mutation is found among the patients; however, most of the patients are homozygotes for one frequent mutation which most probably originated from a common founder; the other patients are compound heterozygotes for the common mutation and a rare mutation. In the third group, more than one frequent mutation is found responsible for each disease. This may be due to a selective advantage which allows the expansion of each new mutation in the particular population or to multiple founder effect with genetic drift in smaller communities which thereafter mixed to form the larger population. © 1994 Wiley-Liss, Inc.     

The population genetics of Duchenne: natural and artificial selection in Duchenne muscular dystrophy.

The dynamics of X linkage was derived by Haldane in 1935. It is clear that the majority of mutations to an X linked lethal are new and that methods of control based on relatives of known cases can have limited impact on future incidence. The ability to define and track neighbouring loci allows some carriers who are daughters of carriers to be detected, and possible carriers to be excluded, with high reliability. Fetal diagnosis may also be made in the same way, but not without a substantial casualty rate. The precision of such diagnosis by proxy is limited both by the estimate of the recombination fraction and its variance, and can rarely exceed 1/s where the recombinational data are based on s informative meioses. Bracketing loci provide greater security from failure to diagnose cases but may involve substantial casualty rates. The estimation of both failure rates and casualty rates is discussed.     

The effect of recombination on the evolution of a population of Neisseria meningitidis

Neisseria meningitidis (the meningococcus) is a major human pathogen with a history of high invasive disease burden, particularly in sub-Saharan Africa. Our current understanding of the evolution of meningococcal genomes is limited by the rarity of large-scale genomic population studies and lack of in-depth investigation of the genomic events associated with routine pathogen transmission. Here, we fill this knowledge gap by a detailed analysis of 2839 meningococcal genomes obtained through a carriage study of over 50,000 samples collected systematically in Burkina Faso, West Africa, before, during, and after the serogroup A vaccine rollout, 2009–2012. Our findings indicate that the meningococcal genome is highly dynamic, with highly recombinant loci and frequent gene sharing across deeply separated lineages in a structured population. Furthermore, our findings illustrate how population structure can correlate with genome flexibility, as some lineages in Burkina Faso are orders of magnitude more recombinant than others. We also examine the effect of selection on the population, in particular how it is correlated with recombination. We find that recombination principally acts to prevent the accumulation of deleterious mutations, although we do also find an example of recombination acting to speed the adaptation of a gene. In general, we show the importance of recombination in the evolution of a geographically expansive population with deep population structure in a short timescale. This has important consequences for our ability to both foresee the outcomes of vaccination programs and, using surveillance data, predict when lineages of the meningococcus are likely to become a public health concern.

