Cross-species Conservation Research Articles

Cross-species comparison of airway epithelium transcriptomics

Studies of lung transcriptomics across species are essential for understanding the complex biology and disease mechanisms of this vital organ. Single-cell RNA sequencing (scRNA-seq) has emerged as a key tool for understanding cell dynamics across various species. However, comprehensive cross-species comparisons are limited. Therefore, the aims of this study was to investigate the transcriptomic similarities and differences in lung cells across four species—humans, monkeys, mice, and rats—in healthy and asthma conditions using scRNA-seq. The results revealed significant transcriptomic similarities between monkeys and humans and significant cross-species conservation of cell-specific marker genes, transcription factors (TFs), and biological pathways. Additionally, we explored sex differences, identifying distinct sex-specific expression patterns that may influence disease susceptibility. These insights refine our understanding of the mechanism underlying airway cell biology across species and have important implications for studying lung diseases, particularly the mechanisms of mucus clearance in asthma.

A resource of identified and annotated lincRNAs expressed during somatic embryogenesis development in Norway spruce.

Long non-coding RNAs (lncRNAs) have emerged as important regulators of many biological processes, although their regulatory roles remain poorly characterized in woody plants, especially in gymnosperms. A major challenge of working with lncRNAs is to assign functional annotations, since they have a low coding potential and low cross-species conservation. We utilised an existing RNA-Sequencing resource and performed short RNA sequencing of somatic embryogenesis developmental stages in Norway spruce (Picea abies L. Karst). We implemented a pipeline to identify lncRNAs located within the intergenic space (lincRNAs) and generated a co-expression network including protein coding, lincRNA and miRNA genes. To assign putative functional annotation, we employed a guilt-by-association approach using the co-expression network and integrated these results with annotation assigned using semantic similarity and co-expression. Moreover, we evaluated the relationship between lincRNAs and miRNAs, and identified which lincRNAs are conserved in other species. We identified lincRNAs with clear evidence of differential expression during somatic embryogenesis and used network connectivity to identify those with the greatest regulatory potential. This work provides the most comprehensive view of lincRNAs in Norway spruce and is the first study to perform global identification of lincRNAs during somatic embryogenesis in conifers. The data have been integrated into the expression visualisation tools at the PlantGenIE.org web resource to enable easy access to the community. This will facilitate the use of the data to address novel questions about the role of lincRNAs in the regulation of embryogenesis and facilitate future comparative genomics studies.

Attenuated total reflection Fourier-transform infrared spectroscopy reveals environment specific phenotypes in clonal Japanese knotweed

BackgroundJapanese knotweed (Reynoutria japonica var. japonica), a problematic invasive species, has a wide geographical distribution. We have previously shown the potential for attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy and chemometrics to segregate regional differentiation between Japanese knotweed plants. However, the contribution of environment to spectral differences remains unclear. Herein, the response of Japanese knotweed to varied environmental habitats has been studied. Eight unique growth environments were created by manipulation of the red: far-red light ratio (R: FR), water availability, nitrogen, and micronutrients. Their impacts on plant growth, photosynthetic parameters, and ATR-FTIR spectral profiles, were explored using chemometric techniques, including principal component analysis (PCA), linear discriminant analysis, support vector machines (SVM) and partial least squares regression. Key wavenumbers responsible for spectral differences were identified with PCA loadings, and molecular biomarkers were assigned. Partial least squared regression (PLSR) of spectral absorbance and root water potential (RWP) data was used to create a predictive model for RWP.ResultsSpectra from plants grown in different environments were differentiated using ATR-FTIR spectroscopy coupled with SVM. Biomarkers highlighted through PCA loadings corresponded to several molecules, most commonly cell wall carbohydrates, suggesting that these wavenumbers could be consistent indicators of plant stress across species. R: FR most affected the ATR-FTIR spectra of intact dried leaf material. PLSR prediction of root water potential achieved an R2 of 0.8, supporting the potential use of ATR-FTIR spectrometers as sensors for prediction of plant physiological parameters.ConclusionsJapanese knotweed exhibits environmentally induced phenotypes, indicated by measurable differences in their ATR-FTIR spectra. This high environmental plasticity reflected by key biomolecular changes may contribute to its success as an invasive species. Light quality (R: FR) appears critical in defining the growth and spectral response to environment. Cross-species conservation of biomarkers suggest that they could function as indicators of plant-environment interactions including abiotic stress responses and plant health.

