RUNX2

匹兹堡大学和鲁汶大学的研究人员发现了一组影响人类头部形状的基因，并将结果发表于《自然通讯》上。该结果有助于解释人类头部形状的多样性，也为研究颅骨疾病（如：颅缝早闭）的遗传基础提供了潜在的重要线索。颅顶是头骨的一部分，形成头顶的圆形部分并保护大脑。研究小组确定了30个与头部形状不同方面相关的基因组区域，其中29个是此前的研究从未报道过的。“自20世纪初以来，人类学家们一直在对颅顶形状的遗传学进行推测和争论。我们从某些罕见的人类和动物案例中知道，基因在穹窿的大小和形状中发挥着重要作用，但对于普通人群的颅顶特征，我们所掌握的遗传学知识少之又少，例如：为什么有些人的头长而窄，有些人的头短而宽？这项研究就揭示了导致人体这部分差异的关键基因，”共同资深作者、皮特牙科医学院口腔和颅面科学教授、颅面和牙科遗传学中心联合主任Seth Weinberg表示。研究人员表示，当我们更好地了解人类颅顶形状多样性背后的驱动因素，就可以为古人类学研究提供相关信息。Weinberg及其同事对6000多名青少年进行了核磁共振扫描并提取了他们的颅顶表面3D图。在将3D穹窿表面划分为更小的解剖子部分并量化了这些子部分的形状后，他们测试了超过1000万个遗传变异以寻找与穹窿形状统计结果相关联的基因证据。从4个区域按照形状区分（蓝色），颅顶形状可分为15类“之前对颅顶的遗传学研究涉及一些相对简单的研究方法，”Weinberg补充道：“这些方法虽然简便，但它们可能无法捕获生物学相关的特征。因此，我们使用了一种创新方法，能够更全面和细致地描述3D拱顶形状，这种方法提高了我们寻找遗传关联的成功率。”一个重要的发现是，许多强关联都出现在对头面部早期形成和骨骼发育调节发挥关键作用的基因附近。研究结果证实，RUNX2基因（协调头骨发育的主要基因）及其附近的变异与拱顶形状的多个方面相关。包括RUNX2在内的一些基因对整个穹窿产生影响，还有一些基因则表现出更局部的影响，仅影响穹窿的特定部分，如：中央前额。研究人员比较了拥有欧洲、非洲和美洲原住民血统参与者的30个基因组区域，他们发现相同祖先的参与者群体共享了大多数的遗传关联。Weinberg表示，尽管这项研究主要在健康参与者中展开，但研究结果可能揭示有关颅顶疾病生物学基础的重要线索。其中一种疾病是颅缝早闭，即当颅骨过早融合而大脑仍在快速生长时就会发生这种情况。如果不进行神经外科手术，颅缝早闭会导致永久性毁容、脑损伤、失明甚至死亡。研究小组发现，与穹窿形状相关的3个基因——BMP2、BBS9和ZIC2附近的变异也与颅缝早闭相关，表明这些基因可能在该疾病的进展中发挥作用。Weinberg 还表示：“公共资助让这项研究成为可能。生成这些核磁共振扫描图是为了重点了解大脑的发育和行为。通过创造性地利用这些资助资源，我们成功地踏足了之前未知的领域。”这项研究得到了国家牙科和颅面研究所和美国国立卫生研究院国家人类基因组研究所的联合支持。参考文献：Goovaerts,S.,et al.(2023).Joint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape.Nature Communications. doi.org/10.1038/s41467-023-43237-8.责编|探索君排版|探索君End往期精选围观科学家称，每25人中就有1人携带“短寿”基因热文表观遗传变化在癌症进展中至关重要热文新型柔性X射线探测器有望彻底改变癌症治疗热文最新发现：人类毛囊具备触觉感知能力热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~

