High-Resolution Structure of ClpC1-Rufomycin and Ligand Binding Studies Provide a Framework to Design and Optimize Anti-Tuberculosis Leads.

Addressing the urgent need to develop novel drugs against drug-resistant Mycobacterium tuberculosis ( M. tb) strains, ecumicin (ECU) and rufomycin I (RUFI) are being explored as promising new leads targeting cellular proteostasis via the caseinolytic protein ClpC1. Details of the binding topology and chemical mode of (inter)action of these cyclopeptides help drive further development of novel potency-optimized entities as tuberculosis drugs. ClpC1 M. tb protein constructs with mutations driving resistance to ECU and RUFI show reduced binding affinity by surface plasmon resonance (SPR). Despite certain structural similarities, ECU and RUFI resistant mutation sites did not overlap in their SPR binding patterns. SPR competition experiments show ECU prevents RUFI binding, whereas RUFI partially inhibits ECU binding. The X-ray structure of the ClpC1-NTD-RUFI complex reveals distinct differences compared to the previously reported ClpC1-NTD-cyclomarin A structure. Surprisingly, the complex structure revealed that the epoxide moiety of RUFI opened and covalently bound to ClpC1-NTD via the sulfur atom of Met1. Furthermore, RUFI analogues indicate that the epoxy group of RUFI is critical for binding and bactericidal activity. The outcomes demonstrate the significance of ClpC1 as a novel target and the importance of SAR analysis of identified macrocyclic peptides for drug discovery.

Rufomycin Targets ClpC1 Proteolysis in Mycobacterium tuberculosis and M. abscessus.

ClpC1 is an emerging new target for the treatment of Mycobacterium tuberculosis infections, and several cyclic peptides (ecumicin, cyclomarin A, and lassomycin) are known to act on this target. This study identified another group of peptides, the rufomycins (RUFs), as bactericidal to M. tuberculosis through the inhibition of ClpC1 and subsequent modulation of protein degradation of intracellular proteins. Rufomycin I (RUFI) was found to be a potent and selective lead compound for both M. tuberculosis (MIC, 0.02 µM) and Mycobacterium abscessus (MIC, 0.4 µM). Spontaneously generated mutants resistant to RUFI involved seven unique single nucleotide polymorphism (SNP) mutations at three distinct codons within the N-terminal domain of clpC1 (V13, H77, and F80). RUFI also significantly decreased the proteolytic capabilities of the ClpC1/P1/P2 complex to degrade casein, while having no significant effect on the ATPase activity of ClpC1. This represents a marked difference from ecumicin, which inhibits ClpC1 proteolysis but stimulates the ATPase activity, thereby providing evidence that although these peptides share ClpC1 as a macromolecular target, their downstream effects are distinct, likely due to differences in binding.

Metabolite Profiling and Classification of DNA-Authenticated Licorice Botanicals.

Raw licorice roots represent heterogeneous materials obtained from mainly three Glycyrrhiza species. G. glabra, G. uralensis, and G. inflata exhibit marked metabolite differences in terms of flavanones (Fs), chalcones (Cs), and other phenolic constituents. The principal objective of this work was to develop complementary chemometric models for the metabolite profiling, classification, and quality control of authenticated licorice. A total of 51 commercial and macroscopically verified samples were DNA authenticated. Principal component analysis and canonical discriminant analysis were performed on (1)H NMR spectra and area under the curve values obtained from UHPLC-UV chromatograms, respectively. The developed chemometric models enable the identification and classification of Glycyrrhiza species according to their composition in major Fs, Cs, and species specific phenolic compounds. Further key outcomes demonstrated that DNA authentication combined with chemometric analyses enabled the characterization of mixtures, hybrids, and species outliers. This study provides a new foundation for the botanical and chemical authentication, classification, and metabolomic characterization of crude licorice botanicals and derived materials. Collectively, the proposed methods offer a comprehensive approach for the quality control of licorice as one of the most widely used botanical dietary supplements.

The cyclic peptide ecumicin targeting ClpC1 is active against Mycobacterium tuberculosis in vivo.

