Preoperative circulating tumor cells to predict microvascular invasion and dynamical detection indicate the prognosis of hepatocellular carcinoma.

BACKGROUND: This study explored the diagnostic power of preoperative circulating tumor cells (CTCs) for the presence of microvascular invasion (MVI) and the relationship between dynamic changes in postoperative CTCs and prognosis. METHODS: A total of 137 patients were recruited for the study. Preoperative blood samples were collected from all patients to detect CTCs. The time points for blood collection were before the operation, during the operation, and at 1 week, 1 month, 2 months, 3 months, 6 months, and 1 year after surgery. The predictive power of CTC count for the presence of MVI was analyzed by receiver operating characteristic (ROC) curve analysis. According to recurrence status, 137 patients were divided into three groups: no recurrence, early recurrence, and non-early recurrence groups. RESULTS: A threshold CTC count of 5 showed the most significant power for predicting the existence of MVI. In multivariate analysis, the parameters of preoperative CTC count, alpha-fetoprotein (AFP) and tumor diameter were independent predictors of MVI (P <  0.05). A CTC count greater than or equal to 5 had better predictive value than AFP > 400 µg/L and tumor diameter > 5 cm. The number of intraoperative CTCs in the three groups did not increase compared to that before surgery (P > 0.05). The number of CTCs in the nonrecurrence group and the non-early recurrence group decreased significantly 1 week after surgery compared with the intraoperative values (P <  0.001), although there was no significant difference in the early recurrence group (P = 0.95). Patients with mean CTC count ≥5 had significantly worse long-term outcomes than those with mean CTC count < 5 (P <  0.001). CONCLUSION: The preoperative CTC counts in the peripheral blood of patients with HCC are closely correlated with MVI. The intraoperative manipulation of the lesion by the surgeon does not increase the number of CTCs in peripheral blood. Surgical removal of the tumor decreases the number of CTCs. The persistence of CTCs at a high level (≥ 5) after surgery suggests a risk of early recurrence. CLINICAL TRIAL REGISTRATION: Registration number is ChiCTR-OOC-16010183 , date of registration is 2016-12-18.

The wave of gene advance under diverse systems of mating.

Mating systems will influence gene spread across the natural distribution of a plant species. Existing theories have not fully explored the role of mating systems on the wave of advance of an advantageous gene. Here, we develop a theory to account for the rate of spread of both advantageous and neutral genes under different mating systems, based on migration-selection processes. We show that a complex relationship exists between selfing rate and the speed of gene spread. The interaction of selfing with gametophytic selection shapes the traveling wave of the advantageous gene. Selfing can impede (or enhance) the spread of an advantageous gene in the presence (or absence) of gametophytic selection. The interaction of selfing with recombination shapes the spread of a neutral gene. Linkage disequilibrium, mainly generated by selfing, enhances the traveling wave of the neutral gene that is tightly linked with the selective gene. Recombination gradually breaks down the genetic hitchhiking effects along the direction of advantageous gene spread, yielding decreasing waves of advance of neutral genes. The stochastic process does not alter the pattern of selfing effects except for increasing the uncertainty of the waves of advance of both advantageous and neutral genes. This theory helps us to explain how mating systems act as a barrier to spread of adaptive and neutral genes, and to interpret species cohesion maintained by a low level of adaptive gene flow.

Estimating the number of sexual events per generation in a facultatively sexual haploid population.

In populations of facultatively sexual organisms, the proportion of sexually produced offspring contributed to each generation is a critical determinant of their evolutionary potential. However, estimating this parameter in natural populations has proved difficult. Here we develop a population genetic model for estimating the number of sexual events occurring per generation for facultatively sexual haploids possessing a biallelic mating-type locus (e.g., Chlamydomonas, ascomycete fungi). Our model treats the population as two subpopulations possessing opposite mating-type alleles, which exchange genes only when a sexual event takes place. Where mating types are equally abundant, we show that, for a neutral genetic marker, genetic differentiation between mating-type subpopulations is a simple function of the effective population size, the frequency of sexual reproduction, and the recombination fraction between the genetic marker and the mating-type locus. We employ simulations to examine the effects of linkage of markers to the mating-type locus, inequality of mating-type frequencies, mutation rate, and selection on this relationship. Finally, we apply our model to estimate the number of sexual reproduction events per generation in populations of four species of facultatively sexual ascomycete fungi, which have been jointly scored for mating type and a range of polymorphic molecular markers. Relative estimates are in line with expectations based on the known reproductive biology of these species.

