Biology subjects

Kauwe, J. S.

Publications and source records attributed to Kauwe, J. S..

5 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↗

bioRxiv2021

Genome of a Giant (Trevally): Caranx ignobilis

Caranx ignobilis, commonly known as the kingfish or giant trevally, is a large, reef-associated apex predator. It is a prized sportfish, targeted heavily throughout its tropical and subtropical range in the Indian and Pacific Oceans, and it has drawn significant interest in aquaculture due to an unusual tolerance for freshwater. In this study, we present a high-quality nuclear genome assembly of a C. ignobilis individual from Hawaiian waters, which have recently been shown to host a genetically distinct population. The assembly has a contig NG50 of 7.3Mbp and scaffold NG50 of 46.3Mbp. Twenty-five of the 203 scaffolds contain 90% of the genome. We also present the raw Pacific Biosciences continuous long-reads from which the assembly was created. A Hi-C dataset (Dovetail Genomics Omni-C) and Illumina-based RNA-seq from eight tissues are also presented; the latter of which can be particularly useful for annotation and studies of freshwater tolerance. Overall, this genome assembly and supporting data is a valuable tool for ecological and comparative genomics studies of kingfish and other carangoid fishes.

genomics↗

bioRxiv2021

Genome Assembly of the Roundjaw Bonefish (Albula glossodonta), a Vulnerable Circumtropical Sportfish

BackgroundBonefishes are cryptic species indiscriminately targeted by subsistence and recreational fisheries worldwide. The roundjaw bonefish, Albula glossodonta is the most widespread bonefish species in the Indo-Pacific and is listed as vulnerable to extinction by the IUCNs Red List due to anthropogenic activities. Whole-genome datasets allow for improved population and species delimitation, which - prior to this study - were lacking for Albula species. ResultsWe generated a high-quality genome assembly of an A. glossodonta individual from Hawai i, USA. The assembled contigs had an NG50 of 4.75 Mbp and a maximum length of 28.2 Mbp. Scaffolding yielded an NG50 of 14.49 Mbp, with the longest scaffold reaching 42.29 Mbp. Half the genome was contained in 20 scaffolds. The genome was annotated with 28.3 K protein-coding genes. We then analyzed 66 A. glossodonta individuals and 38,355 SNP loci to evaluate population genetic connectivity between six atolls in Seychelles and Mauritius in the Western Indian Ocean. We observed genetic homogeneity between atolls in Seychelles and evidence of reduced gene flow between Seychelles and Mauritius. The South Equatorial Current could be one mechanism limiting gene flow of A. glossodonta populations between Seychelles and Mauritius. ConclusionsQuantifying the spatial population structure of widespread fishery species such as bonefishes is necessary for effective transboundary management and conservation. This population genomic dataset mapped to a high-quality genome assembly allowed us to discern shallow population structure in a widespread species in the Western Indian Ocean. The genome assembly will be useful for addressing the taxonomic uncertainties of bonefishes globally.

genomics↗

bioRxiv2019

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson's disease and progressive supranuclear palsy converge on altered glial regulation

Parkinsons disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. To better understand the genetic contribution of this region to PD, we fine-mapped the 17q21.31 locus in order to identify novel mechanisms conferring risk for the disease. We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble -synuclein, and co-localized with Lewy bodies in PD brain tissue. These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with -synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

neuroscience↗

bioRxiv2019

Failure to detect synergy between variants in transferrin and hemochromatosis and Alzheimer’s disease in large cohort

Alzheimers disease (AD) is the most common cause of dementia and, despite decades of effort, there is no effective treatment. In the last decade, many association studies have identified genetic markers that are associated with AD status. Two of these studies suggest that an epistatic interaction between variants rs1049296 in the Transferrin (TF) gene and rs1800562 in the Homeostatic Iron Regulator (HFE) gene, commonly known as \"the hemochromatosis gene\", is in genetic association with AD. TF and HFE are involved in the transport and regulation of iron in the brain, and disrupting these processes exacerbates AD pathology through increased neurodegeneration and oxidative stress. However, by using a significantly larger dataset from the Alzheimers Disease Genetics Consortium (ADGC), we fail to detect an association between TF rs1049296 or HFE rs1800562 with AD risk (TF rs1049296 p=0.38 and HFE rs1800562 p=0.40). In addition, logistic regression with an interaction term and a Synergy Factor Analysis (SFA) both failed to detect epistasis between TF rs1049296 and HFE rs1800562 (SF=0.94; p=0.48) in AD cases. Each of these analyses had sufficient statistical power (Power>0.99), suggesting that previously-reported associations may be the result of more complex epistatic interactions, genetic heterogeneity, or were false-positive associations due to limited sample sizes.

genetics↗