The Role of Selection and Migration in the Evolution of (Auto)Immunity Genes.

The genetic architecture of multiple sclerosis is complicated. Additionally, the disease incidence varies per population or per geographical region. A recent study gives convincing explanations about the north-south incidence gradient of multiple sclerosis in Europe, by analyzing ancient and modern human genomes. Interestingly, the evidence shows that multiple sclerosis associated immunogenetic variants underwent positive selection in Asian and European populations. Lifestyle and pathogen infections probably shaped the overall multiple sclerosis risk. These results complete the findings of previous studies that showed that a high percentage of the autoimmunity associated genetic variants are under selection pressure.

Directed Evolution. The Legacy of a Nobel Prize.

This article is part of an anniversary issue of Journal of Molecular Evolution, commenting on a paper published on 1999 by the Nobel laureate Frances Arnold and her colleague Kentaro Miyazaki. The paper by Miyazaki and Arnold presented saturation mutagenesis as an alternative method to random mutagenesis for obtaining enzymes with increasing stability. Both techniques were conceived to accomplish directed evolution, an approach honoured by the Nobel Prize of Chemistry 2018. Here, I am commenting on the pros and cons of random and saturation mutagenesis, while also discussing important results from directed evolution. I conclude that molecular evolution is finding new applications in science and it is definitely an integral part of the genomic era's revolution.

Animal-to-Human Viral Transitions: Is SARS-CoV-2 an Evolutionarily Successful One?

Transmission of viruses from one species to another is not unusual in nature. Despite this, evolutionarily successful transmissions are rare. Such events can cause pandemics and are followed by host-virus coevolution procedures that can increase the fitness potential of viruses. In this perspective article, I recognize eight main types of trans-species viral transmission. I consider two of them as evolutionarily successful, explaining why coronavirus SARS-CoV-2 could be one of them.

Editorial: A New Bright Era for Evolutionary Medicine.

Evolutionary Medicine is a fast-growing research field providing biomedical scientists with valuable information on molecular and pathophysiological mechanisms of disease. Evolutionary theory explains many medical conditions and it can contribute to new innovative treatments. This is the reason that Journal of Molecular Evolution has devoted this issue to Evolutionary Medicine. Nine detailed review papers are included in this issue, analyzing topics that are among the "hottest" subjects of Evolutionary Medicine. All information is up to date and highly valuable for scientists that would like to start their career or get updated on this field.

Antagonistic Pleiotropy in Human Disease.

Between the 1930s and 1950s, scientists developed key principles of population genetics to try and explain the aging process. Almost a century later, these aging theories, including antagonistic pleiotropy and mutation accumulation, have been experimentally validated in animals. Although the theories have been much harder to test in humans despite research dating back to the 1970s, recent research is closing this evidence gap. Here we examine the strength of evidence for antagonistic pleiotropy in humans, one of the leading evolutionary explanations for the retention of genetic risk variation for non-communicable diseases. We discuss the analytical tools and types of data that are used to test for patterns of antagonistic pleiotropy and provide a primer of evolutionary theory on types of selection as a guide for understanding this mechanism and how it may manifest in other diseases. We find an abundance of non-experimental evidence for antagonistic pleiotropy in many diseases. In some cases, several studies have independently found corroborating evidence for this mechanism in the same or related sets of diseases including cancer and neurodegenerative diseases. Recent studies also suggest antagonistic pleiotropy may be involved in cardiovascular disease and diabetes. There are also compelling examples of disease risk variants that confer fitness benefits ranging from resistance to other diseases or survival in extreme environments. This provides increasingly strong support for the theory that antagonistic pleiotropic variants have enabled improved fitness but have been traded for higher burden of disease later in life. Future research in this field is required to better understand how this mechanism influences contemporary disease and possible consequences for their treatment.

Correction to: Evidence that DNA repair genes, a family of tumor suppressor genes, are associated with evolution rate and size of genomes.

In the original publication of this article [1], the Figure 1 and Figure 2 were wrong. The Figure 1 "Heat map showing the quantity of DNA repair genes, from red to blue in ascending order, per species' genome (numbers at the top of the figure represent the species code that is found in Table 1). Each DNA repair gene pathway was analyzed separately in rows. Radiated species' genomes are richer in DNA repair genes. Analytical data can be found in Additional file 2: Table S2. M mammals, B&R birds and reptiles, BF bony fishes" should be the picture of Figure 2. The figure 2 "Linear regression analysis. The number of DNA repair genes is linearly related to genome size and protein number. As a negative control, we show that genome size is not linearly related with protein number" should be the picture of figure 1.