The large-X effect in plants: increased species divergence and reduced gene flow on the Silene X-chromosome.

The disproportionately large involvement of the X-chromosome in the isolation of closely related species (the large-X effect) has been reported for many animals, where X-linked genes are mostly hemizygous in the heterogametic sex. The expression of deleterious recessive mutations is thought to drive the frequent involvement of the X-chromosome in hybrid sterility, as well as to reduce interspecific gene flow for X-linked genes. Here, we evaluate the role of the X-chromosome in the speciation of two closely related plant species - the white and red campions (Silene latifolia and S. dioica) - that hybridize widely across Europe. The two species evolved separate sexes and sex chromosomes relatively recently (~10(7)  years), and unlike most animal species, most X-linked genes have intact Y-linked homologs. We demonstrate that the X-linked genes show a very small and insignificant amount of interspecific gene flow, while gene flow involving autosomal loci is significant and sufficient to homogenize the gene pools of the two species. These findings are consistent with the hypothesis of the large-X effect in Silene and comprise the first report of this effect in plants. Nonhemizygosity of many X-linked genes in Silene males indicates that exposure of recessive mutations to selection may not be essential for the occurrence of the large-X effect. Several possible causes of the large-X effect in Silene are discussed.

Testing neutrality at copy-number-variable loci under the finite-allele and finite-site models.

Copy-number variation (CNV) is an important form of DNA structural variation because a certain proportion of genomes in many eukaryotic species can contribute to such variations. Owing to the differences between CNVs and single nucleotide polymorphisms (SNPs) in size, mutation rate and maintaining mechanism, it is more realistic to characterize CNV evolution under the finite-allele and finite-site models. Here, we propose a method to test multiple CNVs neutrality under the finite-allele and finite-site models and the assumption of mutation-drift process. The statistical property of the method is evaluated through Monte Carlo simulations under the effects of the sample size, the scaled mutation rates, the number of CNVs, the population demographic change, and selection. Different from Tajima's D test, a bootstrap or a permutation approach is suggested to conduct a neutrality test. Application of this method is illustrated using the diploid CNV genotypes measured in discrete copy numbers in 11 HapMap phase III populations. The results show that the mutation-drift process can explain the variation of genome-wide CNVs among 1184 individuals (856 CNVs, ∼0.02Mb on average in size), irrespective of the historical demographic changes. Patterns from allele-frequency-spectrum analysis also support the hypothesis of neutral CNVs. Our results suggest that most human chromosomal changes in healthy individuals via unbalanced rearrangements of the segments with certain sizes are neutral.

A Community-Based Framework Integrates Interspecific Interactions into Forest Genetic Conservation.

Forest genetic conservation is typically species-specific and does not integrate interspecific interaction and community structure. It mainly focuses on the theories of population and quantitative genetics. This approach depicts the intraspecific patterns of population genetic structure derived from genetic markers and the genetic differentiation of adaptive quantitative traits in provenance trials. However, it neglects possible interspecific interaction in natural forests and overlooks natural hybridization or subspeciation. We propose that the genetic diversity of a given species in a forest community is shaped by both intraspecific population and interspecific community evolutionary processes, and expand the traditional forest genetic conservation concept under the community ecology framework. We show that a community-specific phylogeny derived from molecular markers would allow us to explore the genetic mechanisms of a tree species interacting with other resident species. It would also facilitate the exploration of a species' ecological role in forest community assembly and the taxonomic relationship of the species with other species specific to its resident forest community. Phylogenetic ß-diversity would assess the similarities and differences of a tree species across communities regarding ecological function, the strength of selection pressure, and the nature and extent of its interaction with other species. Our forest genetic conservation proposal that integrates intraspecific population and interspecific community genetic variations is suitable for conserving a taxonomic species complex and maintaining its evolutionary potential in natural forests. This provides complementary information to conventional population and quantitative genetics-based conservation strategies.

