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PubMed2026

Biological Mechanisms Underlying the Cardiovascular Effects of Branched-Chain Amino Acids: A Proteome-Wide Mendelian Randomization Study.

BACKGROUND: Ischemic heart disease (IHD) is the leading cause of morbidity and mortality. Branched-chain amino acids (BCAAs) are associated with higher IHD risk, but the underlying biological pathways remain unclear. OBJECTIVES: This study aims to explore these pathways using 2-step proteome-wide Mendelian randomization. METHODS: We examined the associations between genetic proxies for BCAAs and 2922 proteins in the United Kingdom Biobank Pharma Proteomics Project, supplemented by a meta-analysis with data from deCODE to identify proteins associated with BCAAs. Next, we tested their effects on IHD risk using Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics Consortium (122,733 cases and 424,528 controls) and replicated in FinnGen (31,640 cases and 187,152 controls). We conducted sensitivity analyses using genetic instruments from deCODE. Proteins associated with IHD risk and, in a consistent direction, with genetically predicted BCAAs were considered potential mediators. RESULTS: Genetic proxies for BCAAs were associated with 40 proteins. Among these, 6 proteins showed consistent evidence of mediation, including complement C1s subcomponent, coagulation factor II, granulin, proprotein convertase subtilisin/kexin type 9, sex hormone-binding globulin, and V-set and transmembrane domain-containing protein 2-like. These proteins are involved in inflammation, coagulation, lipid metabolism, and cellular stress response. All associations were robust across different analytical methods and replicated in independent datasets. Mediation analysis showed that these proteins accounted for 6.5% to 32.1% of the association between BCAAs and IHD risk. CONCLUSIONS: This study identified 6 proteins that potentially link BCAAs to IHD, implicating pathways related to inflammation, coagulation, lipid metabolism, and cellular stress responses. To our knowledge, these findings provide novel mechanistic insights into the BCAA-IHD relationship and highlight potential protein targets for future prevention and intervention strategies.

Amino Acids, Branched-Chain↗

PubMed1986

A molecular hypothesis on parallel memory function with relevance to senile dementias.

The hypothesis is presented that closely associated memories can be coded and decoded in a parallel manner analogous to genetic deoxyribonucleic acid (DNA) forming two or more different proteins from a single polynucleotide strand. Iconic, aural, and lexical stimuli could be imprinted and recovered from the same storage molecule. The described process which involved the decoding of the same neuronal DNA macromolecule two or more times but from slightly shifted reading frames has the advantage of promoting fidelity of coding and decoding. The suggested mechanism also explains why it is possible for some mnemonic elements to survive during aphasia and senile dementias, while closely linked synonymous engrams are lost.

Aphasia↗

PubMed2026

Landscape Genomics Reveals Divergent Adaptation Modes and Predicts Climate Vulnerability in Xinjiang Indigenous Sheep.

Climate change increasingly endangers precious indigenous sheep germplasm resources distributed across diverse Chinese landscapes, and systematically decoding their polygenic climate-adaptive genetic mechanisms is essential for targeted breed conservation and long-term sustainable pastoral production. Whole-genome resequencing data from 93 individuals covering six representative local sheep breeds were analyzed in this work. After filtering highly collinear climate variables, three mature landscape genomic approaches were jointly applied to identify environment-linked gene variants, while two predictive metrics across ten CMIP6 future climate scenarios quantified each breed's long-term adaptive risks. Six temperature- and water-related environmental factors jointly drove sheep population genetic differentiation, with temperature fluctuation indices showing markedly stronger explanatory power. Detected adaptive genes were significantly enriched in ion transport, energy metabolism and cellular stress response pathways. Future projections indicated western breeds (Bayinbuluke, Cele Black, Xiahe) face severe maladaptation risks under high-emission SSP370 scenarios by 2100, whereas central and eastern breeds possess much broader climate tolerance. This study systematically reveals the core genomic basis of ovine climate adaptation and quantifies distinct breed-specific climate vulnerability, providing solid reliable theoretical support for precision germplasm conservation and selective breeding of climate-resilient sheep varieties.

adaptive loci↗

PubMed2026

Protein mediators of chronic kidney disease in Type 2 diabetes: A mendelian randomization study.

