On the causal interpretation of heritability from a structural causal modeling perspective.

Heritability estimated using the analysis of variance (ANOVA) for ascribing causal responsibility to genes for a phenotype has been criticized widely. First, there are problems associated with articulating the exact causal meaning of heritability in the standard model. Second, in conditions of gene-environment interaction or covariation that violate the assumptions made by the standard model, a causal interpretation of heritability is thought to be unwarranted. This paper aims to rethink these ideas and associated disputes from a structural causal modeling (SCM) perspective. Using SCM, we show that, in the standard model, heritability reflects the causal effect of eliminating genotypic differences on the change of phenotypic variance of a population. In the presence of interaction or covariation, heritability is estimated incorrectly using ANOVA. However, SCM can provide the causal effect of genotypes on the phenotypic variance regarding particular interventions. We also show that SCM can identify different types of causal effect and answer individual-level causal questions. We conclude that SCM has the resources to provide a systematic causal interpretation that can supplement traditional heritability estimates via ANOVA and offer a more substantial causal analysis of genetic causation.

CHRDL2 promotes osteosarcoma cell proliferation and metastasis through the BMP-9/PI3K/AKT pathway.

Various studies demonstrated that bone morphogenetic proteins (BMPs) and their antagonists contribute to the development of cancers. Chordin-like 2 (CHRDL2) is a member of BMP antagonists. However, the role and its relative mechanism of CHRDL2 in osteosarcoma remains unclear. In the present study, we demonstrated that the expression of CHRDL2 was significantly upregulated in osteosarcoma tissues and cell lines compared with adjacent tissues and human normal osteoblast. Inhibition of CHRDL2 decreased the proliferation and colony formation of osteosarcoma cells in vitro, as well as the migration and invasion. CHRDL2 overexpression induced the opposite effects. CHRDL2 can bind with BMP-9, thus decreasing BMP-9 expression and the combination to its receptor protein kinase ALK1. It was predicted that BMP-9 regulates PI3K/AKT pathways using gene set enrichment analysis. Inhibition of CHRDL2 decreased the activation of PI3K/AKT pathway, while overexpression of CHRDL2 upregulated the activation. Increasing the expression of BMP-9 reversed the effects of CHRDL2 overexpression on the activation of PI3K/AKT pathway, as well as the proliferation and metastasis of osteosarcoma cells. Take together, our present study revealed that CHRDL2 upregulated in osteosarcoma tissues and cell lines, and promoted osteosarcoma cell proliferation and metastasis through the BMP-9/PI3K/AKT pathway. CHRDL2 maybe an oncogene in osteosarcoma, as well as novel biomarker for the diagnosis of osteosarcoma.

Why the missing heritability might not be in the DNA.

There are four major hypotheses (H1, H2, H3, and H4) as to the source of missing heritability. We propose that estimates obtained from GWAS underestimate heritability by not taking into account non-DNA (epigenetic) sources of heritability. Taking those factors into account (H4) should result in increased heritability estimates.

The complete mitogenome sequence of the hawk moth, Theretra latreillii subsp. lucasii (Lepidoptera: Sphingidae) from Zhejiang Province, China.

The sphingid, Theretra latreillii subsp. lucasii is a common hawk moth distributed in southeast Asia and Australian regions. Although barcode analyses have been published, its complete mitogenome sequence has not been deciphered. In this study, the complete mitogenome of T. latreillii lucasii (GeneBank accession no. MW539688) was sequenced using Illumina HiSeq X Ten system for mitogenome-based phylogenetic analysis. The mitogenome was 15,354 bp in length and comprises 13 protein-coding genes (PCGs), two ribosomal RNA (rRNA) genes, and 22 transfer RNAs (tRNAs) with the typical gene order and orientation of Sphingidae mitogenomes. The nucleotide composition of majority strand is 41.2% for A, 7.4% for G, 12.0% for C, and 39.4% for T, with an A + T content of 80.6%. Phylogenetic analysis using the 13 PCGs fully resolved T. latreillii lucasii in a clade with T. japonica, Macroglossum stellatarum, and Ampelophaga rubiginosa, with high nodal support both by Bayesian inference and maximum-likelihood methods, forming the Macroglossini monophyletic group.

Anoctamin 5 promotes osteosarcoma development by increasing degradation of Nel-like proteins 1 and 2.

Anoctamin 5 (ANO5) is a member of the Anoctamin (ANO) family of calcium-activated chloride channels. Although ANO5 expression is upregulated in various cancers, its role in osteosarcoma remains largely unknown. In this study, bioinformatics analysis, western blot, and immunohistochemical staining revealed that ANO5 was upregulated in osteosarcoma cell lines and osteosarcoma tissues, and ANO5 expression was positively associated with tumor size, tumor grade, and metastasis. Functional experiments demonstrated that inhibition of ANO5 decreased, while ANO5 overexpression increased, osteosarcoma cell proliferation and mobility in vitro. Immunoprecipitation, western blot, and confocal microscopy experiments showed that ANO5 bound to and promoted the degradation of Nel-like proteins 1 (NELL1) and 2 (NELL2). Moreover, a subcutaneous tumor transplantation model revealed that ANO5 knockdown reduced osteosarcoma cell proliferation and increased NELL1 and NELL2 expression in vivo. Finally, rescue experiments showed that knockdown of NELL1 or NELL2 reversed the inhibitory effects of ANO5 knockdown on osteosarcoma cell proliferation and migration. These results demonstrated that upregulation of ANO5 promoted osteosarcoma development by decreasing the stability of the NELL1 and NELL2 proteins and that ANO5 may be an effective target for the treatment of osteosarcoma.

MicroRNA­145­5p inhibits osteosarcoma cell proliferation by targeting E2F transcription factor 3.

Osteosarcoma is a common type of bone tumor that primarily occurs in children and young adults. MicroRNA (miRNA/miR) dysregulation is associated with the progression of osteosarcoma; therefore, the aim of the present study was to investigate the biological functions and molecular mechanisms of miR­145­5p in osteosarcoma. The expression of miR­145­5p in osteosarcoma tissues and cell lines was quantified using reverse transcription­quantitative PCR (RT­qPCR). The effect of miR­145­5p on the proliferation of osteosarcoma cells was detected using Cell Counting Kit­8 and colony formation assays, as well as cell cycle distribution analysis. The effect of miR­145­5p on tumor growth was further investigated in vivo using a subcutaneous tumor model in nude mice. The interaction between miR­145­5p and E2F transcription factor 3 (E2F3) was determined using bioinformatics analysis, a luciferase assay, RT­qPCR and western blotting. The results revealed that miR­145­5p expression was decreased in osteosarcoma cell lines and tissues compared with the corresponding normal controls. Increased miR­145­5p expression inhibited the proliferation and colony formation ability of osteosarcoma cells, and induced G1 phase arrest. Furthermore, mice injected with tumor cells overexpressing miR­145­5p exhibited smaller tumors than those in the control group. Further investigation revealed that miR­145­5p binds to and decreases the expression of E2F3. In addition, the mRNA levels of E2F3 were negatively associated with miR­145­5p in osteosarcoma tissues, and increasing E2F3 expression abrogated the inhibitory effects of miR­145­5p on osteosarcoma cells. Collectively, the results obtained in the present study suggest that miR­145­5p may suppress the progression of osteosarcoma, and may serve as a useful biomarker for the diagnosis of osteosarcoma, as well as a therapeutic target.