Population Structure and Genetic Diversity of the Toona ciliata (Meliaceae) Complex Assayed with Chloroplast DNA Markers.

Toona ciliata is a deciduous or semi-deciduous tree species and belongs to the Toona genus of the Meliaceae family. Owing to low natural regeneration and over-exploitation, the species is listed as an endangered species at level II in China and its conservation has received increasing concern. Here, we sampled 447 individuals from 29 populations across the range-wide distribution of the T. ciliata complex in China and assessed their genetic variation using two chloroplast DNA markers. The results showed that the overall haplotype diversity and nucleotide diversity per site were high at h = 0.9767 and π = 0.0303 for the psbA-trnH fragment and h= 0.8999 and π = 0.0189 for the trnL-trnL fragment. Phylogenetic analysis supported the division of the natural distribution of T. ciliata complex into western and eastern regions. The genetic diversity was higher in the western region than in the eastern region, showing significant phylogeographic structure. Genetic differentiation among populations was moderate (Φst=42.87%), and the effects of isolation by distance (IBD) were significant. A neutrality test and mismatch distribution analysis indicated that the distribution of the T. ciliata complex generally did not expand, although a few local populations could likely expand after bottleneck effects. The overall results were complementary to and consolidated previous studies using mitochondrial and nuclear DNA markers. We finally discussed strategies for the genetic conservation of the T. ciliata complex.

The Ka /Ks and πa /πs Ratios under Different Models of Gametophytic and Sporophytic Selection.

Alternation of generations in plant life cycle provides a biological basis for natural selection occurring in either the gametophyte or the sporophyte phase or in both. Divergent biphasic selection could yield distinct evolutionary rates for phase-specific or pleiotropic genes. Here, we analyze models that deal with antagonistic and synergistic selection between alternative generations in terms of the ratio of nonsynonymous to synonymous divergence (Ka/Ks). Effects of biphasic selection are opposite under antagonistic selection but cumulative under synergistic selection for pleiotropic genes. Under the additive and comparable strengths of biphasic allelic selection, the absolute Ka/Ks for the gametophyte gene is equal to in outcrossing but smaller than, in a mixed mating system, that for the sporophyte gene under antagonistic selection. The same pattern is predicted for Ka/Ks under synergistic selection. Selfing reduces efficacy of gametophytic selection. Other processes, including pollen and seed flow and genetic drift, reduce selection efficacy. The polymorphism (πa) at a nonsynonymous site is affected by the joint effects of selfing with gametophytic or sporophytic selection. Likewise, the ratio of nonsynonymous to synonymous polymorphism (πa/πs) is also affected by the same joint effects. Gene flow and genetic drift have opposite effects on πa or πa/πs in interacting with gametophytic and sporophytic selection. We discuss implications of this theory for detecting natural selection in terms of Ka/Ks and for interpreting the evolutionary divergence among gametophyte-specific, sporophyte-specific, and pleiotropic genes.

Population Structure and Genetic Diversity in the Natural Distribution of Neolamarckia cadamba in China.

Neolamarckia cadamba (Roxb.) Bosser is a fast-growing deciduous tree species and belongs to the Neolamarckia genus of the Rubiaceae family. This species has great economic and medical values in addition to being an important timber species for multiple industrial purposes. However, few studies have examined the genetic diversity and population structure in the natural distribution of this species in China. Here, we applied both the haploid nrDNA ITS (619 bp for aligned sequences) and mtDNA (2 polymorphic loci) markers to investigate 10 natural populations (239 individuals in total) that covered most of the distribution of the species in China. The results showed that the nucleotide diversity was π = 0.1185 ± 0.0242 for the nrDNA ITS markers and π = 0.00038 ± 0.00052 for the mtDNA markers. The haplotype diversity for the mtDNA markers was h = 0.1952 ± 0.2532. The population genetic differentiation was small (Fstn = 0.0294) for the nrDNA ITS markers but large (Fstm = 0.6765) for the mtDNA markers. There were no significant effects of isolation by distance (IBD), by elevation, and by two climatic factors (annual average precipitation and tem perature). A geographic structure among populations (Nst

Assessing the phylogenetic relationship among varieties of Toona ciliata (Meliaceae) in sympatry with chloroplast genomes.