BACKGROUND: Chronic kidney disease (CKD) occurs in 20-50% of the people living with Type 2 diabetes (T2D) and is the leading cause of kidney failure worldwide. The cause of CKD is not fully understood, and few interventions prevent CKD in individuals living with diabetes. Here, we use large-scale proteomics data to identify circulating proteins that mediate the relationship between T2D and kidney disorders. METHODS AND FINDINGS: First, we used two-sample mendelian randomization (MR) and identified 71 circulating proteins whose levels were altered by genetic predisposition to T2D based on circulating proteomic GWAS from deCODE with 35,559 individuals and T2D GWAS with 80,154 cases. Then, we used cis-genetic variants to proxy the causal effect of some of these T2D-influenced circulating proteins and found that, collectively, five proteins (INHBC, GNPTG, LPO, AGRN, and CTSD) affected three kidney traits (blood urea nitrogen [BUN], estimated glomerular filtration rate [eGFR] and CKD risk) based on GWAS with up to 1,004,040 participants. Notably, we found that higher levels of circulating INHBC protein were estimated to lead to a lower eGFR and higher BUN based on MR analyses. We then replicated this MR analysis with proteomic GWAS from four additional cohorts, namely, UKB-PPP, Fenland, ARIC, and EPIC-Norfolk. We observed a consistent direction of effect across all four proteomic GWAS datasets, supporting the robustness of our results against platform and cohort variation. In observational analyses, increased circulating INHBC levels were associated with increased hazard for kidney disease diagnosis in 37,854 UK Biobank participants. We estimated that circulating INHBC levels mediate 1.3% (95% confidence interval [0.85%, 1.9%]) of the association between T2D and kidney disease diagnosis. There are important limitations in this study. Firstly, although we observed limited evidence for violations to the MR assumptions, some are untestable. Secondly, our study was not based on individuals with diabetic kidney diseases, but rather independent population-based studies assessing diabetes and kidney function separately. Therefore, additional functional analyses in disease specific cohort are needed. CONCLUSIONS: Collectively, these findings suggest that T2D influences the risk of CKD, in part, through increased circulating INHBC levels.

Humans↗

PubMed2026

A Unified Mechanism of +1 Ribosomal Frameshifting.

Ribosomes decode 3-nucleotide codons and move in 1-codon increments to maintain the messenger RNA (mRNA) frame thereby accurately producing the encoded protein. In special cases, including viral genomes and regulatory cellular proteins, frameshifting occurs to expand the coding repertoire of an mRNA to make more than one protein. How these frameshifting events are induced and regulated is an active area of research. Here, we discuss recent progress in the understanding of +1 frameshifting (+1FS), during which the ribosome shifts by 1 mRNA nucleotide in the 3' direction. Structural and biochemical studies yielded insights into +1FS induced by mRNA slippery sequences and transfer RNA (tRNA) stem-loop expansion or modifications. tRNAs with an additional anticodon nucleotide are explored as a biotechnology tool for expanding the genetic code in an approach termed quadruplet decoding. We revisit the challenges of the quadruplet decoding model, discuss +1FS scenarios in bacteria and eukaryotes, and propose a unifying structural mechanism for +1FS.

Frameshifting, Ribosomal↗

PubMed1997

Carcinogenesis. The fate of intestinal segments used in urinary reconstruction.

The actual mechanism for risk of developing cancer in intestinal segments used for urinary diversion remains uncertain. The clinical and laboratory experiences are reviewed in this article. The pathogenesis is multifaceted, involving initiators and promoters of carcinogenesis. Molecular genetic technology may provide the key to decoding the mechanisms involved.

Humans↗

PubMed2003

Hypomutable regions of yeast TFIIB in a unigenic evolution test represent structural domains.