Drug-resistant tuberculosis (TB) has lent urgency to finding new drug leads with novel modes of action. A high-throughput screening campaign of >65,000 actinomycete extracts for inhibition of Mycobacterium tuberculosis viability identified ecumicin, a macrocyclic tridecapeptide that exerts potent, selective bactericidal activity against M. tuberculosis in vitro, including nonreplicating cells. Ecumicin retains activity against isolated multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis. The subcutaneous administration to mice of ecumicin in a micellar formulation at 20 mg/kg body weight resulted in plasma and lung exposures exceeding the MIC. Complete inhibition of M. tuberculosis growth in the lungs of mice was achieved following 12 doses at 20 or 32 mg/kg. Genome mining of lab-generated, spontaneous ecumicin-resistant M. tuberculosis strains identified the ClpC1 ATPase complex as the putative target, and this was confirmed by a drug affinity response test. ClpC1 functions in protein breakdown with the ClpP1P2 protease complex. Ecumicin markedly enhanced the ATPase activity of wild-type (WT) ClpC1 but prevented activation of proteolysis by ClpC1. Less stimulation was observed with ClpC1 from ecumicin-resistant mutants. Thus, ClpC1 is a valid drug target against M. tuberculosis, and ecumicin may serve as a lead compound for anti-TB drug development.

Species-specific Standardisation of Licorice by Metabolomic Profiling of Flavanones and Chalcones.

INTRODUCTION: Major phenolics from licorice roots (Glycyrrhiza sp.) are glycosides of the flavanone liquiritigenin (F) and its 2'-hydroxychalcone isomer, isoliquiritigenin (C). As the F and C contents fluctuate between batches of licorice, both quality control and standardisation of its preparations become complex tasks. OBJECTIVE: To characterise the F and C metabolome in extracts from Glycyrrhiza glabra L. and Glycyrrhiza uralensis Fisch. ex DC. by addressing their composition in major F­C pairs and defining the total F:C proportion. MATERIAL AND METHODS: Three types of extracts from DNA-authenticated samples were analysed by a validated UHPLC/UV method to quantify major F and C glycosides. Each extract was characterised by the identity of major F­C pairs and the proportion of Fs among all quantified Fs:Cs. RESULTS: The F and C compositions and proportions were found to be constant for all extracts from a Glycyrrhiza species. All G. uralensis extracts contained up to 2.5 more Fs than G. glabra extracts. Major F­C pairs were B-ring glycosidated in G. uralensis, and A-/B-ring apiosyl-glucosidated in the G. glabra extracts. The F:C proportion was found to be linked to the glycosidation site: the more B-ring F-C glycosides were present, the higher was the final F:C proportion in the extract. These results enable the chemical differentiation of extracts from G. uralensis and G. glabra, which are characterised by total F:C proportions of 8.37:1.63 and 7.18:2.82, respectively. CONCLUSION: Extracts from G. glabra and G. uralensis can be differentiated by their respective F and C compositions and proportions, which are both useful for further standardisation of licorice botanicals.

Evaluation of estrogenic activity of licorice species in comparison with hops used in botanicals for menopausal symptoms.

The increased cancer risk associated with hormone therapies has encouraged many women to seek non-hormonal alternatives including botanical supplements such as hops (Humulus lupulus) and licorice (Glycyrrhiza spec.) to manage menopausal symptoms. Previous studies have shown estrogenic properties for hops, likely due to the presence of 8-prenylnarigenin, and chemopreventive effects mainly attributed to xanthohumol. Similarly, a combination of estrogenic and chemopreventive properties has been reported for various Glycyrrhiza species. The major goal of the current study was to evaluate the potential estrogenic effects of three licorice species (Glycyrrhiza glabra, G. uralensis, and G. inflata) in comparison with hops. Extracts of Glycyrrhiza species and spent hops induced estrogen responsive alkaline phosphatase activity in endometrial cancer cells, estrogen responsive element (ERE)-luciferase in MCF-7 cells, and Tff1 mRNA in T47D cells. The estrogenic activity decreased in the order H. lupulus > G. uralensis > G. inflata > G. glabra. Liquiritigenin was found to be the principle phytoestrogen of the licorice extracts; however, it exhibited lower estrogenic effects compared to 8-prenylnaringenin in functional assays. Isoliquiritigenin, the precursor chalcone of liquiritigenin, demonstrated significant estrogenic activities while xanthohumol, a metabolic precursor of 8-prenylnaringenin, was not estrogenic. Liquiritigenin showed ERß selectivity in competitive binding assay and isoliquiritigenin was equipotent for ER subtypes. The estrogenic activity of isoliquiritigenin could be the result of its cyclization to liquiritigenin under physiological conditions. 8-Prenylnaringenin had nanomolar estrogenic potency without ER selectivity while xanthohumol did not bind ERs. These data demonstrated that Glycyrrhiza species with different contents of liquiritigenin have various levels of estrogenic activities, suggesting the importance of precise labeling of botanical supplements. Although hops shows strong estrogenic properties via ERα, licorice might have different estrogenic activities due to its ERß selectivity, partial estrogen agonist activity, and non-enzymatic conversion of isoliquiritigenin to liquiritigenin.