Toona ciliata is an endangered species due to over-cutting and low natural regeneration in China. Its genetic conservation is of an increasing concern. However, several varieties are recognized according to the leaf and flower traits, which complicates genetic conservation of T. ciliata. Here, we sequenced the whole chloroplast genome sequences of three samples for each of four varieties (T. ciliata var. ciliata, T. ciliata var. yunnanensis, T. ciliata var. pubescens, and T. ciliata var. henryi) in sympatry and assessed their phylogenetic relationship at a fine spatial scale. The four varieties had genome sizes ranged from 159,546 to 159,617 bp and had small variations in genome structure. Phylogenomic analysis indicated that the four varieties were genetically well-mixed in branch groups. Genetic diversity from the whole chloroplast genome sequences of 12 samples was low among varieties (average π = 0.0003). Besides, we investigated genetic variation of 58 samples of the four varieties in sympatry using two markers (psaA and trnL-trnF) and showed that genetic differentiation was generally insignificant among varieties (Ф st = 0%-5%). Purifying selection occurred in all protein-coding genes except for the ycf2 gene that was under weak positive selection. Most amino acid sites in all protein-coding genes were under purifying selection except for a few sites that were under positive selection. The chloroplast genome-based phylogeny did not support the morphology-based classification. The overall results implicated that a conservation strategy based on the T. ciliata complex rather than on intraspecific taxon was more appropriate.

Postoperative outcomes and recurrence patterns of intermediate-stage hepatocellular carcinoma dictated by the sum of tumor size and number.

BACKGROUND: The selection criteria for Barcelona Clinic Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) patients who would truly benefit from liver resection (LR) remain undefined. AIM: To identify BCLC-B HCC patients more suitable for LR. METHODS: We included patients undergoing curative LR for BCLC stage A or B multi-nodular HCC (MNHCC) and stratified BCLC-B patients by the sum of tumor size and number (N + S). Overall survival (OS), recurrence-free survival (RFS), recur-rence-to-death survival (RTDS), recurrence patterns, and treatments after recurrence in BCLC-B patients in each subgroup were compared with those in BCLC-A patients. RESULTS: In total, 143 patients who underwent curative LR for MNHCC with BCLC-A (n = 25) or BCLC-B (n = 118) were retrospectively analyzed. According to the N + S, patients with BCLC-B HCC were divided into two subgroups: BCLC-B1 (N + S ≤ 10, n = 83) and BCLC-B2 (N + S > 10, n = 35). Compared with BCLC-B2 patients, those with BCLC-B1 had a better OS (5-year OS rate: 67.4% vs 33.6%; P < 0.001), which was comparable to that in BCLC-A patients (5-year OS rate: 67.4% vs 74.1%; P = 0.250), and a better RFS (median RFS: 19 mo vs 7 mo; P < 0.001), which was worse than that in BCLC-A patients (median RFS: 19 mo vs 48 mo; P = 0.022). Further analysis of patients who developed recurrence showed that both BCLC-B1 and BCLC-A patients had better RTDS (median RTDS: Not reached vs 49 mo; P = 0.599), while the RTDS in BCLC-B2 patients was worse (median RTDS: 16 mo vs not reached, P < 0.001; 16 mo vs 49 mo, P = 0.042). The recurrence patterns were similar between BCLC-B1 and BCLC-A patients, but BCLC-B2 patients had a shorter recurrence time and a higher proportion of patients had recurrence with macrovascular invasion and/or extrahepatic metastasis, both of which were independent risk factors for RTDS. CONCLUSION: BCLC-B HCC patients undergoing hepatectomy with N + S ≤ 10 had mild recurrence patterns and excellent OS similar to those in BCLC-A MNHCC patients, and LR should be considered in these patients.

Evolutionary Divergence between Toona ciliata and Toona sinensis Assayed with Their Whole Genome Sequences.