Neisseria meningitidis, the meningococcus, is a species of bacteria found exclusively in humans. It can cause meningitis, an infection of the membranes covering the brain and spinal cord, as well as septicemia (Stephens et al. 2007). These infections are difficult to treat, even with antimicrobials, and have a high case fatality rate. Of the 12 serogroups defined on the basis of the structure of the capsular polysaccharide, six (A, B, C, W, X, and Y) are responsible for nearly all cases of invasive meningococcal disease (IMD) worldwide. In contrast to strains that are capable of causing disease, non-disease-causing carriage isolates are typically unencapsulated. However, most infections of encapsulated and unencapsulated N. meningitidis are asymptomatic, with the bacteria being carried in the oropharynx of human populations without causing disease with a prevalence of ∼5%–10% (Christensen et al. 2010). It is likely that essentially all individuals will be colonized by potentially IMD-causing bacteria once or even several times during their lifetimes, so there are an uncertain number of carriage infections and transmission events in a human population. This presents a challenge for controlling the disease, and in order to reduce the incidence of IMD, effective polysaccharide-conjugate vaccines against serogroups A, C, W, and Y have been developed and introduced in national vaccination programs. These vaccines are, however, expensive and not affordable for low-income countries. Therefore, a monovalent conjugate serogroup A vaccine was produced and successfully introduced in large-scale vaccination campaigns in countries of the so-called “meningitis belt” of sub-Saharan Africa (Diomandé et al. 2015; Trotter et al. 2017) a region stretching from the Gambia and Senegal to Ethiopia (Molesworth et al. 2002).Prior to the vaccination campaigns that started at the end of 2010, the overall incidence of meningococcal meningitis in the region was substantially higher than anywhere else in the world and included epidemics that occurred in the winter months every five to 12 years (Trotter and Greenwood 2007). Though the vaccine has been very effective at controlling meningitis epidemics caused by serogroup A, the main cause of IMD in the meningitis belt (Diomandé et al. 2015; Trotter et al. 2017), other serogroups (C, W, and X) have emerged or expanded in the region, reducing the initial impact of the vaccine (Topaz et al. 2019). There is also concern that virulent strains circulating in the population might switch capsule or that less virulent strains not covered by the current vaccine might acquire virulence genes (Bårnes et al. 2017; Brynildsrud et al. 2019).Both of these potential scenarios are driven by the ability of bacteria from the genus Neisseria to be naturally transformable and to readily recombine their DNA with one another (Obergfell and Seifert 2015), in concert with selection (Arnold et al. 2020). Various mechanisms of recombination have been described in N. meningitidis (Schoen et al. 2009; Marri et al. 2010; Joseph et al. 2011), involving abundant and diverse repetitive DNA sequences in its chromosome. The evolutionary and epidemiological effects of recombination in N. meningitidis have been studied in some detail (Marri et al. 2010; Joseph et al. 2011; Retchless et al. 2018), but less work has been undertaken to describe how the extent of recombination varies both between different lineages of N. meningitidis and between different regions of its complete genome in a single circulating carriage population. In particular, there is little understanding of how this recombination affects the process of natural selection. Studies across diverse populations and species have suggested that there is likely some variation (Castillo-Ramírez et al. 2012; Ezewudo et al. 2015), and this variation in recombination rate is particularly relevant amid the disruption of population structure caused by large-scale vaccine introduction (Potts et al. 2018).Burkina Faso, located in the center of the meningitis belt, historically has had a high burden of disease caused by serogroup A meningococci (Nicolas et al. 2005) and was one of the first countries to introduce the serogroup A conjugate vaccine in a mass vaccination campaign in 2010 (Kristiansen et al. 2013). Since then, the incidence of IMD has decreased overall, but there have been meningitis outbreaks caused by serogroups W and X, belonging, respectively, to the sequence types (STs) 11 and 181 (Kristiansen et al. 2013).Here, we present a detailed population genetic analysis, focusing on recombination, in a collection of 2838 N. meningitidis carriage isolates collected from three areas of Burkina Faso over the course of the implementation of the serogroup A vaccine, from 2009 to 2012. This collection has been previously studied using molecular typing techniques (Kristiansen et al. 2013, 2014) which identified ST-181 as the dominant lineage in this population during the time period when sampling was performed. It further showed that the vaccine was effective at reducing the incidence of its target, serogroup A isolates, with none of the previously prevalent serogroup A ST-2859 clone detected after vaccination. This was, however, associated with an increase in the incidence of the disease-causing serogroup X ST-181 complex and also with the introduction and expansion of the disease-causing serogroup W ST-11complex. In this study, we use whole-genome sequencing with Illumina short-read technology to generate de novo assemblies for each isolate, which are then used to construct phylogenies, infer recombination events, and perform tests for selection. Our study recapitulates the finding of previous molecular studies on this population, but leveraging whole-genome data, this study additionally sought to determine whether lineages that make up this population have significantly different recombination rate phenotypes; if different lineages have specific recombination hotspot regions—loci where much more recombination takes place compared to elsewhere in their genomes; to what extent recombination is occurring between the different lineages which make up this population; and finally, whether it is possible to ascertain the evolutionary causes and effects for recombination in this population. Though recombination in N. meningitidis has been a known phenomenon and studied for some time (Zhu et al. 1999), we believe this study to be the first to detail the extent of variation in recombination rate within a sampled population and to characterize how and why recombination affects the evolution of the population.     

Second-order selection in bacterial evolution: selection acting on mutation and recombination rates in the course of adaptation

The increase in genetic variability of a population can be selected during adaptation, as demonstrated by the selection of mutator alleles. The dynamics of this phenomenon, named second-order selection, can result in an improved adaptability of bacteria through regulation of all facets of mutation and recombination processes.     

African diversity from the HLA point of view: influence of genetic drift, geography, linguistics, and natural selection.

