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PubMed2026

Cell Type-Resolved Causal Inference and Spatial Transcriptomic Integration Reveal Immune-Specific Genetic Drivers of Autoimmune and Malignant Thyroid Disease.

BACKGROUND: Thyroid diseases, including autoimmune thyroid disease (AITD) and thyroid cancer, are characterized by immune dysregulation, yet the cell type-specific genetic mechanisms underlying these conditions remain poorly understood. Most genome-wide association studies (GWAS) have relied on bulk tissue expression quantitative trait loci (eQTL), which cannot resolve the heterogeneity of immune cell populations. METHODS: We performed two-sample Mendelian randomization (MR) analyses using single-cell cis-eQTLs from 14 immune cell subtypes (OneK1K cohort) as instrumental variables against GWAS summary statistics for four thyroid outcomes: autoimmune hyperthyroidism, autoimmune hypothyroidism, thyroid cancer and autoimmune thyroiditis. Causal associations were validated through Bayesian colocalization, phenome-wide association analysis (PheWAS) and multi-layered transcriptomic validation encompassing spatial transcriptomics of AITD tissue (GSE248205), bulk RNA-seq of thyroid cancer (GSE3678) and single-cell RNA-seq of thyroid tumours (GSE250521). gsMap spatial LD score regression was applied to map disease heritability onto spatial tissue architecture. RESULTS: We identified six Bonferroni-significant causal gene-cell type pairs for autoimmune hyperthyroidism, including protective effects of ABHD16A in naïve/immature B cells (OR = 0.440), HIST1H3H in CD8 NC T cells (OR = 0.324), HMGN4 in NK recruiting cells (OR = 0.556) and ZKSCAN4 in CD8 S100B T cells (OR = 0.427), with five pairs showing strong colocalization (PP.H4 ≥ 86%). Three pairs reached significance for autoimmune hypothyroidism, including a risk association of HLA-F in CD4 NC T cells (OR = 1.139). For autoimmune thyroiditis, FAM134B/RETREG1 showed consistent suggestive protective associations across both CD4 and CD8 NC T cells (PP.H4 ≥ 90% for both), suggesting a possible involvement of ER phagy regulation in thyroiditis susceptibility. Thyroid cancer showed a suggestive association with HLA-G in classical monocytes (OR = 1.899, PP.H4 = 53%). Spatial transcriptomic validation demonstrated progressive immune infiltration from control tissue to Graves' disease to Hashimoto's thyroiditis (7.7%-15.7%, 46.1%-54.1%, respectively) and strong spatial correlation between target gene expression and corresponding cell type enrichment (e.g., plasma cell-HLA-DQB1: r = 0.491, p < 10-300). HLA-G was independently validated in thyroid cancer bulk (log2fc = 0.542, p = 9.51 × 10-3, AUC = 0.857) and single-cell datasets. PheWAS revealed no significant associations detected for the core candidates. gsMap identified significant enrichment of autoimmune hypothyroidism heritability in gastrointestinal tract, adrenal gland and adipose tissue (all Bonferroni p < 0.002). CONCLUSIONS: This study establishes a multi-scale analytical framework integrating cell type-resolved genetic inference with spatial tissue validation, revealing distinct immunogenetic architectures underlying autoimmune versus malignant thyroid disease. Protective genetic programs in autoimmune hyperthyroidism converge on chromatin remodelling (HIST1H3H, HMGN4, ZKSCAN4) and lipid metabolism (ABHD16A) across lymphocyte subsets, whereas thyroid cancer risk involves immune escape mediated by HLA-G in myeloid cells. The ER-phagy receptor RETREG1 represents a candidate pathway warranting further investigation in autoimmune thyroiditis. These findings provide genetically supported, cell type-specific therapeutic targets and demonstrate a generalizable strategy for dissecting the immune-mediated mechanisms of complex thyroid diseases.

Mendelian randomization↗

PubMed2002

Evolution and structure of 5S rDNA loci in allotetraploid Nicotiana tabacum and its putative parental species.