Toona ciliata and Toona sinensis belong to the Toona genus of the Meliaceae family and are important timber species in China. T. ciliata is an endangered species at level II due to overcutting and a low rate of natural regeneration. T. sinensis was cultivated as an economic and nutritious tree for more than 2000 years. The two species differ in flower and leaf morphological traits, reproductive systems, and range size of natural distribution. To reveal the potential molecular basis of these divergences, we examined the similarities and differences in their whole genome sequences. Results indicate that T. ciliata had a higher number of expanded gene families than T. sinensis. The whole genome duplication (WGD) occurred before their speciation. The long-terminal repeats (LTRs) insertion was earlier in the T. ciliata genome (3.2985 ± 2.5007 Mya) than in the T. sinensis genome (3.1516 ± 2.2097 Mya). Twenty-five gene families in the T. ciliata genome were detected to be under positive selection compared with background branches of ten different land species. The T. ciliata genome was highly collinear with the T. sinensis genome, but had low collinearity with the genomes of more distant species. These genomic and evolutionary divergences are potentially associated with the differences between T. ciliata and T. sinensis in terms of their reproductive systems and ecological adaptation.

Phylogeography of Toona ciliata (Meliaceae) Complex in China Inferred from Cytonuclear Markers.

Toona ciliata is an important timber species but is recognized as an endangered species at level II in China. Its genetic conservation is of increasing concern. Provenance trials and other breeding programs were conducted to develop seed transfer rules and multiplications. Here, we investigated twenty-nine populations sampled across the natural distribution of the T. ciliata complex using mtDNA and nrDNA ITS (ribosomal internal transcribed spacer) markers. Haplotype diversity was h = 0.190 ± 0.202 and nucleotide diversity was π = 0.000383 ± 0.000536 for mtDNA marker. Nucleotide diversity for ITS sequences was 0.00837 ± 0.000783. Haplotypes exhibited phylogeographic structure in spatial distribution. The extent of genetic differentiation was significant (Fst = 0.6994 ± 0.0079 for ITS and 0.8870 ± 0.0077 for mtDNA marker). Isolation by distance (IBD) and by elevation (IBE) occurred among populations. Phylogenetic relationships from mtDNA marker indicated three genetically distinct regions, each without IBD effects. Compared with pollen flow, seed flow was strongly impeded in the western region, but extensive in the central region, and less impeded in the eastern region. Most populations did not exhibit expansion, with only a few populations showing expansion after bottleneck effects. We discussed a strategy of region-based genetic conservation and proposed to conserve multiple populations in the western and eastern regions and a few populations in the central region.

A Chromosome-Level Genome Assembly of Toona ciliata (Meliaceae).

Toona ciliata Roem is an important timber species in the Toona genus of the Meliaceae family and an endangered species due to over-cutting and a low rate of natural regeneration in China. Although molecular markers have been applied to studying population genetic diversity, the absence of a reliable reference genome limits in-depth genetic conservation and evolutionary studies of this species. Here, we reported a high-quality assembly of the whole genome sequence of T. ciliata. The total assembled genome has 520.64 Mb in length anchored on 28 chromosomes (contig N50 = 4.48 Mb). A total of 42,159 genes were predicted after the ab initio, homology-based, and transcriptome analyses. A total of 41,284 protein-encoding genes (97.92%) were functionally annotated and 1,246 non-coding RNAs were identified in the T. ciliata genome. Phylogenomic analysis showed that T. ciliata was divergent at 15.06 (6-25) Ma from T. sinensis of the same genus Toona. This whole genome sequence provides a valuable resource to study the genetic conservation and molecular evolution of T. ciliata in the future.

Mating system and the critical migration rate for swamping selection.

