Biology subjects

Erives, A. J.

Publications and source records attributed to Erives, A. J..

8 recordsLinked to original sources

bioRxiv2026

Losses of TMC and CIB neurosensory genes in schizophoran flies at the PETM

The K-Pg extinction ended the world of non-avian dinosaurs 66 Mya and ushered in the Age of Mammals. During the [~]10 My of recovery, Schizophora, an immensely successful group of flies, appeared, flourished and diversified. This large radiation produced over half of all dipteran families ([~]78/150), including the family for Drosophila, the model genetic powerhouse. In the context of this evolutionary radiation, we investigate the loss of two of three highly conserved, neurosensory transmembrane channel (TMC) genes. Here, we show that these genes were separately lost across multiple diverging schizophoran lineages of the early Paleogene, suggesting a powerful environmental driver was involved. We also show that unlinked genes encoding the calcium- and integrin-binding (CIB) subunits of the missing TMC complexes were lost during the same time frame. Because the lost genes encode complexes involved in thermal nociception, we propose the external driver was likely the Paleocene- Eocene thermal maximum (PETM), a 200 ky interval of elevated global temperatures occurring 56 Mya, slightly before the earliest schizophoran fossil from 53 Mya. These results suggest that gene loss may have been adaptive for most schizophoran lineages to emerge past the hothouse Earth of the PETM.

evolutionary biology↗

bioRxiv2024

Two dimensional sequence alignment shows that replication slippage may generate a significant proportion of all transversion substitutions.

Homologous sequences diverge in length via insertions and deletions (indels). Consequently, evolutionary genetic analyses routinely use methods to produce gapped alignment (GA). In GA, artificial null characters (gaps) are inserted into sequences so that nucleotide characters may be placed into homological correspondence within an alignment column. However, this approach sacrifices the homological correspondence of nucleotides diverging via tandem repeats (TRs). To address this deficit, we generalize GA with micro-paralogical gapped alignment (MPGA). While GA operates under a strict two-state homology model of one-to-one and one-to-none (i.e. one-to-gap) relationships, MPGA adds one-to-many, many-to-many, and many-to-none relationships. This expanded, multi-state homology model is motivated by DNA replication slippage (RS). RS produces short tandem repeats, constituting interrelated micro-paralogous sequences. Together, RS and TR-associated instability have a synergistic effect in the production of indels, which generate the need for gap insertions. MPGA reduces the computational cost of determining optimal gap insertions by reducing the number of gaps required by two-dimensional (2D) representations of sequence. A 2D representation of one sequence is achieved when tandem repeats are contracted into the same columns (dimension one) by occupying multiple rows (dimension two), an internal micro-paralogical dimension. To demonstrate the benefits and challenges of 2D representation, we develop a program called LINEUP and identify a pervasive fractal dimension in evolving sequences. We then demonstrate how LINEUP-generated 2D representations provide improved measures of substitution rates and transition-to-transversion ratios. Altogether, these results showcase significant new perspectives on basic mutational and evolutionary processes when multi-state homology models are adopted.

genetics↗

bioRxiv2021

Nuclear localization and transactivation of SYS-1/β-catenin is the result of serial gene duplications and subfunctionalizations

{beta}-catenin is a multifunctional protein capable of mediating cell adhesion via E-cadherin and transactivation of target genes of the canonical Wnt signaling pathway. The nematode, C. elegans contains four paralogs of {beta}-catenin which are highly specific in their functions. Though similar in overall structure, the four beta-catenins are functionally distinct, each regulating different aspects of development. Of the four, SYS-1 is a key player in Wnt dependent asymmetric cell division (ACD). In ACD, a polarized mother will give rise to a daughter with high nuclear SYS-1 and another with low nuclear SYS-1. Despite sequence dissimilarity, SYS-1 shares a close structural resemblance with human {beta}-catenin where it retains an unstructured amino-terminus (NTD) and 12 armadillo repeats. Using existing genome sequence data from several nematode species, we find that the four {beta}-catenin paralogs result from 3 sequential gene duplications and neofunctionalizations during nematode evolution. SYS-1, however, lacks an unstructured carboxyl-terminus (CTD) that is essential for human {beta}-catenin transactivation processes. This work supports the hypothesis that SYS-1 compensated for the lack of CTD by acquiring novel transactivation domains with cryptic nuclear localization signals in the NTD and the first four armadillo repeats, as shown by transactivation assays in worms and yeast. Furthermore, SYS-1 regulatory domains are not localized to the NTD as in canonical {beta}-catenin and instead spans the entire length of the protein. Truncating SYS-1 abolishes the classical SYS-1 nuclear asymmetry, resulting in daughter cells with symmetrical SYS-1 truncation localization. A screen for SYS-1 physical interactors followed by in vivo cell fate and SYS-1 localization analyses suggest that proper SYS-1 nuclear export is facilitated by XPO-1, while an interaction with IMB-3, an importin {beta}-like protein, suggests import mechanisms. Interestingly, XPO-1 is especially required for lowering SYS-1 in the Wnt-unsignaled nucleus, suggesting a distinct mechanism for regulating asymmetric nuclear SYS-1. In summary, we provide insights on the mechanism of {beta}-catenin evolution within nematodes and inform SYS-1 transactivation and nuclear transport.