As genome sequences of many organisms - including humans - are being decoded, there is a great need for genetic tools to analyze newly discovered genes/proteins. A 'unigenic evolution' approach has been previously proposed for dissecting protein domains, which is based on the assumption that functionally important regions of a protein may tolerate missense mutations less well than other regions. We describe a unigenic evolution analysis of general transcription factor IIB (TFIIB) - a protein that is well characterized both structurally and functionally - to better understand the molecular basis of this genetic approach. The overall distribution profile of hypomutable regions within yeast TFIIB correlates extremely well with the known compact structural domains, suggesting that the unigenic evolution approach can help reveal structural properties of a protein. We further show that a small region located immediately carboxyl-terminal to the zinc ribbon motif is functionally important despite its strong hypermutability. Our study further demonstrates the usefulness of the unigenic evolution approach in dissecting protein domains, but suggests that the mutability of different regions of a protein in such a test is determined primarily by their structural properties.

Amino Acid Sequence↗

PubMed2004

[Neurobiology and psychotherapy].

Body, brain and mind are all manifestations of one single organism; all mental processes are based on biological-neuronal processes and events. Advances in neurobiology have increasingly enabled the decoding of the correlates of psychological functions: genetic conditions, brain processes from sensation to cognition and from emotion to empathy, and social interaction. In the latter area, which is decisive for psychosocial research, neurobiological investigations are in their very early stages. Complex psychological functions are represented in networks; this renders it impossible to adopt simple reductionist approaches. Clinical phenomena such as pain or depression are also represented in neuronal networks. An abundance of neurobiological data validates (positively or negatively) psychological, psychotherapeutic or psychiatric theories or therapies. Such validation is indispensable. To date, there are no known fundamentally new approaches to psychiatric and psychotherapeutic practice which are derived from neurobiological data. Psychological phenomena emerge from neurobiological processes. Therefore, psychosocial approaches will be necessary in the future to understand such data in the context of methodological dualism (neurobiological versus psychosocial research methods).

Brain↗

PubMedDate not supplied

Dyslexia: nature and nurture.

This paper explores the balance of genetic and environmental influences on dyslexia in generally supportive educational environments. Evidence from family studies suggests and research with identical and fraternal twins confirms the presence of strong genetic influences on dyslexia, though the way dyslexia is defined influences the degree of genetic influence. The behavioural genetic evidence is supported with molecular genetic evidence from DNA analyses suggesting regions on several different chromosomes where genes related to dyslexia are likely to be found. The behavioural and molecular genetic analyses are also applied to different component word reading skills (orthographic coding and phonological decoding) as well as to related language skills (phoneme awareness) to better understand the genetic and cognitive pathways to dyslexia.

Dyslexia↗

PubMed2004

Large-scale integration of human genetic and physical maps.

Genetic maps are used routinely in family-based linkage studies to identify the rough location of genes that influence human traits and diseases. Unlike physical maps, genetic maps are based on the amount of recombination occurring between adjacent loci rather than the actual number of bases separating them. Genetic maps are constructed by statistically characterizing the number of crossovers observed in parental meioses leading to the transmission of alleles to their offspring. Considerations such as the number of meioses observed, the heterozygosity and physical distance between the loci studied, and the statistical methods used can impact the construction and reliability of a genetic map. As is well known, poorly constructed genetic maps can have adverse effects on linkage mapping studies. With the availability of sequence-based maps, as well as genetic maps generated by different researchers (such as those generated by the Marshfield and deCODE groups), one can investigate the compatibility and properties of different maps. We have integrated information from the most current human genome sequence data (UCSC genome assembly Human July 2003) as well as 8399 microsatellite markers used in the Marshfield and deCODE maps to reconcile the these maps. Our efforts resulted in updated sex-specific genetic maps.

Chromosome Mapping↗

PubMed1998

tRNA imbalance promotes -1 frameshifting via near-cognate decoding.

tRNAGly1 is the Escherichia coli glycine tRNA specific for GGG codons. A genetic selection for multicopy suppressors of a frameshift mutation has shown that increased levels of wild-type tRNAGly1 causes -1 frameshifting. Analysis of the suppression spectrum of this multicopy suppressor and peptide sequencing of the suppressed protein product showed that it promoted GG doublet decoding at the near-cognate GGA codons. It is proposed that increasing the concentration of the GGG-specific tRNAGly1 relative to the cognate GGA-decoding tRNAGly2 allows the near-cognate tRNA to read GGA codons. Near-cognate decoding of GGA codons by tRNAGly1 can occur by a two-out-of-three reading mechanism, in which only the first two bases of the GGA codon are paired with the anticodon, thus permitting doublet translocations. In mycoplasmas, a single tRNA typically decodes all four triplets of a codon family and introduction of a feature of the Mypoplasma mycoides tRNAGly responsible for non-discriminate decoding, a C at position 32, into the anticodon E. coli tRNAGly1, enhanced the efficiency of doublet decoding.