This study investigates the influence of different evolutionary factors on the patterns of human leukocyte antigen (HLA) genetic diversity within sub-Saharan Africa, and between Africa, Europe, and East Asia. This is done by comparing the significance of several statistics computed on equivalent population data sets tested for two HLA class II loci, DRB1 and DPB1, which strongly differ from each other by the shape of their allelic distributions. Similar results are found for the two loci concerning highly significant correlations between geographic and genetic distances at the world scale, high levels of genetic diversity within sub-Saharan Africa and East Asia, and low within Europe, and low genetic differentiations among the three broad continental areas, with no special divergence of Africa. On the other hand, DPB1 behaves as a neutral polymorphism, although a significant excess of heterozygotes is often observed for DRB1. Whereas the pattern observed for DPB1 is explained by geographic differentiations and genetic drift in isolated populations, balancing selection is likely to have prevented genetic differentiations among populations at the DRB1 locus. However, this selective effect did not disrupt the high correlation found between DRB1 and geography at the world scale, nor between DRB1 and linguistic differentiations at the African level.     

Next-Generation Sequencing of the HLA locus: Methods and impacts on HLA typing,population genetics and disease association studies

The human Major Histocompatibility Complex, known as the “Human Leukocyte Antigen (HLA)”, could be defined as a “super locus” (historically called “supergene”) governing the adaptive immune system in vertebrates. It also harbors genes involved in innate immunity. HLA is the most gene-dense, polymorphic and disease-associated region of the human genome. It is of critical medical relevance given its involvement in the fate of the transplanted organs/tissues and its association with more than 100 diseases. However, despite these important roles, comprehensive sequence analysis of the 4 megabase HLA locus has been limited due to technological challenges. Thanks to recent improvements in Next-Generation Sequencing (NGS) technologies however, one is now able to handle the peculiarities of the MHC notably the tight linkage disequilibrium between genes as well as their high degree of polymorphism (and hence heterozygosity). Increased read lengths, throughput, accuracy, as well as development of new bioinformatics tools now enable to efficiently generate complete and accurate full-length HLA haplotypes without phase ambiguities. The present report reviews current NGS approaches to capture, sequence and analyze HLA genes and loci. The impact of these new methodologies on various applications including HLA typing, population genetics and disease association studies are discussed.     

Genetic variability and evolution of broad bean wilt virus 1: role of recombination,selection and gene flow

Analysis of four genomic regions from 37 geographically diverse isolates of broad bean wilt virus 1 (BBWV-1) showed high genetic diversity in comparison to most plant viruses. Comparison of synonymous and nonsynonymous substitutions of the small coat protein gene (SCP) revealed negative selection for most amino acid positions. Phylogenetic analysis of SCP showed that some BBWV-1 isolates from distant geographical areas were genetically close, suggesting long-distance migration. Analysis of genetic differentiation revealed high gene flow between Spanish and Near Eastern subpopulations, which were separated from North-Central and South-Eastern European subpopulations. Finally, putative recombinant and reassortant genomes were also identified.     

Familial Mediterranean fever: prevalence, penetrance and genetic drift

FMF is widely distributed in populations inhabiting the Mediterranean basin. It is mainly attributed to five founder mutations (M680I, M694V, M694I, V726A, E148Q) in the MEFV gene. The frequencies and distribution of these mutations in 146 FMF patients, of Arab and Jewish descent, were compared to that observed in 1173 healthy individuals of pertinent ethnic groups. Five mutations accounted for 91% of FMF chromosomes in our patients. Mutation M694V, predominant in North African Jews, was observed in all patients other than Ashkenazi Jews; mutation V726A was prevalent among all patients other than North African Jews; mutations M694I and M680I were mainly confined to Arab patients. Overall carrier rates, for four mutations (M680I, M694V, V726A, E148Q), were extremely high in our healthy cohort composed of Ashkenazi (n=407); Moroccan (n=243); Iraqi Jews (n=205); and Muslim Arabs (n=318); calculated at 1 : 4.5; 1 : 4.7; 1 : 3.5 and 1 : 4.3 respectively. The V726A allele prevalent among Ashkenazi and Iraqi Jews and Muslim Arabs (carrier rates: 7.4, 12.8 and 7.3%, respectively) was not found among Moroccan Jews. The M694V allele detected among Moroccan and Iraqi Jews and Muslim Arabs (carrier rates 11.1, 2.9 and 0.6%, respectively) was not observed among Ashkenazim. The overall frequency of mutations V726A and E148Q in Ashkenazim, Iraqi Jews and Arabs indicates that the bulk of individuals that comply with the genetic definition of FMF remain asymptomatic.     

