Skulls of early humans carry telltale signs of inbreeding

Buried for 100,000 years at Xujiayao in the Nihewan Basin of northern China, the recovered skull pieces of an early human exhibit a now-rare congenital deformation that indicates inbreeding might well have been common among our ancestors, new research from the Chinese Academy of Sciences and Washington University in St. Louis suggests.

The skull, known as Xujiayao 11, has an unusual perforation through the top of the brain case — an enlarged parietal foramen (EPF) or “hole in the skull” — that is consistent with modern humans diagnosed with a rare genetic mutation in the homeobox genes ALX4 on chromosome 11 and MSX2 on chromosome 5.

These specific genetic mutations interfere with bone formation and prevent the closure of small holes in the back of the prenatal braincase, a process that is normally completed within the first five months of fetal development. It occurs in about one out of every 25,000 modern human births.

Although this genetic abnormality is sometimes associated with cognitive deficits, the older adult age of Xujiayao 11 suggests that any such deficits in this individual were minor.

Traces of genetic abnormalities, such as EPF, are seen unusually often in the skulls of Pleistocene humans, from early Homo erectus to the end of the Paleolithic.

"The probability of finding one of these abnormalities in the small available sample of human fossils is very low, and the cumulative probability of finding so many is exceedingly small," suggests study co-author Erik Trinkaus, the Mary Tileston Hemenway Professor of Anthropology in Arts & Sciences at Washington University in St. Louis.

"The presence of the Xujiayao and other Pleistocene human abnormalities therefore suggests unusual population dynamics, most likely from high levels of inbreeding and local population instability." It therefore provides a background for understanding populational and cultural dynamics through much of human evolution.

Research update: Imaging fish in 3-D

Zebrafish larvae — tiny, transparent and fast-growing vertebrates — are widely used to study development and disease. However, visually examining the larvae for variations caused by drugs or genetic mutations is an imprecise, painstaking and time-consuming process.

Engineers at MIT have now built an automated system that can rapidly produce 3-D, micron-resolution images of thousands of zebrafish larvae and precisely analyze their physical traits. The system, described in the Feb. 12 edition of Nature Communications, offers a comprehensive view of how potential drugs affect vertebrates, says Mehmet Fatih Yanik, senior author of the paper.

“Complex processes involving organs cannot be accurately recapitulated in cell culture today. Existing 3-D tissue models are still far too simple to model live animals,” says Yanik, an MIT associate professor of electrical engineering and computer science and biological engineering. “In whole animals, the biology is far more complicated.”

Lead authors of the paper are MIT graduate student Carlos Pardo-Martin and Amin Allalou, a visiting student at MIT. Other authors are MIT senior research scientist Peter Eimon, MIT intern Jaime Medina, and Carolina Wahlby of the Broad Institute.

Zebrafish are genetically similar to humans and have many of the same developmental pathways, so scientists often use them to model human diseases including cancer, diabetes, Parkinson’s disease and autism.

Using the new technology, researchers can grow larvae in tiny wells and flow them through a channel to an imaging platform. Once there, the embryos are rotated and 320 images are taken from different angles, allowing 3-D reconstructions to be made using optical projection tomography (OPT). Getting larvae to the platform takes about 15 seconds, and the imaging takes only 2.5 seconds. This allows hundreds or thousands of larvae to be imaged within hours.

In a 2010 paper, Yanik’s team described the system that transports the embryos to the imaging platform, which they combined with high-resolution two-dimensional imaging. In the latest version, they developed a high-speed OPT imaging technique, which takes hundreds of two-dimensional images and subsequently generates a 3-D image, similar to a CT scan.

They also created a computer algorithm that can measure hundreds of traits and use that information to create a comprehensive phenotype map — the overall description of an organism’s characteristics — for each larva. This enables rapid and detailed studies of how different drugs affect those phenotypes.

“You could probably look at almost any organ or tissue that you’re interested in,” Eimon says. “It gives researchers a way to rapidly measure and quantify and put numbers on the kinds of phenotypes and gene-expression patterns that they’ve been looking at for years and years.”

In this study, the researchers focused on the craniofacial skeleton, which is analogous to the human skull. They measured the length and volume of each of the bones that make up this structure, as well as the angles between the bones.

Each embryo was imaged five days after being treated with one of nine different teratogens — drugs that cause developmental abnormalities. The researchers compared their results with the drugs’ known effects and found that they were very consistent. They also obtained high-resolution, 3-D images of the craniofacial skeletons, which are less than a millimeter long.

“Now that we’re able to load the animals, and we can image them really quickly, and we have a way to start looking at the information, the sky’s the limit,” Pardo-Martin says. “What we have to do now is ask the big questions, because the technology has advanced.”