Escherichia coli↗

PubMed2005

The role of tRNA as a molecular spring in decoding, accommodation, and peptidyl transfer.

Translation is the process by which the genetic information contained in mRNA is used to link amino acids in a predetermined sequential order into a polypeptide chain, which then folds into a protein. Transfer RNAs (tRNAs) are the adapter molecules designed to provide the "lookup" from codons to amino acids. Cryo-EM has provided evidence that the ribosome, as a molecular machine, undergoes many structural changes during translation. Recent findings show that the tRNA structure itself undergoes large conformational changes as well, and that the decoding process must be seen as a complex dynamic interplay between tRNA and the ribosome.

Cryoelectron Microscopy↗

PubMed2025

Systematic decoding of functional enhancer connectomes and risk variants in human glioma.

Genetic and epigenetic variations contribute to the progression of glioma, but the mechanisms underlying these effects, particularly for enhancer-associated genetic variations in non-coding regions, still remain unclear. Here we performed high-throughput CRISPR interference screening to identify pro-tumour enhancers in glioma cells. By integrating genome-wide H3K27ac HiChIP data, we identified the target genes of these pro-tumour enhancers and revealed the essential role of enhancer connectomes in promoting glioma progression. Through systematic analysis of enhancers carrying glioma risk-associated single-nucleotide polymorphisms (SNPs), we found that these SNPs can promote glioma progression through the enhancer connectome. Using CRISPR-Cas9-mediated enhancer interference and SNP editing, we demonstrated that glioma-specific enhancer carrying the risk SNP rs2297440 regulates SOX18 expression by specifically recruiting transcription factor MEIS1 binding, thereby contributing to glioma progression. Our study sheds light on the molecular mechanisms underlying glioma susceptibility and provides potential therapeutic targets to treat glioma.

Humans↗

PubMed2001

Genetic and environmental influences on orthographic and phonological skills in children with reading disabilities.

Data from identical and fraternal twins were analyzed to estimate the proportions of genetic and environmental influences on group deficits in accuracy and, when available, speed for printed word recognition and for related skills in phonological decoding (PD), orthographic coding (OC), and phoneme awareness (PA). In addition, bivariate genetic analyses were employed to estimate the degree of common genetic influence on group deficits across these different reading and language skills. About half of the group deficits in each of the skills were due to genetic influences, and the genetic origins were largely shared among the measures (r(g) = .53 - .99), except for those between OC and PA (r(g) = .28 - .39). Implications of the results are discussed for models of reading disability and remediation.

Adolescent↗

PubMed1999

Decoding vectorial information from a gradient: sequential roles of the receptors Frizzled and Notch in establishing planar polarity in the Drosophila eye.

The Drosophila eye is composed of several hundred ommatidia that can exist in either of two chiral forms, depending on position: ommatidia in the dorsal half of the eye adopt one chiral form, whereas ommatidia in the ventral half adopt the other. Chirality appears to be specified by a polarizing signal with a high activity at the interface between the two halves (the 'equator'), which declines in opposite directions towards the dorsal and ventral poles. Here, using genetic mosaics, we show that this polarizing signal is decoded by the sequential use of two receptor systems. The first depends on the seven-transmembrane receptor Frizzled (Fz) and distinguishes between the two members of the R3/R4 pair of presumptive photoreceptor cells, predisposing the cell that is located closer to the equator and having higher Fz activity towards the R3 photoreceptor fate and the cell further away towards the R4 fate. This bias is then amplified by subsequent interactions between the two cells mediated by the receptor Notch (N) and its ligand Delta (Dl), ensuring that the equatorial cell becomes the R3 photoreceptor while the polar cell becomes the R4 photoreceptor. As a consequence of this reciprocal cell fate decision, the R4 cell moves asymmetrically relative to the R3 cell, initiating the appropriate chiral pattern of the remaining cells of the ommatidium.