Crow et al. (1990) and Barton (1992) have examined the critical migration rate for swamping selection in the nuclear system. Here, I use the same methodology to examine the critical migration rate in the cytonuclear system for hermaphrodite plants with a mixed mating system. Two selection schemes for a nuclear gene (heterozygote disadvantage and directional selection) and the directional selection scheme for organelle genes are considered. Results show that under random mating, the previous results are applicable to plant species by appropriate re-parameterization of the migration rate for nuclear and paternal organelle genes. A simple complementary relationship exists between seed and pollen flow in contributing to the critical migration rate. Under the mixed mating system, the critical migration rate of seeds and pollen for nuclear and paternal organelle genes can be changed due to the effects of selection and the cytonuclear linkage disequilibrium generated by migration and inbreeding. A negative but not complementary relationship exists between seed and pollen flow in contributing to the critical migration rate, varying with the mating system. Partial selfing can also adjust the critical seed flow for the maternal organelle gene, with a small critical migration rate for species of a high selfing rate. Both concordance and discordance among cytonuclear genes can occur under certain conditions during the process of swamping selection. This theory predicts the presence of various contributions of seed versus pollen flow to genetic swamping for plants with diverse mating systems.

Estimating the correlation of non-allele descents along chromosomes.

The pattern of the correlation of non-allele descents among linked sites is an important aspect for an insight into the genomic evolution at the population level. Here, we present a new statistical method for estimating two types of non-allele descent correlations. One is the standardized parental descent disequilibrium termed by Cockerham & Weir (1973), the other is the standardized disequilibrium between non-allele descent segments from the same chromosome. Essential to this analysis is the partitioning of the joint identity-by-state probability for a random pair of non-allele gametes into the different components of identity by descents at the two or three sites. We consider the samples of phased haplotypes of single nucleotide polymorphism (SNP) markers and the weighted least square method for fast parameter estimation. Monte Carlo simulations demonstrate that robustly unbiased estimates with appropriate precisions can be obtained with certain sample sizes, ~100 diploids, under the impacts of allele frequency distributions and linkage disequilibrium. This method can be used to construct the maps of non-allele descent correlation blocks for the population whose genetic pedigree is not required on a prior basis.

Splenectomy before hepatectomy for patients with hepatocellular carcinoma and hypersplenism: A retrospective study.

ABSTRACT: The spleen plays an important role in tumor progression and the curative effects of splenectomy before hepatectomy for hypersplenism and hepatocellular carcinoma (HCC) are not clear. We investigated whether splenectomy before hepatectomy increases survival rate among patients with HCC and hypersplenism compared with that of patients who underwent synchronous hepatectomy and splenectomy or hepatectomy alone.Between January 2011 and December 2016, 266 patients who underwent hepatectomy as a result of HCC and portal hypertension secondary to hepatitis were retrospectively analyzed. Their perioperative complications and survival outcome were evaluated.Patients underwent synchronous hepatectomy and splenectomy (H-S group) and underwent splenectomy before hepatectomy (H-preS group) exhibited significantly higher disease-free survival (DFS) rates than those of patients underwent hepatectomy alone (H-O group). The DFS rates for patients in the H-S group, H-preS group, and H-O group were 74.6%, 48.4%, 39.8%, and 80.1%, 54.2%, 40.1%, and 60.5%, 30.3%, 13.3%, at 1, 3, and 5 years after surgery, respectively. Tumor size, tumors number, and levels of alpha fetoprotein (AFP) were independent risk factors for DFS. Gender and tumor size were independent prognostic factor for overall survival (OS). The preoperative white blood cell (WBC) and platelet (PLT) counts were significantly higher in the H-preS group than in those of the H-S group and the H-O group. After operation, the WBC and PLT counts in the H-S group and H-preS groups were significantly higher compared to those of the H-O group.No matter splenectomy before hepatectomy or synchronous hepatectomy and splenectomy, hepatectomy with splenectomy may improve DFS rates in patients with HCC and hypersplenism, and splenectomy before hepatectomy alleviates hypersplenism without an increased surgical risk.

A complete sequence of mitochondrial genome of Neolamarckia cadamba and its use for systematic analysis.

