Form, Function, Agency: Sources of Natural Purpose in Animal Evolution

The origination and evolution of multicellular form and function is generally thought to be based on gene-based variation, with natural selection changing the populational composition in the respective variants over time. The criterion for evolutionary success is differential fitness, the relative capacity to leave progeny in the next generation. Theoretical considerations show that this model implies that phenotypic evolution will generally be gradual, based on variations of small effect. But the fossil record of early phylogenesis, notably for the metazoans, or animals, does not support the gradualist scenario. Moreover, discordances of phenotype and genotype in extant species, along with the existence of a pan-metazoan developmental genetic toolkit, does not support the gene-variation-based evolutionary mechanism, at least at the level of phyla. Most importantly, all life-forms, including the cells that constitute animal embryos, exhibit agency, and associations of cells (even constructed ones with no history of natural selection) exhibit novel kinds of agency. This strongly suggests that new multicellular forms can invent new ways of life (e.g., ecological niches) and can persist without supplanting their populational cohorts. This chapter describes how anatomical (e.g., segments, appendages) and functional (e.g., muscle, nerve) phenotypes can emerge without cycles of gradual selection from inherent properties of metazoan cells and their aggregates. While such phenotypic “add-ons” could provide enablements for exploration of new niches, it is implausible that they arose as adaptations to external challenges. Reproductive fitness, which is essential for understanding biogeography and ecology, is unlikely to have played a role in phylum-level evolution.

Systemic lupus erythematosus after delivery and myasthenia gravis with COL6A1 gene mutation: A case report

The coexistence of systemic lupus erythematosus (SLE) and myasthenia gravis (MG) is rarely reported, especially the appearance of SLE before MG. In addition to the production of autoantibodies after thymectomy, gene mutation may be an important contributing factor to the overlap of SLE and MG. Here, we report a case of a female patient diagnosed with SLE before MG and found to carry the heterozygous variation COL6A1 c. 2608G>A. We propose that this gene variation weakens the function of COL6A1 and indirectly activates STAT1, resulting in the phenotype of these two autoimmune diseases. This report suggests that it is feasible to explore common pathogenic genes in SLE and MG through future large-scale research.

Apolipoprotein E Polymorphism and Alzheimer’s Risk in Kashmiri Population

Background: Although the cause of Alzheimer's disease is unknown, most experts feel that the disease is caused by a combination of circumstances rather than a single cause. Age, gene polymorphism, diabetes, and other conditions are all risk factors for Alzheimer's disease. Given the importance of gene polymorphism in different diseases, we intended to find out the association of APOE gene polymorphism with Alzheimer's risk in the Kashmiri population. Method: Out of 300 patients who were referred to the memory clinic of the hospital, to evaluate the probable relation of APOE gene variation in Alzheimer's disease, we conducted the study on 59 clinically confirmed Alzheimer's patients and 52 age and ethnicity-matched healthy controls found in a community survey. Results: Our data revealed a statistically significant association of ε4 variant genotype of the APOE gene with AD susceptibility in the Kashmiri population. Conclusions: The current study's findings provided insight into the role of APOE polymorphisms in Alzheimer's disease susceptibility. The identified susceptibility variant may become a marker genotype for AD.

Human papillomavirus and herpes simplex virus infections in patients with mucocutaneous lesions can be linked to host TBX-21 gene polymorphism

Background and objective: Human papillomavirus (HPV) and herpes simplex-2 (HSV-2) are the common cause of genital lesions in women. The variation in host genetic makeup can determine the consequence of a viral infection in that host. T-bet gene polymorphism has been associated with the incidence of several types of infections. This study investigates the impact of T-bet polymorphism on the incidence of HPV and HSV in genital lesions. Methods: 215 women, including 71 HPV infected, 72 HSV-2 infected, and 72 controls were enrolled. Viral genotyping was done on genital swab samples using Realtime PCR. In all participants, the extracted DNA from blood was tested for T-bet gene variation at Ch17.rs17244587 G>A site using ARMS-PCR. ELISA was done to participants sera to detect HSV-1 IgM. Results: Genotyping of HPV infection revealed that (73.0%) were at low risk. Most individuals (72.5%) were homozygous GG, while (20.9%) were heterozygous AG and (6.5%) were homozygous AA, of which 92.8% were HSV-2 infected patients. None of 18 (8.4%) HSV-1-IgM positive women were homozygous AA. Conclusion: T-bet gene allele A appears to be linked with more incidence of HSV-2 in genital lesions, but such influence was not observed for HPV genotypes and HSV-1. Keywords: HPV genotypes; HSV-2 infection; Genital lesion; T-bet polymorphism.