Differential regulation of detoxification enzymes in hepatic and mammary tissue by hops (Humulus lupulus) in vitro and in vivo.

SCOPE: Hops contain the phytoestrogen, 8-prenylnaringenin, and the cytoprotective compound, xanthohumol (XH). XH induces the detoxification enzyme, NAD(P)H-quinone oxidoreductase (NQO1) in vitro; however, the tissue distribution of XH and 8-prenylnaringenin and their tissue-specific activity have not been analyzed. METHODS AND RESULTS: An orally administered hop extract and subcutaneously injected XH were administered to Sprague-Dawley rats over 4 days. LC-MS-MS analysis of plasma, liver, and mammary gland revealed that XH accumulated in liver and mammary glands. Compared with the low level in the original extract, 8-prenylnaringenin was enriched in the tissues. Hops and XH-induced NQO1 in the liver, while only hops reduced NQO1 activity in the mammary gland. Mechanistic studies revealed that hops modulated NQO1 through three mechanisms. In liver cells, (i) XH modified Kelch-like ECH-associated protein leading to nuclear factor (erythroid-derived 2)-like 2 (Nrf2) translocation and antioxidant response element (ARE) activation; (ii) hop-mediated ARE induction was partially mediated through phosphorylation of Nrf2 by PKC; (iii) in breast cells, 8-prenylnaringenin reduced NQO1 likely through binding to estrogen receptorα, recruiting Nrf2, and downregulating ARE-regulated genes. CONCLUSION: XH and 8-prenylnaringenin in dietary hops are bioavailable to the target tissues. While hops and XH might be cytoprotective in the liver, 8-prenylnaringenin seems responsible for hop-mediated NQO1 reduction in the mammary gland.

Genetic associations in the vitamin D receptor and colorectal cancer in African Americans and Caucasians.

Low vitamin D levels are associated with an increased incidence of colorectal cancer (CRC) and higher mortality from the disease. In the US, African Americans (AAs) have the highest CRC incidence and mortality and the lowest levels of vitamin D. Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene have been previously associated with CRC, but few studies have included AAs. We studied 795 AA CRC cases and 985 AA controls from Chicago and North Carolina as well as 1324 Caucasian cases and 990 Caucasian controls from Chicago and Spain. We genotyped 54 tagSNPs in VDR (46586959 to 46521297 Mb) and tested for association adjusting for West African ancestry, age, gender, and multiple testing. Untyped markers were imputed using MACH1.0. We analyzed associations by gender and anatomic location in the whole study group as well as by vitamin D intake in the North Carolina AA group. In the joint analysis, none of the SNPs tested was significantly associated with CRC. For four previously tested restriction fragment length polymorphisms, only one (referred to as ApaI), tagged by the SNP rs79628898, had a nominally significant p-value in AAs; none of these polymorphisms were associated with CRC in Caucasians. In the North Carolina AAs, for whom we had vitamin D intake data, we found a significant association between an intronic SNP rs11574041 and vitamin D intake, which is evidence for a VDR gene-environment interaction in AAs. In summary, using a systematic tagSNP approach, we have not found evidence for significant associations between VDR and CRC in AAs or Caucasians.

Fly eye based sensor model and animation using matlab - biomed 2011.

A new optical sensor based on the common house fly, Musca domestica, has been under development for some time at the University of Wyoming. Each sensor consists of a series of photodiodes with overlapping Gaussian field of views. The photodiodes share a common facet lens. This type of sensor provides higher movement detection and resolution than can be obtained in current charged-couple detector (CCD) arrays that are commonly used in digital imaging systems. The purpose of this research is to aid in the application and development of the fly based sensor by creating a MATLAB simulation tool to model and study the response signals from various input stimuli. In particular, the sensor detection capability and limits for line, edge and pulse stimuli will be modeled, and analyzed. Increased knowledge of the detection characteristics and limits of this type of sensor will provide insight and guidance to determine possible sensor applications. The signal analysis makes use of the Gaussian profiles that are created in MATLAB. A user-selectable input signal can be applied, while observing the output signal. The information is animated, and plotted for study and analysis. This interactive MATLAB model is a powerful tool to help understand the complex interactions of the optical signals. This sensor configuration has a variety of applications in wheelchair odometry, power line detection by unmanned aerial systems (AES), high speed railroad line inspection, and remote building monitoring.