developmental biology↗

bioRxiv2020

Analysis of zebrafish periderm enhancers facilitates identification of a regulatory variant near human KRT8/18

Genome wide association studies for non-syndromic orofacial cleft (OFC) have identified single nucleotide polymorphisms (SNPs) at loci where the presumed risk-relevant gene is expressed in oral periderm. The functional subsets of such SNPs are difficult to predict because the sequence underpinnings of periderm enhancers are unknown. We applied ATAC-seq to models of human palate periderm, including zebrafish periderm, mouse embryonic palate epithelia, and a human oral epithelium cell line, and to complementary mesenchymal cell types. We identified sets of enhancers specific to the epithelial cells and trained gapped-kmer support-vector-machine classifiers on these sets. We used the classifiers to predict the effect of 14 OFC-associated SNPs at 12q13 near KRT18. All the classifiers picked the same SNP as having the strongest effect, but the significance was highest with the classifier trained on zebrafish periderm. Reporter and deletion analyses support this SNP as lying within a periderm enhancer regulating KRT18/KRT8 expression.

developmental biology↗

bioRxiv2019

A screen for gene paralogies delineating evolutionary branching order of early Metazoa

The evolutionary diversification of animals is one of Earths greatest triumphs, yet its origins are still shrouded in mystery. Animals, the monophyletic clade known as Metazoa, evolved wildly divergent multicellular life strategies featuring ciliated sensory epithelia. In many lineages epithelial sensoria became coupled to increasingly complex nervous systems. Currently, different phylogenetic analyses of single-copy genes support mutually-exclusive possibilities that either Porifera or Ctenophora is sister to all other animals. Resolving this dilemma would advance the ecological and evolutionary understanding of the first animals and the evolution of nervous systems. Here we describe a comparative phylogenetic approach based on gene duplications. We computationally identify and analyze gene families with early metazoan duplications using an approach that mitigates apparent gene loss resulting from the miscalling of paralogs. In the transmembrane channel-like (TMC) family of mechano-transducing channels, we find ancient duplications that define separate clades for Eumetazoa (Placozoa + Cnidaria + Bilateria) versus Ctenophora, and one duplication that is shared only by Eumetazoa and Porifera. In the MLX/MLXIP family of bHLH-ZIP regulators of metabolism, we find that all major lineages from Eumetazoa and Porifera (sponges) share a duplication, absent in Ctenophora. These results suggest a new avenue for deducing deep phylogeny by choosing rather than avoiding ancient gene paralogies.