Nicotiana tabacum (tobacco) is an allotetraploid derived from ancestors of the modern diploids, N. sylvestris and N. tomentosiformis. We identified and characterized two distinct families of 5S ribosomal DNA (rDNA) in N. tabacum; one family had an average 431 bp unit length and the other a 646 bp unit length. In the diploid species, N. sylvestris and N. tomentosiformis, the 5S rDNA unit lengths are 431 bp and 644 bp respectively. The non-coding spacer sequence of the short unit in tobacco had high sequence homology to the spacer of N. sylvestris5S rDNA, while the longer spacer of tobacco had high homology with the 5S spacer of N. tomentosiformis. This suggests that the two 5S families in tobacco have their origin in the diploid ancestors. The longer spacer sequence had a GC rich sub-region (called the T-genome sub-region) that was absent in the short spacer. Pulsed field gel analysis and fluorescent in situ hybridization to tobacco metaphase chromosomes showed that the two families of 5S rDNA units are spatially separate at two chromosomal loci, on chromosomes S8 (short family) and T8 (long family). The repeat copy number at each chromosomal locus showed heterogeneity between different tobacco cultivars, with a tendency for a decrease in the copy number of one family to be compensated by an increase in the copy number of the second family. Sequence analysis reveals there is as much diversity in 5S family units within the diploid species as there is within the T and S-genome 5S family units respectively, suggesting 5S diversification within each family had occurred before tobacco speciation. There is no evidence of interlocus homogenization of the two 5S families in tobacco. This is therefore substantially different to 18-26S rDNA where interlocus gene conversion has substantially influenced most sequences of S and T genome origin; possible reasons are discussed.

DNA, Intergenic↗

PubMed2026

Beyond species trees: pervasive gene flow limits phylogenomic resolution in the diversification of Juniperus from the Qinghai-Tibet Plateau.

Understanding how lineages diversify despite persistent ancestral polymorphism and recurrent gene flow remains a central challenge in evolutionary biology. Juniperus distributed across the Qinghai-Tibet Plateau provide an ideal system for addressing this question because repeated geological uplift and climatic oscillations have likely promoted cycles of lineage divergence, range shifts, and secondary contact. Here, we combined approximately 1.08 million genome-wide SNPs from 164 individuals representing thirteen Juniperus lineages with phylogenomic datasets comprising 3,381 nuclear single-copy genes and nearly complete plastomes. We detected extensive phylogenomic discordance and cytonuclear incongruence across genomic datasets. Topology weighting, coalescent simulations, quartet-based tests, and analyses of gene flow and reticulation collectively support the interpretation that these patterns were shaped by the combined effects of prolonged incomplete lineage sorting and gene flow during lineage diversification. Ecological niche analyses further provide a spatial and climatic context in which environmentally similar lineages may have had greater opportunities for secondary contact during historical range shifts. Collectively, our results reveal that the evolutionary history of Qinghai-Tibet Plateau Juniperus is characterized by reticulate diversification rather than strictly bifurcating evolution, and demonstrate how genome-wide discordance can provide biological insights into the evolutionary processes underlying lineage diversification.

Gene Flow↗

PubMed2026

Beyond the "cold" barrier: Redefining the clinical paradigm of immune checkpoint inhibitor therapy in ovarian cancer.