In vivo quantification of murine aortic cyclic strain, motion, and curvature: implications for abdominal aortic aneurysm growth.

PURPOSE: To develop methods to quantify cyclic strain, motion, and curvature of the murine abdominal aorta in vivo. MATERIALS AND METHODS: C57BL/6J and apoE(-/-) mice underwent three-dimensional (3D) time-of-flight MR angiography to position cardiac-gated 2D slices at four locations along the abdominal aorta where circumferential cyclic strain and lumen centroid motion were calculated. From the 3D data, a centerline through the aorta was created to quantify geometric curvature at 0.1-mm intervals. Medial elastin content was quantified with histology postmortem. The location and shape of abdominal aortic aneurysms (AAAs), created from angiotensin II infusion, were evaluated qualitatively. RESULTS: Strain waveforms were similar at all locations and between groups. Centroid motion was significantly larger and more leftward above the renal vessels than below (P < 0.05). Maximum geometric curvature occurred slightly proximal to the right renal artery. Elastin content was similar around the circumference of the vessel. AAAs developed in the same location as the maximum curvature and grew in the same direction as vessel curvature and motion. CONCLUSION: The methods presented provide temporally and spatially resolved data quantifying murine aortic motion and curvature in vivo. This noninvasive methodology will allow serial quantification of how these parameters influence the location and direction of AAA growth.

Genetic heterogeneity in colorectal cancer associations between African and European americans.

BACKGROUND & AIMS: Genome-wide association studies of colorectal cancer (CRC) have identified risk variants in 10 genomic regions. None of these studies included African Americans, who have the highest incidence and mortality from CRC in the United States. For the 10 genomic regions, we performed an association study of Americans of African and European descent. METHODS: We genotyped 22 single nucleotide polymorphisms (SNPs) in DNA samples from 1194 patients with CRC (795 African Americans and 399 European Americans) and 1352 controls (985 African Americans and 367 European Americans). At chromosome 8q24.21 region 3, we analyzed 6 SNPs from 1000 African American cases and 1393 controls. Association testing was done using multivariate logistic regression controlling for ancestry, age, and sex. RESULTS: Among African Americans, the SNP rs6983267 at 8q24.21 was not associated with CRC (odds ratio, 1.18; P = .12); instead, the 8q24.21 SNP rs7014346 (odds ratio, 1.15; P = .03) was associated with CRC in this population. At 15q13.3, rs10318 was associated with CRC in both populations. At 11q23.1, rs3802842 was significantly associated with rectal cancer risk only among African Americans (odds ratio, 1.34; P = .01); this observation was made in previous studies. Among European Americans, SNPs at 8q24.21, 11q23.1, and 16q22.1 were significantly associated with CRC, and the odds ratios were of the same magnitude and direction for all SNPs tested, consistent with previously published studies. In contrast, in African Americans, the opposite allele of rs10795668 at 10p14 was associated with colorectal cancer (odds ratio, 1.35; P = .04), and altogether the odds ratios were in the opposite direction for 9 of the 22 SNPs tested. CONCLUSIONS: There is genetic heterogeneity in CRC associations in Americans of African versus European descent.

Three-dimensional rendering of segmented object using matlab - biomed 2010.

The three-dimensional rendering of microscopic objects is a difficult and challenging task that often requires specialized image processing techniques. Previous work has been described of a semi-automatic segmentation process of fluorescently stained neurons collected as a sequence of slice images with a confocal laser scanning microscope. Once properly segmented, each individual object can be rendered and studied as a three-dimensional virtual object. This paper describes the work associated with the design and development of Matlab files to create three-dimensional images from the segmented object data previously mentioned. Part of the motivation for this work is to integrate both the segmentation and rendering processes into one software application, providing a seamless transition from the segmentation tasks to the rendering and visualization tasks. Previously these tasks were accomplished on two different computer systems, windows and Linux. This transition basically limits the usefulness of the segmentation and rendering applications to those who have both computer systems readily available. The focus of this work is to create custom Matlab image processing algorithms for object rendering and visualization, and merge these capabilities to the Matlab files that were developed especially for the image segmentation task. The completed Matlab application will contain both the segmentation and rendering processes in a single graphical user interface, or GUI. This process for rendering three-dimensional images in Matlab requires that a sequence of two-dimensional binary images, representing a cross-sectional slice of the object, be reassembled in a 3D space, and covered with a surface. Additional segmented objects can be rendered in the same 3D space. The surface properties of each object can be varied by the user to aid in the study and analysis of the objects. This inter-active process becomes a powerful visual tool to study and understand microscopic objects.