Insights into the Evolutionary Dynamics: Characterization of Disintegrin and Metalloproteinase Proteins in the Venom Gland Transcriptome of the Hemiscorpius lepturus Scorpion.

The Disintegrin and Metalloproteinase (ADAM) family, also known as the metalloproteinase/disintegrin/cysteine-rich (MDC) proteins, includes both secreted and transmembrane molecules involved in critical biological processes, such as cell migration, adhesion, and signaling. This study aimed to investigate the evolutionary relationships and structural characteristics of disintegrin and metalloproteinase proteins identified in the venom gland transcriptome of the scorpion Hemiscorpius lepturus. Using bioinformatics tools, we analyzed the open reading frame, conserved motifs, and primary, secondary, and tertiary structures of these proteins. Five proteins, named HLDis- Met1, HLDisMet2, HLDisMet3, HLDisMet4, and HLDisMet5, were identified. Their predicted 3- D structures were within normal ranges (Z-score between -4 to -9). Phylogenetic analysis revealed that HLDisMet1 shares similarities with proteins from various spider species (Nephila pilipes, Argiope bruennichi, Araneus ventricosus, and Trichonephila inaurata madagascariensis), HLDisMet2 with the scorpion Centruroides sculpturatus, HLDis- Met4 with the scorpion Tityus serrulatus, and HLDisMet5 with several snake species (Python bivittatus, Vipera anatolica senliki, Protobothrops mucrosquamatus, and Naja naja). These findings highlight the significant similarities between HLDisMet proteins and those found in other venomous species, suggesting a complex and diverse evolutionary pathway for venom components. The cross-species conservation observed may indicate a convergent evolutionary strategy, where different species independently develop similar venom components to adapt to similar ecological niches or prey types. This study highlights the evolutionary significance of venom diversification and its potential applications in understanding venom biology across different species.

Evidence for widespread translation of 5' untranslated regions.

Ribosome profiling experiments support the translation of a range of novel human open reading frames. By contrast, most peptides from large-scale proteomics experiments derive from just one source, 5' untranslated regions. Across the human genome we find evidence for 192 translated upstream regions, most of which would produce protein isoforms with extended N-terminal ends. Almost all of these N-terminal extensions are from highly abundant genes, which suggests that the novel regions we detect are just the tip of the iceberg. These upstream regions have characteristics that are not typical of coding exons. Their GC-content is remarkably high, even higher than 5' regions in other genes, and a large majority have non-canonical start codons. Although some novel upstream regions have cross-species conservation - five have orthologues in invertebrates for example - the reading frames of two thirds are not conserved beyond simians. These non-conserved regions also have no evidence of purifying selection, which suggests that much of this translation is not functional. In addition, non-conserved upstream regions have significantly more peptides in cancer cell lines than would be expected, a strong indication that an aberrant or noisy translation initiation process may play an important role in translation from upstream regions.

Cross-species analysis uncovers the mitochondrial stress response in the hippocampus as a shared mechanism in mouse early life stress and human depression

Depression, or major depressive disorder, poses a significant burden for both individuals and society, affecting approximately 10.8% of the general population. This psychiatric disorder leads to approximately 800,000 deaths per year. A combination of genetic and environmental factors such as early life stress (ELS) increase the risk for development of depression in humans, and a clear role for the hippocampus in the pathophysiology of depression has been shown. Nevertheless, the underlying mechanisms of depression remain poorly understood, resulting in a lack of effective treatments. To better understand the core mechanisms underlying the development of depression, we used a cross-species design to investigate shared hippocampal pathophysiological mechanisms in mouse ELS and human depression. Mice were subjected to ELS by a maternal separation paradigm, followed by RNA sequencing analysis of the adult hippocampal tissue. This identified persistent transcriptional changes linked to mitochondrial stress response pathways, with oxidative phosphorylation and protein folding emerging as the main mechanisms affected by maternal separation. Remarkably, there was a significant overlap between the pathways involved in mitochondrial stress response we observed and publicly available RNAseq data from hippocampal tissue of depressive patients. This cross-species conservation of changes in gene expression of mitochondria-related genes suggests that mitochondrial stress may play a pivotal role in the development of depression. Our findings highlight the potential significance of the hippocampal mitochondrial stress response as a core mechanism underlying the development of depression. Further experimental investigations are required to expand our understanding of these mechanisms.