Ovarian cancer remains an immunologically "cold" tumor, with early all-comer immune checkpoint inhibitor (ICI) trials largely negative despite underlying immunogenicity. This review takes a clinician-centric, stage-specific view linking regimen choice, treatment line, and tumor-immune context to observed outcomes. In the neoadjuvant and first-line settings, unselected ICI combinations with chemotherapy and anti-angiogenic agents failed to improve progression-free survival, whereas adding a poly (ADP-ribose) polymerase (PARP) inhibitor to ICI maintenance yielded modest gains in biomarker-enriched cohorts. In recurrent disease, single-agent ICIs produced objective response rates of 8-15%, and most randomized combinations were negative. The phase III KEYNOTE-B96 trial in platinum-resistant disease demonstrated a progression-free survival benefit in the intention-to-treat population and an overall survival benefit in tumors with programmed death ligand 1 (PD-L1) combined positive score ≥ 1 when pembrolizumab was paired with weekly paclitaxel with or without bevacizumab, underscoring the value of an immunomodulatory chemotherapy backbone in earlier lines. Ovarian clear cell carcinoma emerges as an immunotherapy-sensitive, chemo-resistant subtype that warrants dedicated stratification. We explain why single-analyte biomarkers-PD-L1, tumor mutational burden, homologous recombination deficiency/BRCA1/2-have not reliably enriched benefit and outline a multidimensional approach integrating genomic scars (e.g., mutational signature 3), immune functional state (Immunoscore, CD8⁺ tumor-infiltrating lymphocyte density and CD8⁺: regulatory T-cell ratio), and spatial architecture (inflamed, excluded, desert phenotypes). This framework aims to move beyond the all-comer era toward context-informed precision immunotherapy in ovarian cancer.

Humans↗

PubMed2003

Functional analysis of the human Sprouty2 gene promoter.

Sprouty2 plays a key role in negatively modulating the fibroblast growth factor signaling pathway, which is required for early branching events in embryonic development. The expression of the murine Sprouty2 gene shows a temporally and spatially restricted pattern in developing lung. In order to clarify the molecular mechanisms governing the transcription of the Sprouty2 gene, we first characterized the genomic organization of the human Sprouty2 (hSpry2) gene and mapped its transcription start sites by 5'-rapid amplification of cDNA ends. Subsequently, a 4-kb sequence from the 5'-flanking region of the gene was cloned and determined to contain promoter activity. Detailed truncation analysis of the hSpry2 promoter revealed the presence of context-specific suppressor activity in the distal upstream region. More importantly, we demonstrated that all the elements necessary to achieve strong basal transcription activity were located within the proximal 0.4-kb region. Sequence analysis revealed that this functionally important proximal region contains neither TATA nor CAAT box but an initiator element around the transcription start site. Several cis-acting elements (including AP2, CREB, SP1 and Ets-1) were found to be present in the proximal region, and their interactions with specific nuclear proteins were confirmed by electrophoretic mobility shift assays. To our knowledge, this is the first promoter study of any mammalian Sprouty gene. We propose that the high-level basal expression of hSpry2 is controlled by multiple transcription factors binding to its proximal promoter.

5' Flanking Region↗

PubMed2006

A global genomic transcriptional code associated with CNS-expressed genes.

Highly conserved non-coding DNA regions (HCNR) occur frequently in vertebrate genomes, but their functional roles remain unclear. Here, we provide evidence that a large portion of HCNRs are enriched for binding sites for Sox, POU and Homeodomain transcription factors, and such HCNRs can act as cis-regulatory regions active in neural stem cells. Strikingly, these HCNRs are linked to several hundreds of genes expressed in the developing CNS and they may exert locus-wide regulatory effects on multiple genes flanking their genomic location. Moreover, these data imply a unifying transcriptional logic for a large set of CNS-expressed genes in which Sox and POU proteins act as generic promoters of transcription while Homeodomain proteins control the spatial expression of genes through active repression.

Animals↗

PubMed2003

Conservation of chromosome arrangement and position of the X in mammalian sperm suggests functional significance.

We used chromosome painting to show directly that chromosomes occupy fixed positions in the nuclei of mammal but not chicken sperm. We found that the positions of homologous chromosomes are conserved in sperm of two marsupial species that diverged 50-60 million years ago. We also discovered that the X chromosome lies in the region that makes first contact with the egg in marsupial and monotreme mammals, as well as eutherians, and suggest that this position may be related to its propensity for inactivation, and its high rate of loss from ICSI embryos. We propose that nuclear architecture in sperm is important for spatial chromatin differentiation and normal development of the fertilized egg, and evolved along with mammal-specific regulatory systems such as X inactivation and genomic imprinting.