Novel single nucleotide polymorphism associations with colorectal cancer on chromosome 8q24 in African and European Americans.

Regions on chromosome 8q24 harbor susceptibility alleles for multiple cancers including colorectal (region 3) and prostate cancer (regions 1-4). The objectives of the present study were (i) to test whether single-nucleotide polymorphisms (SNPs) in region 4 are associated with colorectal cancer (CRC) in European or African Americans; (ii) to test whether 8q24 SNPs previously shown to be associated with colorectal and prostate cancer also show association in our multiethnic series and (iii) to test for association between 100 ancestry informative markers (AIMs) and CRC in both the African American and European American cohorts. In total, we genotyped nine markers on 8q24 and 100 unlinked AIMs in 569 CRC cases and 439 controls (490 European Americans and 518 African Americans) obtained retrospectively from a hospital-based sample. We found rs7008482 in 8q24 region 4 to be significantly associated with CRC in European Americans (P = 0.03). Also in region 4, we found that a second SNP, rs16900305, trended toward association with CRC in African Americans. The rs6983267 in region 3, previously implicated in CRC risk, trended toward association with disease in European Americans but not in African Americans. Finally, none of the 100 AIMs tested for association reached statistical significance after correction for multiple hypothesis testing. In summary, these results are evidence that 8q24 region 4 contains novel CRC-associated alleles in European and African Americans.

Graphical user interface to optimize image contrast parameters used in object segmentation - biomed 2009.

Image segmentation is the process of isolating distinct objects within an image. Computer algorithms have been developed to aid in the process of object segmentation, but a completely autonomous segmentation algorithm has yet to be developed [1]. This is because computers do not have the capability to understand images and recognize complex objects within the image. However, computer segmentation methods [2], requiring user input, have been developed to quickly segment objects in serial sectioned images, such as magnetic resonance images (MRI) and confocal laser scanning microscope (CLSM) images. In these cases, the segmentation process becomes a powerful tool in visualizing the 3D nature of an object. The user input is an important part of improving the performance of many segmentation methods. A double threshold segmentation method has been investigated [3] to separate objects in gray scaled images, where the gray level of the object is among the gray levels of the background. In order to best determine the threshold values for this segmentation method the image must be manipulated for optimal contrast. The same is true of other segmentation and edge detection methods as well. Typically, the better the image contrast, the better the segmentation results. This paper describes a graphical user interface (GUI) that allows the user to easily change image contrast parameters that will optimize the performance of subsequent object segmentation. This approach makes use of the fact that the human brain is extremely effective in object recognition and understanding. The GUI provides the user with the ability to define the gray scale range of the object of interest. These lower and upper bounds of this range are used in a histogram stretching process to improve image contrast. Also, the user can interactively modify the gamma correction factor that provides a non-linear distribution of gray scale values, while observing the corresponding changes to the image. This interactive approach gives the user the power to make optimal choices in the contrast enhancement parameters.

A confocal laser scanning microscope segmentation method applied to magnetic resonance images.

Segmentation is the process of defining distinct objects in an image. A semi-automatic segmentation method has been developed for biological objects that have been recorded with a confocal laser scanning microscope (CLSM). The CLSM produces a sequence of thinly "sliced" images that represent cross-sectional views of the sample containing the object of interest. The cross-sectional representation, or "seed" is created of the object of interest within a single slice of the image stack. The segmentation method uses this "seed" to segment the same object in the adjacent image slice. The new "seed" is used for the next image slice and so on, until the object of interest is segmented in all images of the data set. The segmentation method is based on the idea that the object of interest does not change significantly from one image slice to the next. The segmented information is then used to create 3D renderings of the object. These renderings can be studied and analyzed on the computer screen. Previous work has demonstrated the usefulness of the algorithm as applied to the CLSM images. This paper explores the application of the segmentation method to a standard sequence of magnet resonance imaging (MRI) images. Typical MRI machines can produce impressive images of the human body. The resulting data set is often a sequence, or "stack" of cross-sectional slice images of a particular region of the body. The goal then, is to use the previously described segmentation method on a standard sequence of MRI images. This process will expose limitations with the segmentation method and areas where further work can be directed. This paper illustrates and discusses some of the differences between the data sets that make the current segmentation method inadequate for segmentation of MRI data set. Some of the differences can be corrected with modification of the segmentation algorithm, but other differences are beyond the capabilities of the segmentation method, and can possibly be addressed in other ways. The lessons learned from this research process will lead to a more capable and robust segmentation algorithm.