evolutionary biology↗

bioRxiv2019

An axiomatic basis for maximal homology alignment

Maximal homology alignment is a new biologically-relevant approach to DNA sequence alignment that maps the internal dispersed microhomology of individual sequences onto two dimensions. It departs from the current method of gapped alignment, which uses a simplified binary state model of nucleotide position. In gapped alignment nucleotide positions have either no relationship (1-to-None) or else orthological relationship (1-to-1) with nucleotides in other sequences. Maximal homology alignment, however, allows additional states such as 1-to-Many and Many-to-Many, thus modeling both orthological and paralogical relationships, which together comprise the main homology types. Maximal homology alignment collects dispersed microparalogy into the same alignment columns on multiple rows, and thereby generates a two-dimensional representation of a single sequence. Sequence alignment then proceeds as the alignment of two-dimensional topological objects. The operations of producing and aligning two-dimensional auto-alignments motivate a need for tests of two-dimensional homological integrity. Here, I work out and implement basic principles for computationally testing the two dimensions of positional homology, which are inherent to biological sequences due to replication slippage and related errors. I then show that maximal homology alignment is more informative than gapped alignment in modeling the evolution of genetic sequences. In general, MHA is more suited when small insertions and deletions predominantly originate as local microparalogy. These results show that both conserved and non-conserved genomic sequences are enriched with a signature of replication slippage relative to their random permutations.

genetics↗

bioRxiv2018

Episodic evolution of a eukaryotic NADK repertoire of ancient provenance

NAD kinase (NADK) is the sole enzyme that phosphorylates nicotinamide adenine dinucleotide (NAD+/NADH) into NADP+/NADPH, which provides the chemical reducing power in anabolic (biosynthetic) pathways. While prokaryotes typically encode a single NADK, eukaryotes encode multiple NADKs. How these different NADK genes are all related to each other and those of prokaryotes is not known. Here we conduct phylogenetic analysis of NADK genes and identify major clade-defining patterns of NADK evolution. First, almost all eukaryotic NADK genes belong to one of two ancient eukaryotic sister clades corresponding to cytosolic (\"cyto\") and mitochondrial (\"mito\") clades. Secondly, we find that the cyto-clade NADK gene is duplicated in connection with loss of the mito-clade NADK gene in several eukaryotic clades or with acquisition of plastids in Archaeplastida. Thirdly, we find that horizontal gene transfers from proteobacteria have replaced mitochondrial NADK genes in only a few rare cases. Last, we find that the eukaryotic cyto and mito paralogs are unrelated to independent duplications that occurred in sporulating bacteria, once in mycelial Actinobacteria and once in aerobic endospore-forming Firmicutes. Altogether these findings show that the eukaryotic NADK gene repertoire is ancient and evolves episodically with major evolutionary transitions.\n\nAuthor SummaryMetabolic enzymes are central to all living organisms and key to understanding the evolution of life on Earth. One important component of all metabolic pathways is the participation of chemically-reducing cofactors such as the redox system of NAD+ and NADH molecules. All living cells also possess a system for shifting their intracellular pool of NAD+ and NADH into NADP+ and NADPH via phosphorylation by the NAD kinase (NADK). Phosphorylation by NADK allows cells to regulate the use of their main chemical redox system for anabolic growth and the synthesis of basic cellular components. In our study we provide the first comprehensive analysis of the NAD kinase family. We find that eukaryotes possess two ancient NADK gene families of unknown provenance and also find unrelated bacterial families that also possess dual NADK genes. We also find that while NADK evolution has been mostly stable through the eons, this family has evolved substantially in association with the evolution of specific clades of organisms. Altogether these results provide a metabolic picture of the tree of life and its evolution.

evolutionary biology↗

bioRxiv2018

Genetic sequences are two-dimensional

In attempting to align divergent homologs of a conserved developmental enhancer, a flaw in the homology concept embedded in gapped alignment (GA) was discovered. To correct this flaw, we developed a methodological approach called maximal homology alignment (MHA). The goal of MHA is to rescue internal microparalogy of biological sequences rather than to insert a pattern of gaps (null characters), which transform homologous sequences into strings of uniform size (1-dimensional lengths). The core operation in MHA is the \"cinch\", whereby inferred tandem microparalogy is represented in multiple rows across the same span of alignment columns. Thus, MHAs have a second (vertical) paralogy dimension, which re-categorizes most indel mutations as replication slippage and attenuates the indel problem. Furthermore, internally-cinched, inferred microparalogy in a self-MHA can later be relaxed to restore uniformity to 2-dimensional widths in a multiple sequence alignment. This de-cinching operation is used as a first resort before artificial null characters are used. We implement MHA in a program called maximal, which is composed of a series of modules for cinching and cyclelizing divergent tandem repeats. In conclusion, we find that the MHA approach is of higher utility than GA in non-protein-coding regulatory sequences, which are unconstrained by codon-based reading frames and are enriched in dense microparalogical content.

genetics↗