Neolamarckia cadamba is an important tropical and subtropical tree for timber industry in southern China and is also a medicinal plant because of the secondary product cadambine. N. cadamba belongs to Rubiaceae family and its taxonomic relationships with other species are not fully evaluated based on genome sequences. Here, we report the complete sequences of mitochondrial genome of N. cadamba, which is 414,980 bp in length and successfully assembled in two genome circles (109,836 bp and 305,144 bp). The mtDNA harbors 83 genes in total, including 40 protein-coding genes (PCGs), 31 transfer RNA genes, 6 ribosomal RNA genes, and 6 other genes. The base composition of the whole genome is estimated as 27.26% for base A, 22.63% for C, 22.53% for G, and 27.56% for T, with the A + T content of 54.82% (54.45% in the small circle and 54.79% in the large circle). Repetitive sequences account for ~ 0.14% of the whole genome. A maximum likelihood (ML) tree based on DNA sequences of 24 PCGs supports that N. cadamba belongs to order Gentianales. A ML tree based on rps3 gene of 60 species in family Rubiaceae shows that N. cadamba is more related to Cephalanthus accidentalis and Hymenodictyon parvifolium and belongs to the Cinchonoideae subfamily. The result indicates that N. cadamba is genetically distant from the species and genera of Rubiaceae in systematic position. As the first sequence of mitochondrial genome of N. cadamba, it will provide a useful resource to investigate genetic variation and develop molecular markers for genetic breeding in the future.

Autophagy-Related Gene Pairs Signature for the Prognosis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has been recognized as the third leading cause of cancer-related deaths worldwide. There is increasing evidence that the abnormal expression of autophagy-related genes plays an important role in the occurrence and development of HCC. Therefore, the study of autophagy-related genes can further elucidate the genetic drivers of cancer and provide valuable therapeutic targets for clinical treatment. In this study, we used 232 autophagy-related genes extracted from the Human Autophagy Database (HADb) and Molecular Signatures Database (MSigDB) to construct 1884 autophagy-related gene pairs. On this basis, we developed a prognostic model based on autophagy-related gene pairs using least absolute shrinkage and selection operator (LASSO) Cox regression to evaluate the prognosis of patients after liver cancer resection. We then used 845 liver cancer samples from three different databases to test the reliability of the risk signature through survival analysis, receiver operating characteristic (ROC) curve analysis, univariate and multivariate analysis. To further explore the underlying biological mechanisms, we conducted an enrichment analysis of autophagy-related genes. Finally, we combined the signature with independent prognostic factors to construct a nomogram. Based on the autophagy-related gene pair (ARGP) signature, we can divide patients into high- or low-risk groups. Survival analysis and ROC curve analysis verified the validity of the signature (AUC: 0.786-0.828). Multivariate Cox regression showed that the risk score can be used as an independent predictor of the clinical outcomes of liver cancer patients. Notably, this model has a more accurate predictive effect than most prognostic models for hepatocellular carcinoma. Moreover, our model is a powerful supplement to the HCC staging indicator, and a nomogram comprising both indicators can provide a better prognostic effect. Based on pairs of multiple autophagy-related genes, we proposed a prognostic model for predicting the overall survival rate of HCC patients after surgery, which is a promising prognostic indicator. This study confirms the importance of autophagy in the occurrence and development of HCC, and also provides potential biomarkers for targeted treatments.

F(ST) in the cytonuclear system.

Selection on nuclear (or organelle) sites inevitably affects the spatial distribution of a neutral organelle (or nuclear) allele via transient cytonuclear disequilibrium. Here I examine this effect in terms of F(st) for a neutral allele by bringing together cytonuclear genomes with contrasting modes of inheritance. The relationships between cytonuclear disequilibrium and increment in F(st) are explored and confirmed through Monte Carlo simulations. Results show that the transient increment in F(st) for a neutral allele is not only related to the vectors of seed and pollen dispersal but also to the mode of its inheritance. Such increments can be substantial under certain conditions. Seed dispersal is more effective than pollen dispersal in changing the transient increment. The cumulative effects from multiple selective nuclear sites can amplify the transient increment in F(st) for a neutral paternal or maternal organelle allele. Selection on selective organelle sites facilitates the transient increment in F(st) for a neutral nuclear allele. Partial selfing can significantly reinforce the transient increment in F(st). These theoretical insights highlight the roles of transient cytonuclear disequilibrium as a biological factor in evolving population differentiation and refine our practical interpretations of F(st) with cytonuclear markers.