A quantitative comparison between manual segmentation and threshold-based segmentation of CLSM recorded images.

Segmentation is the process of defining distinct objects in an image. Object segmentation of two-dimensional images is often accomplished by a time consuming manual process where trained persons trace a line along the boundary of the object. Significant effort has been directed towards various computer segmentation algorithms to reduce the time required to segment each object. Often the question arises as to the accuracy of the computer segmentation results. This paper makes a quantitative comparison between the segmented object from a threshold-based computer segmentation process and the manual segmentation results from a group of volunteers. This comparison is based on the fact that humans have an intuitive capability to recognize objects. The image sample used in this report is a portion of the brain of the common housefly, Musca domestica. The very small size of the object makes it impractical to compare the computer segmentation results to the actual object.

Sonic Hedgehog, a key development gene, experienced intensified molecular evolution in primates.

Sonic Hedgehog (SHH) is one of the most intensively studied genes in developmental biology. It is a highly conserved gene, found in species as diverse as arthropods and mammals. The mammalian SHH encodes a signaling molecule that plays a central role in developmental patterning, especially of the nervous system and the skeletal system. Here, we show that the molecular evolution of SHH is markedly accelerated in primates relative to other mammals. We further show that within primates, the acceleration is most prominent along the lineage leading to humans. Finally, we show that the acceleration in the lineage leading to humans is coupled with signatures of adaptive evolution. In particular, the lineage leading to humans is characterized by a rampant and statistically highly non-random gain of serines and threonines, residues that are potential substrates of post-translational modifications. This suggests that SHH might have evolved more complex post-translational regulation in the lineage leading to humans. Collectively, these findings implicate SHH as a potential contributor to the evolution of primate- or human-specific morphological traits in the nervous and/or skeletal systems and provide the impetus for additional studies aimed at identifying the primate- or human-specific functions of this key development gene.

Trak1 mutation disrupts GABA(A) receptor homeostasis in hypertonic mice.

Hypertonia, which results from motor pathway defects in the central nervous system (CNS), is observed in numerous neurological conditions, including cerebral palsy, stroke, spinal cord injury, stiff-person syndrome, spastic paraplegia, dystonia and Parkinson disease. Mice with mutation in the hypertonic (hyrt) gene exhibit severe hypertonia as their primary symptom. Here we show that hyrt mutant mice have much lower levels of gamma-aminobutyric acid type A (GABA(A)) receptors in their CNS, particularly the lower motor neurons, than do wild-type mice, indicating that the hypertonicity of the mutants is likely to be caused by deficits in GABA-mediated motor neuron inhibition. We cloned the responsible gene, trafficking protein, kinesin binding 1 (Trak1), and showed that its protein product interacts with GABA(A) receptors. Our data implicate Trak1 as a crucial regulator of GABA(A) receptor homeostasis and underscore the importance of hyrt mice as a model for studying the molecular etiology of hypertonia associated with human neurological diseases.

Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.

The gene Microcephalin (MCPH1) regulates brain size and has evolved under strong positive selection in the human evolutionary lineage. We show that one genetic variant of Microcephalin in modern humans, which arose approximately 37,000 years ago, increased in frequency too rapidly to be compatible with neutral drift. This indicates that it has spread under strong positive selection, although the exact nature of the selection is unknown. The finding that an important brain gene has continued to evolve adaptively in anatomically modern humans suggests the ongoing evolutionary plasticity of the human brain. It also makes Microcephalin an attractive candidate locus for studying the genetics of human variation in brain-related phenotypes.

Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.

The gene ASPM (abnormal spindle-like microcephaly associated) is a specific regulator of brain size, and its evolution in the lineage leading to Homo sapiens was driven by strong positive selection. Here, we show that one genetic variant of ASPM in humans arose merely about 5800 years ago and has since swept to high frequency under strong positive selection. These findings, especially the remarkably young age of the positively selected variant, suggest that the human brain is still undergoing rapid adaptive evolution.