Evidence that DNA repair genes, a family of tumor suppressor genes, are associated with evolution rate and size of genomes.

Adaptive radiation and evolutionary stasis are characterized by very different evolution rates. The main aim of this study was to investigate if any genes have a special role to a high or low evolution rate. The availability of animal genomes permitted comparison of gene content of genomes of 24 vertebrate species that evolved through adaptive radiation (representing high evolutionary rate) and of 20 vertebrate species that are considered as living fossils (representing a slow evolutionary rate or evolutionary stasis). Mammals, birds, reptiles, and bony fishes were included in the analysis. Pathway analysis was performed for genes found to be specific in adaptive radiation or evolutionary stasis respectively. Pathway analysis revealed that DNA repair and cellular response to DNA damage are important (false discovery rate = 8.35 × 10-5; 7.15 × 10-6, respectively) for species evolved through adaptive radiation. This was confirmed by further genetic in silico analysis (p = 5.30 × 10-3). Nucleotide excision repair and base excision repair were the most significant pathways. Additionally, the number of DNA repair genes was found to be linearly related to the genome size and the protein number (proteome) of the 44 animals analyzed (p < 1.00 × 10-4), this being compatible with Drake's rule. This is the first study where radiated and living fossil species have been genetically compared. Evidence has been found that cancer-related genes have a special role in radiated species. Linear association of the number of DNA repair genes with the species genome size has also been revealed. These comparative genetics results can support the idea of punctuated equilibrium evolution.

Combination of 247 Genome-Wide Association Studies Reveals High Cancer Risk as a Result of Evolutionary Adaptation.

Analysis of GLOBOCAN-2012 data shows clearly here that cancer incidence worldwide is highly related with low average annual temperatures and extreme low temperatures. This applies for all cancers together or separately for many frequent or rare cancer types (all cancers P = 9.49×10-18). Supporting fact is that Inuit people, living at extreme low temperatures, have the highest cancer rates today. Hypothesizing an evolutionary explanation, 240 cancer genome-wide association studies, and seven genome-wide association studies for cold and high-altitude adaptation were combined. A list of 1,377 cancer-associated genes was created to initially investigate whether cold selected genes are enriched with cancer-associated genes. Among Native Americans, Inuit and Eskimos, the highest association was observed for Native Americans (P = 6.7×10-5). An overall or a meta-analysis approach confirmed further this result. Similar approach for three populations living at extreme high altitude, revealed high association for Andeans-Tibetans (P = 1.3×10-11). Overall analysis or a meta-analysis was also significant. A separate analysis showed special selection for tumor suppressor genes. These results can be viewed along with those of previous functional studies that showed that reduced apoptosis potential due to specific p53 variants (the most important tumor suppressor gene) is beneficial in high-altitude and cold environments. In conclusion, this study shows that genetic variants selected for adaptation at extreme environmental conditions can increase cancer risk later on age. This is in accordance with antagonistic pleiotropy hypothesis.

The "cancer-cold" hypothesis and possible extensions for the Nordic populations.

Cancer incidence is inexplicably high in cold countries. This has been revealed by recent genetic and epidemiological studies. These studies used data from the GLOBOCAN-2012 database, for 186 populations and for a variety of cancer types. Cancer incidence in Nordic people is particularly high for the frequent cancer forms, like breast, prostate and colon cancer. A relationship of cancer with cold is suspected since Inuit and Alaska Indians that live in even more extreme low temperatures have the higher cancer rates in the world. In this article, possible reasons for this phenomenon are discussed. These explanations are related with: evolutionary adaptation to extreme cold, the genetic background of Nordic people, the experimentally proven fast growth and metastasis of tumors at low temperatures, high concentration of certain air pollutants at cold environments, low levels of serum Vitamin D, overdiagnosis by the medical doctors and high quality of the health system in Nordic countries. Lifestyle parameters are not discussed in detail, although these may be equally crucial for cancer risk in cold countries. In conclusion, more studies are needed to elucidate the real causes of this epidemiological pattern.

Group Selection May Explain Cancer Predisposition and Other Human Traits' Evolution.