Animals↗

PubMed2005

Detection of DNA copy number alterations using penalized least squares regression.

MOTIVATION: Genomic DNA copy number alterations are characteristic of many human diseases including cancer. Various techniques and platforms have been proposed to allow researchers to partition the whole genome into segments where copy numbers change between contiguous segments, and subsequently to quantify DNA copy number alterations. In this paper, we incorporate the spatial dependence of DNA copy number data into a regression model and formalize the detection of DNA copy number alterations as a penalized least squares regression problem. In addition, we use a stationary bootstrap approach to estimate the statistical significance and false discovery rate. RESULTS: The proposed method is studied by simulations and illustrated by an application to an extensively analyzed dataset in the literature. The results show that the proposed method can correctly detect the numbers and locations of the true breakpoints while appropriately controlling the false positives. AVAILABILITY: http://bioinformatics.med.yale.edu/DNACopyNumber CONTACT: hongyu.zhao@yale.edu SUPPLEMENTARY INFORMATION: http://bioinformatics.med.yale.edu/DNACopyNumber.

Algorithms↗

PubMed2001

Differential expression of the actin-binding proteins, alpha-actinin-2 and -3, in different species: implications for the evolution of functional redundancy.

The alpha-actinins are a multigene family of four actin-binding proteins related to dystrophin. The two skeletal muscle isoforms of alpha-actinin (ACTN2 and ACTN3) are major structural components of the Z-line involved in anchoring the actin-containing thin filaments. In humans, ACTN2 is expressed in all muscle fibres, while ACTN3 expression is restricted to a subset of type 2 fibres. We have recently demonstrated that alpha-actinin-3 is absent in approximately 18% of individuals in a range of human populations, and that homozygosity for a premature stop codon (577X) accounts for most cases of true alpha-actinin-3 deficiency. Absence of alpha-actinin-3 is not associated with an obvious disease phenotype, raising the possibility that ACTN3 is functionally redundant in humans, and that alpha-actinin-2 is able to compensate for alpha-actinin-3 deficiency. We now present data concerning the expression of ACTN3 in other species. Genotyping of non-human primates indicates that the 577X null mutation has likely arisen in humans. The mouse genome contains four orthologues which all map to evolutionarily conserved syntenic regions for the four human genes. Murine Actn2 and Actn3 are differentially expressed, spatially and temporally, during embryonic development and, in contrast to humans, alpha-actinin-2 expression does not completely overlap alpha-actinin-3 in postnatal skeletal muscle, suggesting independent function. Furthermore, sequence comparison of human, mouse and chicken alpha-actinin genes demonstrates that ACTN3 has been conserved over a long period of evolutionary time, implying a constraint on evolutionary rate imposed by continued function of the gene. These observations provide a real framework in which to test theoretical models of genetic redundancy as they apply to human populations. In addition we highlight the need for caution in making conclusions about gene function from the phenotypic consequences of loss-of-function mutations in animal knockout models.

Actinin↗

PubMed2025

CCDC137 knockdown suppresses bladder cancer progression by downregulating SCD.