Pathogenic variants in human DNA damage repair genes mostly arose in recent human history.

Genome stability is maintained by the DNA damage repair (DDR) system composed of multiple DNA repair pathways of hundreds of genes. Germline pathogenic variation (PV) in DDR genesdamages function of the affected DDR genes, leading to genome instability and high risk of diseases, in particular, cancer. Knowing evolutionary origin of the PVs inhuman DDR genes is essential to understand the etiology of human diseases. However, answer to the issue remains largely elusive. In this study, we analyzed evolutionary origin for the PVs inhuman DDR genes. We identified 169 DDR genes by referring tovarious databases and identified PVs in theDDR genes of modern humans from ClinVar database. We performed a phylogenetic analysis to analyze the conservation of human DDR PVs in 100 vertebrates through cross-species genomic data comparison using the phyloFit program of the PHAST package and visualized the resultsusing theGraphPad Prism software and the ggplot module. We identified DDR PVs from over 5000ancient humansdeveloped a database to host the DDR PVs ( https://genemutation.fhs.um.edu.mo/dbDDR-AncientHumans ). Using the PV data,we performed a molecular archeological analysis tocompare theDDR PVs between modern humans and ancient humans. We analyzed evolution selection of DDR genes across 20 vertebrates using theCodeML in PAML for phylogenetic analysis. Ourphylogenic analysis ruled out cross-species conservation as the origin of human DDR PVs. Ourarcheological approach identified rich DDR PVs shared between modern and ancient humans, which were mostly dated within the last 5000 years. We alsoobserved similar pattern of quantitative PV distribution between modern and ancient humans. We furtherdetected a setof ATM, BRCA2 and CHEK2 PVs shared between human and Neanderthals. Our study reveals that human DDR PVs mostly arose in recent human history. We propose that human high cancer risk caused by DDR PVs can be a by-product of human evolution.

Three HPS5 mutations associated with depigmentation in diverse horse breeds

Depigmentation is a common phenotype in Equus caballus (horse); over 50 identified variants cause white spotting on the skin and coat. HPS5 may influence melanocyte proliferation and mutations in this gene cause depigmentation in humans, mice, and zebrafish. Here we report three equine HPS5 mutations, found in most major breed groups and associated with white spotting. We used a standardized method to quantitatively grade depigmentation, creating a White Score for each horse. We identified associations to each of three variants in HPS5 by comparing the average white score for carriers to that of 41 control horses possessing none of the studied variants. We estimated the functional impact of each mutation using SIFT, GenScan, I-TASSER and cross-species conservation. The first mutation, S1013C termed Eden White 1 (EDXW1), is a missense mutation found to increase average depigmentation by 5.56 points (p = 6.47E-6, n = 70, t-test). Eden White 2 (EDXW2), a missense mutation L560F, increased depigmentation by 9.5 points for individuals with one copy of the variant, but we were unable to phenotype homozygotes (p = 5.55E-16, n = 47, t-test). Eden White 3 (EDXW3), a putative donor splice site mutation at exon 4 + 4, increased white by 5.59 points on average (p = 9.56E-6, n = 101). EDXW1 and EDXW3 are epistatically influenced by MC1R, the gene that controls black vs red coat color in horses. Individuals possessing the dominant E allele produce black pigment, and this allele was associated with higher levels of depigmentation than individuals with the recessive chestnut genotype (e/e) (p = 1.50E-5, p = 1.26E-5 respectively). We tested for epistatic interactions between EDXW1 and Dominant White 20 and found that horses with one copy of each allele had increased average white spotting by 8 points with respect to EDXW1/n or W20/n horses. Compound heterozygotes were significantly more white than horses with one copy of either mutation (p = 7.33E-5), but interactions between other white spotting alleles and EDXW alleles remain to be tested. We propose the convention Eden White (EDXW) for HPS5 mutations in the domestic horse.