Group selection is a matter of acute controversy among evolutionary biologists. The most well-publicized debate in this regard is that between Edward O. Wilson and Richard Dawkins. As is widely known, Edward O. Wilson is very excited about the idea of social selection and eusociality; by contrast Richard Dawkins favors the idea of gene selection. As is often the case, the truth is somewhere in the middle. Evolution is most likely a multilevel procedure, where selection forces act on genes, individuals, and groups. Here, I would like to emphasize that group selection may be a possible cause of increased genetic variation on DNA repair genes, subsequently this driving to high cancer incidence. Additionally, if group selection is indeed happening in humans, maybe this is the reason that few adaptive loci have been discovered in human genome, even though thousands of sequenced genomes exist today.

COL4A5 and LAMA5 variants co-inherited in familial hematuria: digenic inheritance or genetic modifier effect?

BACKGROUND: About 40-50% of patients with familial microscopic hematuria (FMH) caused by thin basement membrane nephropathy (TBMN) inherit heterozygous mutations in collagen IV genes (COL4A3, COL4A4). On long follow-up, the full phenotypic spectrum of these patients varies a lot, ranging from isolated MH or MH plus low-grade proteinuria to chronic renal failure of variable degree, including end-stage renal disease (ESRD). METHODS: Here, we performed Whole Exome Sequencing (WES) in patients of six families, presenting with autosomal dominant FMH, with or without progression to proteinuria and loss of renal function, all previously found negative for severe collagen IV mutations. Hierarchical filtering of the WES data was performed, followed by mutation prediction analysis, Sanger sequencing and genetic segregation analysis. RESULTS: In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-p.Pro1243Leu and COL4A5-p.Asp654Tyr. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts. CONCLUSIONS: A modifier role of LAMA5 on the background of a hypomorphic Alport syndrome causing mutation is a possible explanation of our findings. Digenic inheritance is another scenario, following the concept that mutations at both loci more accurately explain the spectrum of symptoms, but further investigation is needed under this concept. This is the third report linking a LAMA5 variant with human renal disease and expanding the spectrum of genes involved in glomerular pathologies accompanied by familial hematurias. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced Lama5 protein levels and produced kidney cysts.

Evidence for activation of the unfolded protein response in collagen IV nephropathies.

Thin-basement-membrane nephropathy (TBMN) and Alport syndrome (AS) are progressive collagen IV nephropathies caused by mutations in COL4A3/A4/A5 genes. These nephropathies invariably present with microscopic hematuria and frequently progress to proteinuria and CKD or ESRD during long-term follow-up. Nonetheless, the exact molecular mechanisms by which these mutations exert their deleterious effects on the glomerulus remain elusive. We hypothesized that defective trafficking of the COL4A3 chain causes a strong intracellular effect on the cell responsible for COL4A3 expression, the podocyte. To this end, we overexpressed normal and mutant COL4A3 chains (G1334E mutation) in human undifferentiated podocytes and tested their effects in various intracellular pathways using a microarray approach. COL4A3 overexpression in the podocyte caused chain retention in the endoplasmic reticulum (ER) that was associated with activation of unfolded protein response (UPR)-related markers of ER stress. Notably, the overexpression of normal or mutant COL4A3 chains differentially activated the UPR pathway. Similar results were observed in a novel knockin mouse carrying the Col4a3-G1332E mutation, which produced a phenotype consistent with AS, and in biopsy specimens from patients with TBMN carrying a heterozygous COL4A3-G1334E mutation. These results suggest that ER stress arising from defective localization of collagen IV chains in human podocytes contributes to the pathogenesis of TBMN and AS through activation of the UPR, a finding that may pave the way for novel therapeutic interventions for a variety of collagenopathies.

Investigating the shared genetic basis and causal relationships between mucosa-associated lymphoid tissue inflammation and psychiatric disorders.

Background: Chronic and acute inflammation of the mucosa-associated lymphoid tissue have been positively linked to the development of psychiatric disorders in observational studies. However, it remains unclear whether this association is causal. In the present study, we investigated this association, using as proxies genetically predicted tonsillectomy, appendectomy and appendicitis on psychiatric disorders including major depressive disorder (MDD), schizophrenia (SCZ), bipolar depression (BD) and anxiety (ANX) via a two-sample Mendelian randomization (MR) analysis. Methods: Genetic association summary statistics for tonsillectomy, appendectomy and appendicitis were sourced from FinnGen Consortium, comprising data from 342,000 participants. Genetic correlations between all exposures and outcome were calculated with Linkage Disequilibrium Score (LDSC) Regression analysis. MR estimates were then calculated to assess their impact on the risk of developing psychiatric disorders. Sensitivity analysis was employed to test for any directional pleiotropy. Results: Our results suggest that there is no direct causal association between tonsillectomy, appendectomy or appendicitis with a heightened risk for development of psychiatric disorders. The robustness of the results of the main MR analysis was further confirmed with additional sensitivity analyses. However, a moderate inverse genetic correlation was observed between tonsillectomy and MDD traits (rg=-0.39, p-value (P)=7.5x10-5). Conclusion: Our findings provide, for the first time, evidence that there is no causal association between tonsillectomy or appendectomy on subsequent vulnerability of developing psychiatric disorders. Future studies using larger sample size GWAS should focus on unraveling the confounding factors and mediators to investigate this relationship further.