Evolution of stickleback spines through independent cis-regulatory changes at HOXDB

Understanding the genetic mechanisms leading to new traits is a fundamental goal of evolutionary biology. We show that HOXDB regulatory changes have been used repeatedly in different stickleback fish species to alter the length and number of bony dorsal spines. In Gasterosteus aculeatus, a variant HOXDB allele is genetically linked to shortening an existing spine and adding a spine. In Apeltes quadracus, a variant allele is associated with lengthening an existing spine and adding a spine. The alleles alter the same conserved non-coding HOXDB enhancer by diverse molecular mechanisms, including SNPs, deletions, and transposable element insertions. The independent cis-acting regulatory changes are linked to anterior expansion or contraction of HOXDB expression. Our findings support the long-standing hypothesis that natural Hox gene variation underlies key morphological patterning changes in wild populations and illustrate how different mutational mechanisms affecting the same region may produce opposite gene expression changes with similar phenotypic outcomes.

Ovine Toll-like Receptor 9 (TLR9) Gene Variation and Its Association with Flystrike Susceptibility

Toll-like receptors (TLRs) are a family of proteins that play a role in innate immune responses by recognising pathogen-associated molecular patterns derived from various microbes. Of these receptors, TLR9 recognises bacterial and viral DNA containing unmethylated cytosine-phosphate-guanine (CpG) motifs, and variation in TLR9 has been associated with resistance to various infectious diseases. Flystrike is a problem affecting the sheep industry globally and the immune response of the sheep has been suggested as one factor that influences the response to the disease. In this study, variation in ovine TLR9 from 178 sheep with flystrike and 134 sheep without flystrike was investigated using a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) approach. These sheep were collected from both commercial and stud farms throughout New Zealand and they were of 13 different breeds, cross-breds and composites. Four alleles of TLR9 were detected, including three previously identified alleles (*01, *02 and *03) and a new allele (*04). In total six single nucleotide polymorphisms (SNPs) were found. Of the three common alleles in the sheep studied, the presence of *03 was found to be associated with a reduced likelihood of flystrike being present (OR = 0.499, p = 0.024). This suggests that variation in ovine TLR9 may affect a sheep’s response to flystrike, and thus the gene may have value as a genetic marker for improving resistance to the disease.

De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy

Pathogenic variants in SETX cause two distinct neurological diseases, a loss-of-function recessive disorder, ataxia with oculomotor apraxia type 2 (AOA2), and a dominant gain-of-function motor neuron disorder, amyotrophic lateral sclerosis type 4 (ALS4). We identified two unrelated patients with the same de novo c.23C > T (p.Thr8Met) variant in SETX presenting with an early-onset, severe polyneuropathy. As rare private gene variation is often difficult to link to genetic neurological disease by DNA sequence alone, we used transcriptional network analysis to functionally validate these patients with severe de novo SETX-related neurodegenerative disorder. Weighted gene co-expression network analysis (WGCNA) was used to identify disease-associated modules from two different ALS4 mouse models and compared to confirmed ALS4 patient data to derive an ALS4-specific transcriptional signature. WGCNA of whole blood RNA-sequencing data from a patient with the p.Thr8Met SETX variant was compared to ALS4 and control patients to determine if this signature could be used to identify affected patients. WGCNA identified overlapping disease-associated modules in ALS4 mouse model data and ALS4 patient data. Mouse ALS4 disease-associated modules were not associated with AOA2 disease modules, confirming distinct disease-specific signatures. The expression profile of a patient carrying the c.23C > T (p.Thr8Met) variant was significantly associated with the human and mouse ALS4 signature, confirming the relationship between this SETX variant and disease. The similar clinical presentations of the two unrelated patients with the same de novo p.Thr8Met variant and the functional data provide strong evidence that the p.Thr8Met variant is pathogenic. The distinct phenotype expands the clinical spectrum of SETX-related disorders.