Researchers have discovered a suite of genes that influence head shape in humans. These findings help explain the diversity of human head shapes and may also offer important clues about the genetic basis of conditions that affect the skull, such as craniosynostosis. Researchers at the University of Pittsburgh and KU Leuven have discovered a suite of genes that influence head shape in humans. These findings, published this week in Nature Communications, help explain the diversity of human head shapes and may also offer important clues about the genetic basis of conditions that affect the skull, such as craniosynostosis. By analyzing measurements of the cranial vault -- the part of the skull that forms the rounded top of the head and protects the brain -- the team identified 30 regions of the genome associated with different aspects of head shape, 29 of which have not been reported previously. "Anthropologists have speculated and debated the genetics of cranial vault shape since the early 20th century," said co-senior author Seth Weinberg, Ph.D., professor of oral and craniofacial sciences in the Pitt School of Dental Medicine and co-director of the Center for Craniofacial and Dental Genetics. "We knew from certain rare human conditions and animal experiments that genes play an important role in vault size and shape, but very little was known about the genetic basis for typical features we see in the general population, such as what makes someone's head long and narrow versus short and wide. This study reveals some of the key genes driving variation in this part of the human body." According to the researchers, one application of better understanding the factors that drive natural variation in human head shape is informing paleoanthropology studies, potentially shedding light on the early development of modern humans. Weinberg and colleagues used magnetic resonance (MR) scans from more than 6,000 adolescents to extract 3D surfaces corresponding to the cranial vault. After dividing the 3D vault surfaces into incrementally smaller anatomical subparts and quantifying the shape of these subparts, they tested more than 10 million genetic variants for evidence of statistical association with measures of vault shape. "Previous genetic studies of the cranial vault involved a small number of relatively simple measures," added Weinberg. "While such measures are often easy to obtain, they may fail to capture features that are biologically relevant. Our analysis used an innovative approach capable of describing 3D vault shape in much more comprehensive and nuanced ways. This approach increased our ability to find genetic associations." An important discovery was that many of the strong associations are near genes that play key roles in the early formation of the head and face and regulation of bone development. For example, variants in and near the gene RUNX2, a major player in coordinating development of the skull, were associated with multiple aspects of vault shape. While some genes, including RUNX2, had global effects involving the entire vault, others showed more localized effects that only impacted a specific portion of the vault, such as the central forehead. When the researchers compared the 30 genomic regions associated with head shape across participants with European, African and Indigenous American ancestry, they found that the majority of genetic associations were shared across these different ancestral groups. Although the study focused on healthy participants, the findings may reveal important clues about the biological basis of diseases involving the cranial vault, according to Weinberg. One of these conditions is craniosynostosis, which occurs when the bones of the skull fuse too early while the brain is still growing rapidly. Without neurosurgery, craniosynostosis can cause permanent disfigurement, brain damage, blindness and even death. The team showed that variants near three genes associated with vault shape, BMP2, BBS9 and ZIC2, were also associated with craniosynostosis, suggesting that these genes could play a role in the development of the disease. "This kind of study is possible due to the availability of publicly funded resources," said Weinberg. "The original study that generated these MR scans is focused on understanding brain development and behavior. By creatively leveraging these resources, we have managed to advance discovery beyond that original scope." Other authors on the study were Seppe Goovaerts, Hanne Hoskens, Ph.D., Meng Yuan, Dirk Vandermeulen, Ph.D., all of KU Leuven; Ryan J. Eller, Ph.D., Noah Herrick, Ph.D., and Susan Walsh, Ph.D., all of Indiana University-Purdue University Indianapolis; Anthony M. Musolf, Ph.D., and Cristina M. Justice, Ph.D., both of the National Human Genome Research Institute; Sahin Naqvi, Ph.D., and Joanna Wysocka, Ph.D., both of Stanford University; Myoung Keun Lee, Heather L. Szabo-Rogers, Ph.D., Mary L. Marazita, Ph.D., and John R. Shaffer, Ph.D., all of Pitt; Paul A. Romitti, Ph.D., of the University of Iowa; Simeon A. Boyadjiev, M.D., of the University of California, Davis; Mark D. Shriver, Ph.D., of Penn State University; and Peter Claes, Ph.D., of KU Leuven and Murdoch Children's Research Institute. This research was supported by the National Institute of Dental and Craniofacial Research (R01DE027023, R01DE016886, R03DE031061 and X01HL14053) and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health

Researchers have found that bone repair can be improved in mice with large bone lesions by injecting a combination of RNA encoding two different proteins. Their technique is a promising candidate for clinical use. This study provides new hope for patients with large bone lesions as a result of injury or surgery, in whom bone repair is often difficult to achieve. Although bones have the ability to regenerate and repair themselves, they are generally unable to do so when the injury is larger than a small break or chip. In a study just published in Inflammation and Regeneration, Japanese researchers have developed a technique for improving bone regeneration over large areas in rats -- and their findings may translate well to clinical settings. As most of us know from experience, bones can repair themselves after a minor break or fracture, leaving us as good as new. Unfortunately, after a larger injury -- or if a lot of bone needs to be removed because of something like a tumor -- bones often don't heal well. Although there are many different ways to improve bone repair over larger areas in animal models, very few techniques translate well into the clinic. A research team from Tokyo Medical and Dental University (TMDU) decided to tackle this challenge using vascular endothelial growth factor (VEGF), which improves regeneration of the blood circulatory system, and Runt-related transcription factor 2 (Runx2), which is important for bone regeneration. "We had already used these two factors to improve bone regeneration in mice in a previous study," explains senior author of the study Keiji Itaka. "But we injected DNA, which can insert itself into the body's genetic information, rather than RNA, which cannot; this meant that our findings had little clinical relevance because of the risks involved." In their new study, the researchers used messenger RNA encoding VEGF and Runx2. They first demonstrated that the combination of these two RNAs led to a better regenerative response in bone cells than each RNA alone. Next, they injected the RNA combination into rats with large jawbone lesions. After three weekly injections, the jawbones of these mice were almost completely healed, unlike those of control mice. Importantly, their technique may have similar results in a clinical setting and is likely to be safe for use in humans. "Our technique is especially promising for clinical use because of the coating that we used for the VEGF and Runx2 RNA," explains Maorui Zhang, lead author of the study. "Many previous studies have used lipid nanoparticles, but this coating leads to inflammation, limiting its clinical use. We used a coating that we had developed previously, known as polyplex nanomicelles, which leads to very little inflammation." Given that large bone injuries can be difficult to repair in the clinic, the findings of this study bring new hope to patients. The use of combinations of RNA coated in polyplex nanomicelles is potentially an effective, low-risk technique for improving bone repair in humans and has many promising clinical applications.