Molecular genetics of familial hematuric diseases.

The familial hematuric diseases are a genetically heterogeneous group of monogenic conditions, caused by mutations in one of several genes. The major genes involved are the following: (i) the collagen IV genes COL4A3/A4/A5 that are expressed in the glomerular basement membranes (GBM) and are responsible for the most frequent forms of microscopic hematuria, namely Alport syndrome (X-linked or autosomal recessive) and thin basement membrane nephropathy (TBMN). (ii) The FN1 gene, expressed in the glomerulus and responsible for a rare form of glomerulopathy with fibronectin deposits (GFND). (iii) CFHR5 gene, a recently recognized regulator of the complement alternative pathway and mutated in a recently revisited form of inherited C3 glomerulonephritis (C3GN), characterized by isolated C3 deposits in the absence of immune complexes. A hallmark feature of all conditions is the age-dependent penetrance and a broad phenotypic heterogeneity in the sense that subsets of patients progress to added proteinuria or proteinuria and chronic renal failure that may or may not lead to end-stage kidney disease (ESKD) anywhere between the second and seventh decade of life. In addition to other excellent laboratory tools that assist the clinician in reaching the correct diagnosis, the molecular analysis emerges as the gold standard in establishing the diagnosis in many cases of doubt due to equivocal findings that complicate the differential diagnosis. Recent work led to the description of candidate genetic modifiers which confer a variable risk for progressing to chronic renal failure when co-inherited on the background of a primary glomerulopathy. Finally, more families are still waiting to be studied and more genes to be mapped and cloned that are responsible for other forms of heritable hematuric diseases. The study of such genes and their protein products will likely shed more light on the structure and function of the glomerular filtration barrier and other important glomerular components.

C3 glomerulonephritis/CFHR5 nephropathy is an endemic disease in Cyprus: clinical and molecular findings in 21 families.

Microscopic haematuria is the presenting symptom of several conditions, either heritable or acquired. A well-recognized familial condition is Alport syndrome, either of X-linked or autosomal recessive inheritance, as well as thin basement membrane nephropathy (TBMN) because of heterozygous collagen IV mutations. Even though microscopic haematuria of TBMN was long considered as a benign disease with excellent prognosis, more recent data suggest that development of chronic kidney disease (CKD) and even end-stage kidney disease (ESKD) is not a rare finding, perhaps owing to the cofounding role of modifier genes and other factors. Recent investigations in London and Cyprus culminated in the identification of another autosomal dominant condition that presents with microscopic haematuria because of heterozygous mutations in the CFHR5 gene, which apparently plays a pivotal role in the regulation of the alterative pathway of complement system, which constitutes a significant part of innate immunity in humans. Histologically, the hallmark observation is the isolated glomerular deposition of C3 complement in the absence of immune complexes. It is considered one of the C3 glomerulopathies, and it may or may not be accompanied by mild membranoproliferative glomerulonephritis. Interestingly, a single mutation has been identified so far, a duplication of exons 2-3 of the CFHR5 gene, and it has been described in patients of Greek-Cypriot descend only, perhaps originating on the Troodos mountains of Cyprus. Thus far, no patient with a mutation in this gene has been diagnosed in any other population. In Cyprus, it has been found in clusters of families in neighbouring villages in a total of 136 patients, and it constitutes a strong founder phenomenon. About 50% of patients over 50 years have progressed to CKD, and 14% of all patients progressed to ESKD. It is not quite well understood why males run a much higher risk to progress to CKD, compared to women.

The double face of cold in cancer.