Animals↗

PubMed2002

Differential genetic etiology of reading component processes as a function of IQ.

Results obtained from previous studies of word recognition, reading component skills, and reading composite measures suggest that genetic factors may be more important as a cause for reading disability among children with higher IQ scores than among those with lower IQ scores. To investigate the genetic etiology of reading disability further, measures of word recognition, phonological decoding, orthographic coding, and phoneme awareness were obtained from a total of 465 twin pairs with a positive school history of reading problems. The basic and extended DeFries and Fulker (DF) multiple regression models for the analysis of selected twin data were employed to investigate the etiology of group deficits in reading and language skills, as well as to assess differential genetic etiology for the reading-related measures as a function of IQ. Data from 168 sibling pairs (drawn from the twins' families), including fraternal twin pairs and their siblings, as well as non-twin siblings of identical twins were subjected to single-marker analyses using the DF basic linkage model to examine evidence for linkage of a quantitative-trait locus (QTL) for reading and language deficits to the short arm of chromosome 6. Lastly, to investigate the possible differential influence of this QTL as a function of IQ, the sibling pair data were fitted to an extension of the DF basic linkage model. Results indicated that reading and language deficits are significantly heritable and that differential genetic influences as a function of IQ are evident for measures of word recognition and phonological decoding. Results obtained from linkage analyses confirmed the presence of a QTL on chromosome 6p that influences phonological and orthographic skills, as well as phoneme awareness measures, and suggest that this QTL may influence phoneme awareness differentially as a function of IQ: however, future analyses with considerably larger samples are needed to test the hypothesis of differential QTL influence more rigorously.

Adolescent↗

PubMed2000

Decoding of tandem quadruplets by adjacent tRNAs with eight-base anticodon loops.

To expand the genetic code for specification of multiple non-natural amino acids, unique codons for these novel amino acids are needed. As part of a study of the potential of quadruplets as codons, the decoding of tandem UAGA quadruplets by an engineered tRNA(Leu) with an eight-base anticodon loop, has been investigated. When GCC is the codon immediately 5' of the first UAGA quadruplet, and release factor 1 is partially inactivated, the tandem UAGAs specify two leucines with an overall efficiency of at least 10%. The presence of a purine at anticodon loop position 32 of the tRNA decoding the codon 5' to the first UAGA seems to influence translation of the following codon. Another finding is intraribosomal dissociation of anticodons from codons and their re-pairing to mRNA at overlapping or nearby codons. In one case where GCC is replaced by CGG, only a single Watson-Crick base pair can form upon re-pairing when decoding is resumed. This has implications for the mechanism of some cases of programmed frameshifting.

Anticodon↗

PubMed2004

Yeast as a model organism for studying the evolution of non-standard genetic codes.

During the last 30 years, a number of alterations to the standard genetic code have been uncovered both in prokaryotes and eukaryotic nuclear and mitochondrial genomes. But, the study of the evolutionary pathways and molecular mechanisms of codon identity redefinition has been largely ignored due to the assumption that non-standard genetic codes can only evolve through neutral evolutionary mechanisms and that they have no functional significance. The recent discovery of a genetic code change in the genus Candida that evolved through an ambiguous messenger RNA decoding mechanism is bringing that naive assumption to an abrupt end by showing, in a rather dramatic way, that genetic code changes have profound physiological and evolutionary consequences for the species that redefine codon identity. In this paper, the recent data on the evolution of the Candida genetic code are reviewed and an experimental framework based on forced evolution, molecular genetics and comparative and functional genomics methodologies is put forward for the study of non-standard genetic codes and genetic code ambiguity in general. Additionally, the importance of using Saccharomyces cerevisiae as a model organism for elucidating the evolutionary pathway of the Candida and other genetic code changes is emphasised.

Candida↗