Variants in the ZNF469 gene in families with Brittle cornea syndrome and keratoconus

BackgroundBrittle cornea syndrome 1 (BCS1) is a rare autosomal recessive disorder characterized by corneal and sclera thinning and fragility that is caused by zinc finger protein 469 (ZNF469) gene mutation. Keratoconus is another disease related to corneal thinning. Several reports have linked ZNF469 variants and keratoconus. We recruited a four-generation BCS1 family and two keratoconus families to explore pathogenic ZNF469 variants. MethodsThis study included 11 members from a family with BCS1, 2 families with keratoconus, 368 sporadic keratoconus patients and 325 unrelated healthy controls. Whole exome sequencing of DNA from peripheral blood and cross species conservation analysis was used to investigate and verify ZNF469 variants. ResultsA new homozygous frameshift mutation c. 6727del (p.Asp2243Thr fs*8) in ZNF469 was detected in the BSC1 family. Two ZNF469 heterozygous variants g.88494671G > A (c.793G > A, p.G265S, rs754776767) were detected in keratoconus family 1 and a heterozygous missense variant g.88498262G > A (c.4384G > A, p.D1462 N, rs577890057) was found in keratoconus family 2. Based on the American College of Medical Genetics and Genomics guidelines, rs577890057 and rs754776767 were predicted to be variants of uncertain significance. c. 6727del (p. Asp2243Thr fs*8) in ZNF469 was identified to be pathogenic. ConclusionsWe identified a new homozygous frameshift mutation and two heterozygous missense variations in ZNF469 in the three families. Our findings extend the spectrum of ZNF469 variants associated with keratoconus.

Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes

BackgroundMismatch repair (MMR) system is evolutionarily conserved for genome stability maintenance. Germline pathogenic variants (PVs) in MMR genes that lead to MMR functional deficiency are associated with high cancer risk. Knowing the evolutionary origin of germline PVs in human MMR genes will facilitate understanding the biological base of MMR deficiency in cancer. However, systematic knowledge is lacking to address the issue. In this study, we performed a comprehensive analysis to know the evolutionary origin of human MMR PVs.MethodsWe retrieved MMR gene variants from the ClinVar database. The genomes of 100 vertebrates were collected from the UCSC genome browser and ancient human sequencing data were obtained through comprehensive data mining. Cross-species conservation analysis was performed based on the phylogenetic relationship among 100 vertebrates. Rescaled ancient sequencing data were used to perform variant calling for archeological analysis.ResultsUsing the phylogenetic approach, we traced the 3369 MMR PVs identified in modern humans in 99 non-human vertebrate genomes but found no evidence for cross-species conservation as the source for human MMR PVs. Using the archeological approach, we searched the human MMR PVs in over 5000 ancient human genomes dated from 45,045 to 100 years before present and identified a group of MMR PVs shared between modern and ancient humans mostly within 10,000 years with similar quantitative patterns.ConclusionOur study reveals that MMR PVs in modern humans were arisen within the recent human evolutionary history.

Cross-species conservation in the regulation of parvalbumin by perineuronal nets.

Parvalbumin (PV) neurons play an integral role in regulating neural dynamics and plasticity. Therefore, understanding the factors that regulate PV expression is important for revealing modulators of brain function. While the contribution of PV neurons to neural processes has been studied in mammals, relatively little is known about PV function in non-mammalian species, and discerning similarities in the regulation of PV across species can provide insight into evolutionary conservation in the role of PV neurons. Here we investigated factors that affect the abundance of PV in PV neurons in sensory and motor circuits of songbirds and rodents. In particular, we examined the degree to which perineuronal nets (PNNs), extracellular matrices that preferentially surround PV neurons, modulate PV abundance as well as how the relationship between PV and PNN expression differs across brain areas and species and changes over development. We generally found that cortical PV neurons that are surrounded by PNNs (PV+PNN neurons) are more enriched with PV than PV neurons without PNNs (PV-PNN neurons) across both rodents and songbirds. Interestingly, the relationship between PV and PNN expression in the vocal portion of the basal ganglia of songbirds (Area X) differed from that in other areas, with PV+PNN neurons having lower PV expression compared to PV-PNN neurons. These relationships remained consistent across development in vocal motor circuits of the songbird brain. Finally, we discovered a causal contribution of PNNs to PV expression in songbirds because degradation of PNNs led to a diminution of PV expression in PV neurons. These findings reveal a conserved relationship between PV and PNN expression in sensory and motor cortices and across songbirds and rodents and suggest that PV neurons could modulate plasticity and neural dynamics in similar ways across songbirds and rodents.