In a recent paper published in Nature, multiple evidence is provided that cold exposure causes tumor growth restriction in mice, by activating brown adipose tissue metabolism and by subsequent cancer cells' glucose starvation. The paper shows a tumor growth inhibition by 80% for multiple cancer types in mice exposed to 4 °C in comparison with mice exposed to 30 °C. These results are very promising since cost effective protocols could be designed for future clinical trials, for several cancer forms. In this commentary, an extensive analysis is performed on the potential of these results. Some previous published studies are discussed as well, showing differences in tumor growth for mice housed in different external temperatures.

The Role of TP53 in Adaptation and Evolution.

The TP53 gene is a major player in cancer formation, and it is considered the most important tumor suppressor gene. The p53 protein acts as a transcription factor, and it is involved in DNA repair, senescence, cell-cycle control, autophagy, and apoptosis. Beyond cancer, there is evidence that TP53 is associated with fertility, aging, and longevity. Additionally, more evidence exists that genetic variants in TP53 are associated with environmental adaptation. Special TP53 amino-acid residues or pathogenic TP53 mutations seem to be adaptive for animals living in hypoxic and cold environments or having been exposed to starvation, respectively. At the somatic level, it has recently been proven that multiple cancer genes, including TP53, are under positive selection in healthy human tissues. It is not clear why these driver mutations do not transform these tissues into cancerous ones. Other studies have shown that elephants have multiple TP53 copies, probably this being the reason for the very low cancer incidence in these large animals. This may explain the famous Peto's paradox. This review discusses in detail the multilevel role of TP53 in adaptation, according to the published evidence. This role is complicated, and it extends from cells to individuals and to populations.

Insights into suicidal behavior among psoriatic arthritis patients: A systematic review and a genetic linkage disequilibrium analysis.

OBJECTIVES: To systematically assess the magnitude of suicidal behavior among PsA patients and identify associated risk factors. Also identify common genes or coinherited single nucleotide polymorphisms (SNPs) implicated in suicidal behavior and PsA. METHODS: Based on the PRISMA guidelines, we conducted a systematic literature review of the online databases PubMed/Medline, Web of Science, and EMBASE from inception to May 2022. Full-text original articles that describe suicidal behavior in PsA patients were eligible. All registered genome-wide association study (GWAS) data in the GWAS catalog database for PsA and psychiatric traits, such as suicidal behavior, and depression, were downloaded for further analysis. RESULTS: A total of 48 articles were identified, and 6 were relevant to the study question .Among the 122,160 PsA patients, 700 had suicidal behavior (0,57%). The range of age in one study was between 30 and 49 years, and 64% of PsA patients with suicidal behavior were female. Among 13,899 PsA patients 74 had suicidal ideation (0.53%) and 125 suicide attempts occurred (0.9%). In two studies, among 17,383 patients, 13 complete suicides occurred (0.07%). A genetic haplotype on chromosomal region 6p21.1, spanning from 29,597,596 to 32,251,264 Mb, contains predisposing SNPs for PsA and depression. 6p21.1-6p21.3 is the chromosomal region containing the HLA genes of classes I, II and III. CONCLUSION: Suicide behavior in PsA patients was associated with depression and other psychiatric comorbidities. Further evidence supports a genetic origin, at least partly. Awareness of these findings can help clinicians to recognize suicide behavior and prevent suicide attempts.

Genome-wide association studies reveal shared genetic haplotypes of autoimmune rheumatic and endocrine diseases with psychiatric disorders.

BACKGROUND: Several studies have shown that autoimmune diseases are associated with psychiatric diseases like depression and psychosis. Genetic evidence supports this association. The aim of this study was to investigate if genetic variants predisposing to autoimmune diseases and psychiatric disorders are genetically linked, constructing the common haplotypes. METHODS: All registered single nucleotide polymorphisms (SNPs) in the Genome-wide association studies ("GWAS catalog") having been associated with autoimmune rheumatic and endocrine diseases were investigated for being in linkage disequilibrium with any psychiatric disorders' associated SNPs. Analysis was performed by the LDtrait and LDhap bioinformatics tools. RESULTS: Multiple chromosomal regions have been detected containing rheumatic/endocrine diseases' predisposing SNPs and psychiatric disorders' predisposing SNPs. The genetic haplotypes have been constructed for some of these genetic regions. Six of the autoimmune rheumatic and endocrine diseases examined here share a common haplotype with psychiatric diseases at the HLA locus 6p21-22. CONCLUSION: Our study shows that autoimmune diseases and psychiatric diseases are genetically linked. Genetic haplotypes have been constructed, showing in detail this genetic linkage.