BACKGROUND: The Coiled-coil domain-containing (CCDC) family, due to its unique protein structural domain and broad involvement in diverse biological processes, has emerged as a focus in oncology research. Nevertheless, its clinical significance and function in bladder cancer (BLCA) remain poorly defined. METHODS: Machine learning algorithms were employed to identify pivotal CCDC genes in the cancer genome atlas (TCGA), and a prognostic model was subsequently constructed. Multi-omics data encompassing pan-cancer cohorts, single-cell sequencing, and spatial transcriptomics were integrated to characterize the expression patterns and prognostic significance of Coiled-coil domain-containing 137 (CCDC137), a previously uncharacterized CCDC family member in BLCA. Tissue microarray confirmed CCDC137 abnormal expression in bladder carcinoma specimens. The effect of CCDC137 knockdown on BLCA progression was evaluated through CCK8 assay, clonogenic formation, wound healing, Transwell, and subcutaneous xenograft models. RNA sequencing, quantitative RT-PCR, and western blot were utilized to delineate its regulatory network. RESULTS: A prognostic model incorporating 10 CCDC genes was successfully established in the TCGA-BLCA cohort. Then, we found that CCDC137 exhibited pan-cancer overexpression and usually correlation with poor clinical outcomes. Immunohistochemistry further substantiated its dysregulation in bladder carcinoma. Integrated multi-omics analyses suggested associations between CCDC137 expression and a tumor immunosuppressive microenvironment. CCDC137 knockdown significantly suppressed bladder cancer cell proliferation and migratory capacity in vitro. Correspondingly, subcutaneous xenograft tumor growth was inhibited in vivo. Moreover, decreased expression of stearoyl-CoA desaturase (SCD), a key lipid metabolic enzyme, accompanied CCDC137 depletion. These findings collectively suggest a cancer-promoting role for CCDC137 in bladder carcinoma. CONCLUSIONS: This systematic investigation combining multi-omics bioinformatics analyses and experimental validation demonstrates the role of CCDC137 in bladder carcinoma progression, providing novel mechanistic insights into the pathogenesis of BLCA and offering a theoretical foundation for therapeutic targeting of CCDC137 in urothelial malignancies.

Urinary Bladder Neoplasms↗

PubMed1998

Nuclear dreams: the malignant alteration of nuclear architecture.

Cancer is diagnosed by examining the architectural alterations to cells and tissues. Changes in nuclear structure are among the most universal of these and include increases in nuclear size, deformities in nuclear shape, and changes in the internal organization of the nucleus. These may all reflect changes in the nuclear matrix, a non-chromatin nuclear scaffolding determining nuclear form, higher order chromatin folding, and the spatial organization of nucleic acid metabolism. Malignancy-induced changes in this structure may have profound effects on chromatin folding, on the fidelity of genome replication, and on gene expression. Elucidating the mechanisms and the biological consequences of nuclear changes will require the identification of the major structural molecules of the internal nuclear matrix and an understanding of their assembly into structural elements. If biochemical correlates to malignant alterations in nuclear structure can be identified then nuclear matrix proteins and, perhaps nuclear matrix-associated structural RNAs, may be an attractive set of diagnostic markers and therapeutic targets.

Animals↗

PubMed2001

Applying functional genomics research to the study of pig reproduction.

Functional genomics is an experimental approach that incorporates genome-wide or system-wide experimentation, expanding the scope of biological investigation from studying single genes to studying potentially all genes at once in a systematic manner. This technology is highly appealing because of its high throughput and relatively low cost. Furthermore, analysis of gene expression using microarrays is likely to be more biologically relevant than the conventional paradigm of reductionism, because it has the potential to uncover new biological connections between genes and biochemical pathways. However, functional genomics is still in its infancy, especially with regard to the study of pig reproduction. Currently, efforts are centred on developing the necessary resources to enable high throughput evaluation and comparison of gene expression. However, it is clear that in the near future functional genomics will be applied on a large scale to study the biology and physiology of reproduction in pigs, and to understand better the complex nature of genetic control over polygenic characteristics, such as ovulation rate and litter size. We can look forward to generating a significant amount of new data on differences in gene expression between genotypes, treatments, or at various temporal and spatial coordinates within a variety of reproductively relevant systems. Along with this capability will be the challenge of collating, analysing and interpreting datasets that are orders of magnitude more extensive and complex than those currently used. Furthermore, integration of functional genomics with traditional genetic approaches and with detailed analysis of the proteome and relevant whole animal phenotypes will be required to make full use of this powerful new experimental paradigm as a beneficial research tool.

Animals↗

PubMed2003

Spatial patterns of mitochondrial and nuclear gene pools in chamois (Rupicapra r. rupicapra) from the Eastern Alps.

