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PNAS Studies Tackle Syndromic Craniosynostosis, Colorectal Cancer Drivers, More

A Yale University-led team unearths gene mutations in individuals with syndromic craniosynostosis. The researchers did exome sequencing in a dozen individuals with the congenital premature cranial vault fusion condition and in their unaffected parents, uncovering suspicious loss-of-function mutations in eight mutation-intolerant genes and a rare, damaging SOX11 mutation. Along with genes from pathways already known to contribute to syndromic craniosynostosis, including the Hedgehog, BMP, and Wnt signaling pathways, they saw alterations affecting chromatin modifier genes as well as a neural crest cell-regulating transcription factor called TFAP2B. The authors argue that these and other results from the study "have implications for determining risk of disease in subsequent offspring and demonstrate that unexplained syndromic [craniosynostosis] cases are a particularly rich vein for discovery of [craniosynostosis] loci."

Researchers in Japan and the US characterize suspected colorectal cancer drivers with the help of gene knockouts made in tumor organoids. Using CRISPR-Cas9-based gene editing in mouse intestinal tumor organoids and in xenograft mice with organoids developed from human CRC tumors, the researchers did functional validation analyses on 29 candidate tumor suppressor genes previously uncovered in mice using transposon mutagenesis screening. Their results supported apparent tumor suppressor roles for the ACVR1B, ACVR2A, and ARID2 genes, for example, and suggested that TRP53 may contribute to CRC tumor metastasis. "This experimental system can also be applied to mouse intestinal organoids carrying other sensitizing mutations as well as organoids derived from other organs, which could further contribute to identification of novel cancer driver genes and new drug targets," they write.

A team from the Max Planck Institute for Evolutionary Anthropology and elsewhere takes a look at Neanderthal relationships using new nuclear and mitochondrial DNA data generated for Neanderthals found in Gibraltar, a warm coastal site where DNA preservation is less than ideal. The researchers relied on an improved sample preparation and library construction approaches to deal with highly contaminated DNA isolated from petrous bone samples of an aged female Neanderthal from Forbes' Quarry and a young male Neanderthal from Devil's Tower, dated broadly between 30,000 and 130,000 years old. Their analyses suggested that the Forbes' Quarry Neanderthal shared more genetic features with ancient Neanderthals previously profiled in Belgium, Germany, and Russia than with Neanderthals that lived more recently in Spain and other parts of Europe and western Asia. GenomeWeb has more on the study, here