Molecular basis and genetics of hypohidrotic ectodermal dysplasias.

Ectodermal dysplasia (ED) is a heterogeneous group of hereditary diseases of the skin and its appendages, which are characterized by impaired development and/or homeostasis of two or more ectoderm derivatives, including: hair, teeth, nails, sweat glands and their modifications (mammary glands, for instance). The overall prevalence of ectodermal dysplasia remains precisely unknown not only in Russia, but also in the world, nor is known the contribution of individual genes to its structure. This complicates the DNA diagnosis establishment of this disease due to the lack of an accurate diagnostic algorithm and a universal cost-effective method of analysis. To date, the most highly-researched genes involved in the development of anhydrous or hypohidrotic forms of ED are EDA, EDAR, EDARADD and WNT10A. The ectodysplasin A (EDA) gene is the cause of the most common X-linked form of ED, a gene from the Wnt family (WNT10A) is responsible for the autosomal recessive form of the disease, and two other genes (EDAR and EDARADD) can cause both autosomal recessive and autosomal dominant forms. This review provides the characteristics of the genes involved in ED, their mutation spectra, the level of their expression in human tissues, as well as the interrelation of the aforementioned genes. The domain structures of the corresponding proteins are considered, as well as the molecular genetic pathways in which they are involved. Animal models for studying this disorder are also taken into consideration. Due to the cross-species genes conservation, their mutations cause the disruption of the development of ectoderm derivatives not only in humans, but also in mice, cows, dogs, and even fish. It can be exploited for a better understanding of the etiopathogenesis of ectodermal dysplasias. Moreover, this article brings up the possibility of recurrent mutations in the EDA and WNT10A genes. The review also presents data on promising approaches for intrauterine ED treatment.

Genomic and Transcriptomic Landscape of an Oral Squamous Cell Carcinoma Mouse Model for Immunotherapy.

The immune checkpoint inhibitor (ICI), anti-programmed death-1 (anti-PD-1), has shown moderate efficacy in some patients with head and neck squamous cell carcinoma (HNSCC). Because of this, it is imperative to establish a mouse tumor model to explore mechanisms of antitumor immunity and to develop novel therapeutic options. Here, we examined the 4-nitroquinoline-1-oxide (4NQO)-induced oral squamous cell carcinoma (OSCC) model for genetic aberrations, transcriptomic profiles, and immune cell composition at different pathologic stages. Genomic exome analysis in OSCC-bearing mice showed conservation of critical mutations found in human HNSCC. Transcriptomic data revealed that a key signature comprised of immune-related genes was increased beginning at the moderate dysplasia stages. We first identified that macrophage composition in primary tumors differed across pathologic stages, leading to an oncogenic evolution through a change in the M1/M2 macrophage ratio during tumorigenesis. We treated the 4NQO-induced OSCC-bearing mice with anti-PD-1 and agonistic anti-CD40, which modulated multiple immune responses. The growth of tumor cells was significantly decreased by agonistic anti-CD40 by promoting an increase in the M1/M2 ratio. By examining cross-species genomic conservation in human and mouse tumors, our study demonstrates the molecular mechanisms underlying the development of OSCC and the regulation of contributing immune-related factors, and aims to facilitate the development of suitable ICI-based treatments for patients with HNSCC.

5'UTR Variant in KIT Associated With White Spotting in Horses.

Mutations in KIT, a gene that influences melanoblast migration and pigmentation, often result in mammalian white spotting. As of February 2023, over 30 KIT variants associated with white spotting were documented in Equus caballus (horse). Here we report an association of increased white spotting on the skin and coat with a variant in the 5'UTR of KIT (rs1149701677: g.79,618,649A>C). Horses possessing at least one alternate allele demonstrate phenotypic characteristics similar to other KIT mutations: clear borders around unpigmented regions on the body, face, and limbs. Using a quantitative measure of depigmentation, we observed an average white score of 10.70 among individuals with rs1149701677, while the average score of the control, homozygous reference sample was 2.23 (P=1.892e-11, n=109, t-test). The rs1149701677 site has a cross-species conservation score of 3.4, one of the highest scores across the KIT 5'UTR, implying regulatory importance for this site. Ensembl also predicted a "moderately impactful" functional effect for the rs1149701677 variant. We propose that this single nucleotide variant likely alters the regulation of KIT, which in turn may disrupt melanoblast migration causing an increase in white spotting on the coat. Alternatively, the rs1149701677 variant may be in linkage with another nearby variant with an as-yet-undiscovered functional impact. We propose to term this new allele "Holiday White" or W35 based on conventional nomenclature.

