Biology subjects

McKinnon, L. M.

Publications and source records attributed to McKinnon, L. M..

3 recordsLinked to original sources

bioRxiv2025

Ramp sequence may explain synonymous variant association with Alzheimer's disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA)

BACKGROUNDSynonymous variant NC_000007.14:g.100373690T>C (rs2405442:T>C) in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) gene was previously associated with decreased risk for Alzheimers disease (AD) in genome-wide association studies, but its biological impact is largely unknown. OBJECTIVEWe hypothesized that rs2405442:T>C decreases mRNA and protein levels by destroying a ramp of slowly translated codons at the 5 end of PILRA. METHODSWe assessed rs2405442:T>C predicted effects on PILRA through quantitative polymerase chain reactions (qPCR) and enzyme-linked immunosorbent assays (ELISA) using Chinese hamster ovary (CHO) cells. RESULTSBoth mRNA (P=1.9184 x 10-13) and protein (P=0.01296) levels significantly decreased in the mutant versus the wildtype in the direction that we predicted based on destroying a ramp sequence. CONCLUSIONSWe show that rs2405442:T>C alone directly impacts PILRA mRNA and protein expression, and ramp sequences may play a role in regulating AD-associated genes without modifying the protein product. Research in ContextO_LISystematic review: Genetic variants identified through genome-wide association studies often lack biological support for their association with Alzheimers disease. Although synonymous variant rs2405442:T>C in PILRA was previously reported as protective against Alzheimers disease, its effects have generally been attributed to linkage with missense variant, rs1859788:A>G. C_LIO_LIInterpretation: We show that rs2405442:T>C alone decreases mRNA and protein levels by destroying a ramp of slowly translated codons at the beginning of PILRA. We also show that a ramp sequence is present in PILRA and likely regulates mRNA and protein levels, thus offering a plausible biological mechanism explaining rs2405442:T>C association with Alzheimers disease independent of rs1859788:A>G. C_LIO_LIFuture directions: We provide the first protocol to evaluate how disease-associated variants impact ramp sequences, which could explain why some genetic variants are reported by genome-wide association studies. Future studies might examine if the ramp sequence could be therapeutically targeted to regulate PILRA expression without changing the protein product. C_LI

genetics↗

bioRxiv2020

A Comprehensive Analysis of the Phylogenetic Signal in Ramp Sequences in 211 Vertebrates

BackgroundRamp sequences increase translational speed and accuracy when rare, slowly-translated codons are found at the beginnings of genes. Here, the results of the first analysis of ramp sequences in a phylogenetic construct are presented. MethodsRamp sequences were compared from 211 vertebrates (110 Mammalian and 101 non-mammalian). The presence and absence of ramp sequences was analyzed as a binary character in a parsimony and maximum likelihood framework. Additionally, ramp sequences were mapped to the Open Tree of Life taxonomy to determine the number of parallelisms and reversals that occurred, and these results were compared to what would be expected due to random chance. Lastly, aligned nucleotides in ramp sequences were compared to the rest of the sequence in order to examine possible differences in phylogenetic signal between these regions of the gene. ResultsParsimony and maximum likelihood analyses of the presence/absence of ramp sequences recovered phylogenies that are highly congruent with established phylogenies. Additionally, the retention index of ramp sequences is significantly higher than would be expected due to random chance (p-value = 0). A chi-square analysis of completely orthologous ramp sequences resulted in a p-value of approximately zero as compared to random chance. DiscussionRamp sequences recover comparable phylogenies as other phylogenomic methods. Although not all ramp sequences appear to have a phylogenetic signal, more ramp sequences track speciation than expected by random chance. Therefore, ramp sequences may be used in conjunction with other phylogenomic approaches.

evolutionary biology↗

bioRxiv2019

Codon Use and Aversion is Largely Phylogenetically Conserved Across the Tree of Life

Using parsimony, we analyzed codon usages across 12 337 species and 25 727 orthologous genes to rank specific genes and codons according to their phylogenetic signal. We examined each codon within each ortholog to determine the codon usage for each species. In total, 890 814 codons were parsimony informative. Next, we compared species that used a codon with species that did not use the codon. We assessed each codons congruence with species relationships provided in the Open Tree of Life (OTL) and determined the statistical probability of observing these results by random chance. We determined that 25 771 codons had no parallelisms or reversals when mapped to the OTL. Codon usages from orthologous genes spanning many species were 1 109x more likely to be congruent with species relationships in the OTL than would be expected by random chance. Using the OTL as a reference, we show that codon usage is phylogenetically conserved within orthologous genes in archaea, bacteria, plants, mammals, and other vertebrates. We also show how to use our provided framework to test different tree hypotheses by confirming the placement of turtles as sister taxa to archosaurs.\n\nAvailabilityAll scripts, a README, and necessary test files are freely available on GitHub at https://github.com/ridgelab/codon_congruence\n\nContactperry.ridge@byu.edu

evolutionary biology↗