We have assessed the variability of maternally (mtDNA) and biparentally (allozymes) inherited genes of 443 chamois (Rupicapra r. rupicapra) from 19 regional samples in the Eastern Alps, to estimate the degree and patterns of spatial gene pool differentiation, and their possible causes. Based on a total mtDNA-RFLP approach with 16 hexanucleotide-recognizing restriction endonucleases, we found marked substructuring of the maternal gene pool into four phylogeographic groups. A hierarchical AMOVA revealed that 67.09% of the variance was partitioned among these four mtDNA-phylogroups, whereas only 8.04% were because of partitioning among regional samples within the populations, and 24.86% due to partitioning among individuals within regional samples. We interpreted this spatial pattern of mtDNA variability as a result of immigration of chamois from different Pleistocene refugia surrounding the Alps after the withdrawal of glaciers, rather than from topographic barriers to gene flow, such as Alpine valleys, extended glaciers or woodlands. However, this striking geographical structuring of the maternal genome was not paralleled by allelic variation at 33 allozyme loci, which were used as nuclear DNA markers. Wright's hierarchical F-statistics revealed that only < or =0.45% of the explained allozymic diversity was because of partitioning among the four mtDNA-phylogroups. We conclude that this discordance of spatial patterns of nuclear and mtDNA gene pools results from a phylogeographic background and sex-specific dispersal, with higher levels of philopatry in females.

Animals↗

PubMed2002

Overlapping of MINK and CHRNE gene loci in the course of mammalian evolution.

Overlapping of genes, especially in an anti-parallel fashion, is quite rare in eukaryotic genomes. We have found a rare instance of exon overlapping involving CHRNE and MINK gene loci on chromosome 17 in humans. CHRNE codes for the epsilon subunit of the nicotinic acetylcholine receptor (AChRepsilon) whereas MINK encodes a serine/threonine kinase belonging to the GCK family. To elucidate the evolutionary trail of this gene overlapping event, we examined the genomes of a number of primates and found that mutations in the polyadenylation signal of the CHRNE gene in early hominoids led to the overlap. Upon extending this analysis to genomes of other orders of placental mammals, we observed that the overlapping occurred at least three times independently during the course of mammalian evolution. Because CHRNE and MINK are differentially expressed, the potentially hazardous mutations responsible for the exon overlap seem to have escaped evolutionary pressures by differential temporo-spatial expression of the two genes.

Animals↗

PubMed2002

Stage-specific chromosomal association of Drosophila dMBD2/3 during genome activation.

The Drosophila gene dMBD2/3 encodes a protein with significant homologies to the mammalian methyl-DNA binding proteins MBD2 and MBD3. These proteins are essential components of chromatin complexes involved in epigenetic gene regulation. Because the available in vitro data on dMBD2/3 are conflicting we have started an in vivo characterization of dMBD2/3. We detected expression of two isoforms specifically during embryonic development. Staining of whole embryos combined with high-resolution confocal microscopy revealed a highly regulated spatial distribution. During the syncytial blastoderm stage, dMBD2/3 formed speckles that localized to the cytoplasm. Shortly after, during the cellular blastoderm stage, the protein entered the nucleus and formed bright foci that associated with DNA. This rapid transition coincided with the activation of the embryonic genome. A similar observation was made during activation of the spermatocyte genome as dMBD2/3 formed distinct foci associated with the activated Y chromosome. Our results indicate that dMBD2/3 forms specialized nuclear compartments to keep certain genes epigenetically silenced during genome activation.

Animals↗

PubMed2005

Using BAC clones to characterize unbalanced chromosome abnormalities in interphase cells.