Evolutionary Origin of Human PALB2 Germline Pathogenic Variants.

PALB2 (Partner and localizer of BRCA2) is crucial for repairing DNA double-stranded breaks (DSBs) through homologous recombination (HR). Germline pathogenic variation in PALB2 disrupts DNA damage repair and increases the risk of Fanconi Anemia, breast cancer, and ovarian cancer. Determination of the evolutionary origin of human PALB2 variants will promote a deeper understanding of the biological basis of PALB2 germline variation and its roles in human diseases. We tested the evolution origin for 1444 human PALB2 germline variants, including 484 pathogenic and 960 benign variants. We performed a phylogenic analysis by tracing the variants in 100 vertebrates. However, we found no evidence to show that cross-species conservation was the origin of PALB2 germline pathogenic variants, but it is indeed a rich source for PALB2 germline benign variants. We performed a paleoanthropological analysis by tracing the variants in over 5000 ancient humans. We identified 50 pathogenic in 71 ancient humans dated from 32,895 to 689 before the present, of which 90.1% were dated within the recent 10,000 years. PALB2 benign variants were also highly shared with ancient humans. Data from our study reveal that human PALB2 pathogenic variants mostly arose in recent human history.

Developmental dynamics of the single nucleus regulatory landscape of pig hippocampus.

The hippocampus is a brain region associated with memory, learning and spatial navigation, its aging-related dysfunction is a common sign of Alzheimer's disease. Pig is a good model for human neurodegenerative disease, but our understanding of the regulatory program of the pig hippocampus and its cross-species conservation in humans remains limited. Here, we profiled chromatin accessibility in 33,409 high-quality nuclei and gene expression in 8,122 high-quality nuclei of the pig hippocampus at four postnatal stages. We identified 510,908 accessible chromatin regions (ACRs) in 12 major cell types, among which progenitor cells such as neuroblasts and oligodendrocyte progenitor cells showed a dynamic decrease from early to later developmental stages. We revealed significant enrichment of transposable elements in cell type-specific ACRs, particularly in neuroblasts. We identified oligodendrocytes as the most prominent cell type with the greatest number of genes that showed significant changes during the development. We identified ACRs and key transcription factors underlying the trajectory of neurogenesis (such as POU3F3 and EGR1) and oligodendrocyte differentiation (RXRA and FOXO6). We examined 27 Alzheimer's disease-related genes in our data and found that 15 showed cell type-specific activity (TREM2, RIN3 and CLU), and 15 genes displayed age-associated dynamic activity (BIN1, RABEP1 and APOE). We intersected our data with human genome-wide association study results to detect neurological disease-associated cell types. The present study provides a single nucleus-accessible chromatin landscape of the pig hippocampus at different developmental stages and is helpful for the exploration of pigs as a biomedical model in human neurodegenerative diseases.

TP53 germline pathogenic variants in modern humans were likely originated during recent human history.

TP53 is crucial for maintaining genome stability and preventing oncogenesis. Germline pathogenic variation in TP53 damages its function, causing genome instability and increased cancer risk. Despite extensive study in TP53, the evolutionary origin of the human TP53 germline pathogenic variants remains largely unclear. In this study, we applied phylogenetic and archaeological approaches to identify the evolutionary origin of TP53 germline pathogenic variants in modern humans. In the phylogenic analysis, we searched 406 human TP53 germline pathogenic variants in 99 vertebrates distributed in eight clades of Primate, Euarchontoglires, Laurasiatheria, Afrotheria, Mammal, Aves, Sarcopterygii and Fish, but we observed no direct evidence for the cross-species conservation as the origin; in the archaeological analysis, we searched the variants in 5031 ancient human genomes dated between 45045 and 100 years before present, and identified 45 pathogenic variants in 62 ancient humans dated mostly within the last 8000 years; we also identified 6 pathogenic variants in 3 Neanderthals dated 44000 to 38515 years before present and 1 Denisovan dated 158550 years before present. Our study reveals that TP53 germline pathogenic variants in modern humans were likely originated in recent human history and partially inherited from the extinct Neanderthals and Denisovans.

