Biology subjects

Lucaci, A. G.

Publications and source records attributed to Lucaci, A. G..

5 recordsLinked to original sources

bioRxiv2022

Human HspB1, HspB3, HspB5 and HspB8: Shaping these Disease Factors during Vertebrate Evolution

Small heat shock proteins (sHSPs) emerged early in evolution and occur in all domains of life and nearly in all species, including humans. Mutations in four sHSPs (HspB1, HspB3, HspB5, HspB8) are associated with neuromuscular disorders. The aim of this study is to investigate the evolutionary forces shaping these sHSPs during vertebrate evolution. We performed comparative evolutionary analyses on a set of orthologous sHSP sequences, based on the ratio of non-synonymous: synonymous substitution rates for each codon. We found that these sHSPs had been historically exposed to different degrees of purifying selection, decreasing in this order: HspB8 > HspB1, HspB5 > HspB3. Within each sHSP, regions with different degrees of purifying selection can be discerned, resulting in characteristic selective pressure profiles. The conserved -crystallin domains were exposed to the most stringent purifying selection compared to the flanking regions, supporting a dimorphic pattern of evolution. Thus, during vertebrate evolution the different sequence partitions were exposed to different and measurable degrees of selective pressures. Among the disease-associated mutations, most are missense mutations primarily in HspB1 and to a minor extent in the other sHSPs. Our data provide an explanation for this disparate incidence. Contrary to the expectation, most missense mutations cause dominant disease phenotypes. Theoretical considerations support a connection between the historic exposure of these sHSP genes to a high degree of purifying selection and the unusual prevalence of genetic dominance of the associated disease phenotypes. Our study puts the genetics of inheritable sHSP-borne diseases into the context of vertebrate evolution.

evolutionary biology↗

bioRxiv2022

The evolution of BDNF is defined by strict purifying selection and prodomain spatial coevolution, but what does it mean for human brain disease?

The mammalian gene Brain-Derived Neurotrophic Factor (BDNF) is an essential mediator of brain assembly, development, and maturation which has been implicated in a variety of brain disorders such as neurodevelopmental disorders (e.g. autism spectrum disorder), neuropsychiatric disorders (e.g. depression, PTSD, schizophrenia), and neurodegenerative disorders (e.g. Parkinsons). Loss of BDNF during early development is embryonic lethal, and depletion of BDNF during adolescence or adulthood can result in disease-related neuropathology across a broad range of model organisms. In order to better understand the role of BDNF in disease, we seek to provide an evolutionary context to BDNFs role within the brain by elucidating the molecular and genetic comparative history of BDNF across species. We conduct sequence alignment and phylogenetic reconstruction of the BDNF gene across a diverse selection of over 160 mammalian species spanning [~]177 million years of evolution. Selective evolutionary change was examined via several independent computational models of codon evolution including FEL, MEME, and BGM. We report strict purifying selection in the main functional domain of BDNF (NGF domain, essentially comprising the mature BDNF protein). Specifically, we discover 6 sites in our homologous alignment which are under episodic selection in the early regulatory region of BDNF (i.e. the prodomain) and 23 pairs of coevolving sites that are a part of complex spatial relationships that are distributed across the entire BDNF gene. Thus, we propose that our discovery of both local and distal sites of co-evolution within the pro- and mature-domains of BDNF that likely reflect the evolutionary fine-tuning of BDNFs unique and complex regulatory capacities whilst also retaining its core yet diverse ontogenic functionality within the central nervous system. This discovery consequently supports the idea that the BDNF prodomain is more prone to change than the mature domain, however the fact that this region has also been subject to negative purifying selection also highlights genetic sensitivity and thus partially explains the prodomains disease relevance (e.g. Val66Met and other variants) to numerous neuropsychiatric disorders. HIGHLIGHTSO_LIWe extracted coding sequences for Brain-Derived Neurotrophic Factor (BDNF) from over 160 mammalian genomes that span approximately [~]177 million years of evolution. C_LIO_LIWe observe strict purifying selection in the main functional domain (NGF) of the BDNF gene in mammals. C_LIO_LIWe observe novel results with 6 sites in our homologous alignment which are under episodic selection in the early regulatory region of BDNF (i.e. the prodomain). C_LIO_LIWe observe 23 pairs of coevolving sites within BDNF. Many of which are a part of complex spatial relationships and are distributed across the entire BDNF gene. C_LIO_LIThese data define exactly how "BDNF is highly conserved" by defining exactly where and how the mammalian BDNF has evolved, confirming the widespread belief that the BDNF prodomain is more prone to change than the mature BDNF protein. C_LI

neuroscience↗

bioRxiv2022

Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function

Among the 30 non-synonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (i) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (ii) interactions of Spike with ACE2 receptors, and (iii) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations in intrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any genomes within which they occurred. We further propose that the mutations in each of the three clusters therefore cooperatively interact to both mitigate their individual fitness costs, and adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron over all previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected.

evolutionary biology↗

bioRxiv2022

RASCL: Rapid Assessment Of SARS-CoV-2 Clades Through Molecular Sequence Analysis

An important component of efforts to manage the ongoing COVID19 pandemic is the Rapid Assessment of how natural selection contributes to the emergence and proliferation of potentially dangerous SARS-CoV-2 lineages and CLades (RASCL). The RASCL pipeline enables continuous comparative phylogenetics-based selection analyses of rapidly growing clade-focused genome surveillance datasets, such as those produced following the initial detection of potentially dangerous variants. From such datasets RASCL automatically generates down-sampled codon alignments of individual genes/ORFs containing contextualizing background reference sequences, analyzes these with a battery of selection tests, and outputs results as both machine readable JSON files, and interactive notebook-based visualizations. AvailabilityRASCL is available from a dedicated repository at https://github.com/veg/RASCL and as a Galaxy workflow https://usegalaxy.eu/u/hyphy/w/rascl. Existing clade/variant analysis results are available here: https://observablehq.com/@aglucaci/rascl. ContactDr. Sergei L Kosakovsky Pond (spond@temple.edu). Supplementary informationN/A

bioinformatics↗

bioRxiv2020

Extra base hits: widespread empirical support for instantaneous multiple-nucleotide changes

Despite many attempts to introduce evolutionary models that permit substitutions that instantly alter more than one nucleotide in a codon, the prevailing wisdom remains that such changes are rare and generally negligible (or are reflective of non-biological artifacts, such as alignment errors), and codon models continue to posit that only single nucleotide change have non-zero rates. We develop and test a simple hierarchy of codon-substitution models with non-zero evolutionary rates for only one-nucleotide (1H), one- and two-nucleotide (2H), or any (3H) codon substitutions. Using 35,000 empirical alignments, we find widespread statistical support for multiple hits: 58% of alignments prefer models with 2H allowed, and 22% - with 3H allowed. Analyses of simulated data suggest that these results are not likely to be due to simple artifacts such as model misclassification or alignment errors. Further modeling revealed that synonymous codon island jumping among codons encoding serine, especially along short branches, contributes significantly to this 3H signal. While serine codons were prominently involved in multiple-hit substitutions, there were other common exchanges contributing to better model fit. It appears that a small subset of sites in most alignments have unusual evolutionary dynamics not well explained by existing model formalisms, and that commonly estimated quantities, such as dN/dS ratios may be biased by model misspecification. Our findings highlight the need for continued evaluation of assumptions underlying workhorse evolutionary models and subsequent evolutionary inference techniques. We provide a software implementation for evolutionary biologists to assess the potential impact of extra base hits in their data in the HyPhy package.

bioinformatics↗