Carriers of balanced translocations usually carry alterations in gene sequences, which lead to dysfunction during early and late embryogenesis. Related spatial rearrangement causes either cumulative delay in cell cycles and/or anomalies in transcription and translation. This has also an important impact at the time of genomic activation, the longest cell cycle of preimplantation development. Carrier patients may be affected either with primary infertility or by repeated miscarriages [Hum. Reprod. 12 (1997) 2019.]. Assuming that a fraction of the germ cells is karyotypically normal, these patients would greatly benefit from efficient procedures for generation and use of breakpoint-specific DNA hybridisation probes in preconception and preimplantation genetic diagnosis (PGD) after polar body or blastomere biopsy of the embryos. The objective of this research was to design an approach of patient-specific probes for preimplantation diagnosis of chromosome translocations and which could be used eventually to select chromosomally normal embryos from balanced or unbalanced interphase cells prior to their transfer to the mother's womb. This approach was used for a couple, where the female partner was a carrier of a balanced translocation 46,XX,t(4;12)(p16.1;q24.31). First, BAC/PAC clones were chosen from specific chromosome bands from the genome sequence that hybridise adjacent to the chromosomal breakpoints or span them. Then, the probes and hybridisation conditions were optimised using unrelated normal amniocytes, lymphoblastoid cells and lymphocytes from the carrier to increase hybridisation signal intensity and decrease background. Finally, the probes were tested on target cells before they were used for mimicking preconception or preimplantation genetic diagnosis. Three slides were analysed blindly from a normal karyotype, an unbalanced and a balanced translocation. A total of 78 cells were analysed of which in the slide A 19/22 (86%) were found to be unbalanced, in slide B 25/31 (81%) were normal and in slide C 21/25 (84%) were balanced. Thus, it was demonstrated that cells with known structural abnormalities could be detected, based on hybridisation of breakpoint spanning bacterial artificial chromosome (BAC) DNA probes in interphase cells.

Adult↗

PubMed2026

Expression patterns of risk genes associated with three evolutionarily relevant syndromes in rhesus macaque and human brains.

Depressive disorder (DD), Alzheimer's disease (AD), and schizophrenia (SZ) are evolutionarily relevant traits that disrupt neural networks supporting affect and cognition. While genome-wide association studies have identified risk-related genes for these diseases, how the expression of these genes compare across species remains unclear. In this study, we examined the spatial and temporal expression of ~2000 disease-associated genes in human and rhesus macaque brains. Distinct cross-species signatures emerged. DD-linked genes showed broad cortical-subcortical expression in humans but were confined to subcortical regions in macaques. The divergent subset was enriched for neuron differentiation, migration, synaptic signalling, and cognition. SZ-linked genes were expressed across cortical-subcortical-cerebellar structures in humans. AD-linked genes showed postnatal cortical-hippocampal macaque expression, and broader cortical-subcortical human expression. Cross-species spatial comparisons revealed a significant negative correlation for DD genes, suggesting a broader spatial distribution of DD-related gene expression in humans, extending to distributed emotion-cognition networks, compared to affective hubs in macaques. SZ genes exhibited a similar, though non-significant, negative trend, while AD genes showed a weak, non-significant correlation, indicating an absence of systematic expression shifts. Together, evolutionary shifts in gene expression may have shaped emotional and cognitive functions in humans, and susceptibility to psychiatric and neurodegenerative disorders.

Animals↗

PubMed1998

Transgenic modification of cows milk for value-added processing.

The application of transgenic technologies in dairy cattle has been restricted largely to producing potential pharmaceutical or nutriceutical products in the mammary gland. Broader application of transgenesis in dairy cattle production will require identifying target traits that are both amenable to transgenic modification and economically important to the dairy industry. The casein proteins are the most valuable component of cows milk destined for value-added processing. The four bovine casein genes lie within a single, multi-gene locus of approximately 200 kb in length. The working hypothesis is that this multi-gene locus contains all of the DNA sequences required to regulate the coordinated expression of all four individual casein genes (i.e. a locus control region or LCR). The initial research aim is to clone the entire casein locus into a bacterial artificial chromosome (BAC) vector, thus preserving the extended 5'and 3' regions that flank the locus, as well as maintaining the spatial integrity of the four individual casein genes that comprise the locus. The author's laboratory has prepared a bacterial artificial chromosome (BAC) library of genomic DNA from elite dairy cattle. Partial, non-elite BAC clones of the casein gene locus are being tested in transgenic mice to establish proof of concept. Advances in nuclear transfer of transfected somatic cells should improve the efficiency of producing transgenic calves that possess a BAC casein construct introduced into an elite genetic background.

Animals↗