Evolutionary Origin of MUTYH Germline Pathogenic Variations in Modern Humans

MUTYH plays an essential role in preventing oxidation-caused DNA damage. Pathogenic germline variations in MUTYH damage its function, causing intestinal polyposis and colorectal cancer. Determination of the evolutionary origin of the variation is essential to understanding the etiological relationship between MUTYH variation and cancer development. In this study, we analyzed the origins of pathogenic germline variants in human MUTYH. Using a phylogenic approach, we searched MUTYH pathogenic variants in modern humans in the MUTYH of 99 vertebrates across eight clades. We did not find pathogenic variants shared between modern humans and the non-human vertebrates following the evolutionary tree, ruling out the possibility of cross-species conservation as the origin of human pathogenic variants in MUTYH. We then searched the variants in the MUTYH of 5031 ancient humans and extinct Neanderthals and Denisovans. We identified 24 pathogenic variants in 42 ancient humans dated between 30,570 and 480 years before present (BP), and three pathogenic variants in Neanderthals dated between 65,000 and 38,310 years BP. Data from our study revealed that human MUTYH pathogenic variants mostly arose in recent human history and partially originated from Neanderthals.

A Cross-Species Neuroimaging Study of Sex Chromosome Dosage Effects on Human and Mouse Brain Anatomy.

All eutherian mammals show chromosomal sex determination with contrasting sex chromosome dosages (SCDs) between males (XY) and females (XX). Studies in transgenic mice and humans with sex chromosome trisomy (SCT) have revealed direct SCD effects on regional mammalian brain anatomy, but we lack a formal test for cross-species conservation of these effects. Here, we develop a harmonized framework for comparative structural neuroimaging and apply this to systematically profile SCD effects on regional brain anatomy in both humans and mice by contrasting groups with SCT (XXY and XYY) versus XY controls. Total brain size was substantially altered by SCT in humans (significantly decreased by XXY and increased by XYY), but not in mice. Robust and spatially convergent effects of XXY and XYY on regional brain volume were observed in humans, but not mice, when controlling for global volume differences. However, mice do show subtle effects of XXY and XYY on regional volume, although there is not a general spatial convergence in these effects within mice or between species. Notwithstanding this general lack of conservation in SCT effects, we detect several brain regions that show overlapping effects of XXY and XYY both within and between species (cerebellar, parietal, and orbitofrontal cortex), thereby nominating high priority targets for future translational dissection of SCD effects on the mammalian brain. Our study introduces a generalizable framework for comparative neuroimaging in humans and mice and applies this to achieve a cross-species comparison of SCD effects on the mammalian brain through the lens of SCT.SIGNIFICANCE STATEMENT Sex chromosome dosage (SCD) affects neuroanatomy and risk for psychopathology in humans. Performing mechanistic studies in the human brain is challenging but possible in mouse models. Here, we develop a framework for cross-species neuroimaging analysis and use this to show that an added X- or Y-chromosome significantly alters human brain anatomy but has muted effects in the mouse brain. However, we do find evidence for conserved cross-species impact of an added chromosome in the fronto-parietal cortices and cerebellum, which point to regions for future mechanistic dissection of sex chromosome dosage effects on brain development.

FungiExp: a user-friendly database and analysis platform for exploring fungal gene expression and alternative splicing.

Fungi form a large and heterogeneous group of eukaryotic organisms with diverse ecological niches. The high importance of fungi contrasts with our limited understanding of fungal lifestyle and adaptability to environment. Over the last decade, the high-throughput sequencing technology produced tremendous RNA-sequencing (RNA-seq) data. However, there is no comprehensive database for mycologists to conveniently explore fungal gene expression and alternative splicing. Here, we have developed FungiExp, an online database including 35821 curated RNA-seq samples derived from 220 fungal species, together with gene expression and alternative splicing profiles. It allows users to query and visualize gene expression and alternative splicing in the collected RNA-seq samples. Furthermore, FungiExp contains several online analysis tools, such as differential/specific, co-expression network and cross-species gene expression conservation analysis. Through these tools, users can obtain new insights by re-analyzing public RNA-seq data or upload personal data to co-analyze with public RNA-seq data. The FungiExp is freely available at https://bioinfo.njau.edu.cn/fungiExp. Supplementary data are available at Bioinformatics online.