This kind of analysis could be very valuable for drug developers who need to efficiently screen thousands of drug candidates. It could also be used to study hard-to-detect changes in phenotype caused by genetic mutations, says Joseph Fetcho, a professor of neurobiology and behavior at Cornell University.

“A really high-throughput way to assess phenotype is very important for measuring small effects on the development of an organism,” says Fetcho, who was not part of the research team. “You can see what the phenotype looks like in a large population and quantify it in a very rigorous way.”

Some Autism Behaviors Linked to Altered Gene

Scientists at Washington University School of Medicine in St. Louis have identified a genetic mutation that may underlie common behaviors seen in some people with autism, such as difficulty communicating and resistance to change.

An error in the gene, CELF6, leads to disturbances in serotonin, a chemical that relays messages in the brain and has long been suspected to be involved in autism.

The researchers identified the error in a child with autism and then, working in mice, showed that the same genetic alteration results in autism-related behaviors and a sharp drop in the level of serotonin circulating in the brain.

While the newly discovered mutation appears to be rare, it provides some of the first clues to the biological basis of the disease, the scientists report Feb. 13 in the Journal of Neuroscience.

“Genetically, autism looks very complicated, with many different genetic routes that lead to the disease,” says lead author Joseph D. Dougherty, PhD, an assistant professor of genetics at Washington University. “But it’s not possible to design a different drug for every child. The real key is to find the common biological pathways that link these different genetic routes and target those pathways for treatment.”

Autism is known to have a strong genetic component, but the handful of genes implicated in the condition so far explain only a small number of cases or make a small contribution to symptoms.

This led Dougherty and senior author Nathaniel Heintz, PhD, a Howard Hughes Medical Institute investigator at Rockefeller University, to speculate that some of the most common behavioral symptoms of autism may be caused by disruptions in a common biological pathway, like the one involved in serotonin signaling.

Genome-wide Atlas of Gene Enhancers in the Brain On-line

Future research into the underlying causes of neurological disorders such as autism, epilepsy and schizophrenia, should greatly benefit from a first-of-its-kind atlas of gene-enhancers in the cerebrum (telencephalon). This new atlas, developed by a team led by researchers with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) is a publicly accessible Web-based collection of data that identifies and locates thousands of gene-regulating elements in a region of the brain that is of critical importance for cognition, motor functions and emotion.

“Understanding how the brain develops and functions, and how it malfunctions in neurological disorders, remains one of the most daunting challenges in contemporary science,” says Axel Visel, a geneticist with Berkeley Lab’s Genomics Division. “We’ve created a genome-wide digital atlas of gene enhancers in the human brain – the switches that tell genes when and where they need to be switched on or off. This enhancer atlas will enable other scientists to study in more detail how individual genes are regulated during development of the brain, and how genetic mutations may impact human neurological disorders.”

Visel is the corresponding author of a paper in the journal Cell that describes this work. The paper is titled “A High-Resolution Enhancer Atlas of the Developing Telencephalon.”

A model-free way to characterize polymodal ion channel gating

Two studies in The Journal of General Physiology (JGP) help pave the way for a “shortcut” model-free approach to studying activation of “polymodal” ion channels—channels that open in response to multiple stimuli. Transmembrane ion channels respond to various physiological stimuli to regulate numerous cellular functions. Different classes of channels respond to different types of stimuli; some channels, for instance, respond to changes in membrane potential whereas others are activated by ligand binding. Polymodal channels integrate different cellular signals, enabling them to mediate a more precise and flexible physiological response. Understanding the mechanisms involved in polymodal channel activation has been a challenge, however, in part because of the complexity of the models required.

Now, two studies in the January issue of JGP use straightforward thermodynamically rigorous analysis to parse the free energy of polymodal voltage- and ligand-dependent ion channels.

In one study, University of Wisconsin–Madison researchers Sandipan Chowdhury and Baron Chanda examine the BK channel—a channel activated by both changes in membrane potential and calcium binding to an intracellular domain. In the second study, Daniel Sigg (dPET Professional Services) explores gating of polymodal ion channels in general. Specifically, the authors show how to use G-V (conductance-voltage), Q-V (charge-voltage) and conductance vs. ligand concentration measurements to extract the free energies of interaction of the modules of a polymodal channel that respond to these distinct modalities.

This new approach opens the door for a model-independent way to studying ion channel gating, which could be useful both for constraining future atomic-scale models of channel gating, and in understanding the disruptions that result from disease causing genetic mutations.

Chowdhury, S., and B. Chanda. 2013. J. Gen. Physiol. doi:10.1085/jgp.201210860
Sigg, D., et al. 2013. J. Gen. Physiol. doi:10.1085/jgp.201210859
Yifrach, O. 2013. J. Gen. Physiol. doi:10.1085/jgp.201210929