Genetic drift from the out-of-Africa bottleneck leads to biased estimation of genetic architecture and selection

Most complex traits evolved in the ancestors of all modern humans and have been under negative or balancing selection to maintain the distribution of phenotypes observed today. Yet all large studies mapping genomes to complex traits occur in populations that have experienced the Out-of-Africa bottleneck. Does this bottleneck affect the way we characterise complex traits? We demonstrate using the 1000 Genomes dataset and hypothetical complex traits that genetic drift can strongly affect the joint distribution of effect size and SNP frequency, and that the bias can be positive or negative depending on subtle details. Characterisations that rely on this distribution therefore conflate genetic drift and selection. We provide a model to identify the underlying selection parameter in the presence of drift, and demonstrate that a simple sensitivity analysis may be enough to validate existing characterisations. We conclude that biobanks characterising more worldwide diversity would benefit studies of complex traits.Subject terms: Genetic variation, Genome-wide association studies     

The apolipoprotein multigene family: Structure,expression, evolution,and molecular genetics

Summary The plasma apolipoproteins can be classified into two subgroups: the soluble apolipoproteins including apolipoprotein (apo) A-I, A-II, A-IV, C-I, C-II, C-III, and E, and the apoBs including apoB-100 and apoB-48. The soluble apolipoproteins have very similar genomic structures, each having a total of three introns at the same locations; apoA-IV is an exception in that it has lost its first intron. Using the exon/intron junctions as reference points, we can obtain an alignment of the coding regions of all the soluble apolipoprotein genes. The mature peptide regions of the genes are almost completely made up of tandem repeats of 11 codons. The part of mature peptide region encoded by exon 3 contains a common block of 33 codons, whereas the part encoded by exon 4 contains a much more variable number of internal repeats of 11 codons. On the basis of the degree of homology of the various sequences, and the pattern of the internal repeats in these genes, an evolutionary tree has been proposed for the soluble apolipoprotein genes. ApoB-100 differs considerably from the soluble apolipoproteins. It is the largest apolipoprotein containing 4536 amino acid residues. Two types of internal repeats are identified in apoB-100: amphipathic -helical repeats and proline-containing repeats with high -sheet content. The apoB gene contains 29 exons and 28 introns. Its evolutionary relationship to the soluble apolipoprotein genes is unclear. The 3 end of the apoB gene contains a region of variable number of tandem 12–16-base pair repeats. We have applied the polymerase chain reaction technique to characterize this highly polymorphic locus. The same technique can be used to accurately type other variable number of tandem repeats loci. Finally, apoB-48 was shown to be the product of an RNA editing mechanism involving an intestinal mRNA that has an in-frame UAA stop codon resulting from a CU change in the codon CAA encoding Gln-2153 in apoB-100 mRNA. Using a molecular approach to apolipoprotein synthesis, structure and genetic analysis, we have generated information important to our understanding of lipoprotein metabolism; we also uncovered unexpected experimental results that are relevant to general cell and molecular biology and molecular evolution.Abbreviations LDL low density lipoproteins - HDL high density lipoproteins - IDL intermediate density lipoproteins - apo apolipoprotein(s) - mRNA messenger ribonucleic acid - VNTR variable number of tandem repeats - PCR polymerase chain reaction - Myr million years - RFLP restriction fragment length polymorphism(s) Heinrich-Wieland Prize lecture delivered on October 28, 1988     

Human sapoviruses: genetic diversity, recombination, and classification

The family Caliciviridae contains four genera Sapovirus, Norovirus, Lagovirus and Vesivirus, which include Sapporo virus (SaV), Norwalk virus (NoV), Rabbit hemorrhagic disease virus (RHDV) and Feline calicivirus (FCV), respectively. SaV is a causative agent of gastroenteritis in children and adults. SaV can be divided into five genogroups (GI-GV), among which GI, GII, GIV and GV are known to infect humans, whereas SaV GIII infects porcine species. Detection methods include ELISA, RT-PCR and real-time RT-PCR. Since few SaV studies have been conducted, it is difficult to draw correlations between or conclusions about rates of incidence, detection and overall prevalence. Nevertheless, most studies agree that SaV infection is more frequent in young children than adults and that infection in children almost always occurs by 5 years of age. In addition, children at day-care centres and institutions are at greatest risk of SaV-associated infection and transmission. Recently, a number of important findings concerning human SaV were discovered. SaV strains were detected in water samples, which included untreated wastewater specimens, treated wastewater samples and river samples. SaV strains were also detected in shellfish samples destined for human consumption, and recombinant SaV strains were identified in a number of different countries. The purpose of this review was to highlight the current knowledge of human SaV, which appears to be an increasingly important virus causing gastroenteritis in humans.