Next-Generation Mapping of Complex Traits with Phenotype-Based Selection and Introgression

Finding the genes underlying complex traits is difficult. We show that new sequencing technology combined with traditional genetic techniques can efficiently identify genetic regions underlying a complex and quantitative behavioral trait. As a proof of concept we used phenotype-based introgression to backcross loci that control innate food preference in Drosophila simulans into the genomic background of D. sechellia, which expresses the opposite preference. We successfully mapped D. simulans introgression regions in a small mapping population (30 flies) with whole-genome resequencing using light coverage (∼1×). We found six loci contributing to D. simulans food preference, one of which overlaps a previously discovered allele. This approach is applicable to many systems, does not rely on laborious marker development or genotyping, does not require existing high quality reference genomes, and needs only small mapping populations. Because introgression is used, researchers can scale mapping population size, replication, and number of backcross generations to their needs. Finally, in contrast to more widely used mapping techniques like F2 bulk-segregant analysis, our method produces near-isogenic lines that can be kept and reused indefinitely

Improved control of a prosthetic limb by surgically creating electro-neuromuscular constructs with implanted electrodes

: Remnant muscles in the residual limb after amputation are the most common source of control signals for prosthetic hands, because myoelectric signals can be generated by the user at will. However, for individuals with amputation higher up the arm, such as an above-elbow (transhumeral) amputation, insufficient muscles remain to generate myoelectric signals to enable control of the lost arm and hand joints, thus making intuitive control of wrist and finger prosthetic joints unattainable. We show that severed nerves can be divided along their fascicles and redistributed to concurrently innervate different types of muscle targets, particularly native denervated muscles and nonvascularized free muscle grafts. We engineered these neuromuscular constructs with implanted electrodes that were accessible via a permanent osseointegrated interface, allowing for bidirectional communication with the prosthesis while also providing direct skeletal attachment. We found that the transferred nerves effectively innervated their new targets as shown by a gradual increase in myoelectric signal strength. This allowed for individual flexion and extension of all five fingers of a prosthetic hand by a patient with a transhumeral amputation. Improved prosthetic function in tasks representative of daily life was also observed. This proof-of-concept study indicates that motor neural commands can be increased by creating electro-neuromuscular constructs using distributed nerve transfers to different muscle targets with implanted electrodes, enabling improved control of a limb prosthesis

A highly integrated bionic hand with neural control and feedback for use in daily life

Restoration of sensorimotor function after amputation has remained challenging because of the lack of human-machine interfaces that provide reliable control, feedback, and attachment. Here, we present the clinical implementation of a transradial neuromusculoskeletal prosthesis-a bionic hand connected directly to the user's nervous and skeletal systems. In one person with unilateral below-elbow amputation, titanium implants were placed intramedullary in the radius and ulna bones, and electromuscular constructs were created surgically by transferring the severed nerves to free muscle grafts. The native muscles, free muscle grafts, and ulnar nerve were implanted with electrodes. Percutaneous extensions from the titanium implants provided direct skeletal attachment and bidirectional communication between the implanted electrodes and a prosthetic hand. Operation of the bionic hand in daily life resulted in improved prosthetic function, reduced postamputation, and increased quality of life. Sensations elicited via direct neural stimulation were consistently perceived on the phantom hand throughout the study. To date, the patient continues using the prosthesis in daily life. The functionality of conventional artificial limbs is hindered by discomfort and limited and unreliable control. Neuromusculoskeletal interfaces can overcome these hurdles and provide the means for the everyday use of a prosthesis with reliable neural control fixated into the skeleton

Genetic polymorphisms and expression of Rhesus blood group RHCE are associated with 2,3-bisphosphoglycerate in humans at high altitude

Red blood cell (RBC) metabolic reprogramming upon exposure to high altitude contributes to physiological human adaptations to hypoxia, a multifaceted process critical to health and disease. To delve into the molecular underpinnings of this phenomenon, first, we performed a multi-omics analysis of RBCs from six lowlanders after exposure to high-altitude hypoxia, with longitudinal sampling at baseline, upon ascent to 5,100 m and descent to sea level. Results highlighted an association between erythrocyte levels of 2,3-bisphosphoglycerate (BPG), an allosteric regulator of hemoglobin that favors oxygen off-loading in the face of hypoxia, and expression levels of the Rhesus blood group RHCE protein. We then expanded on these findings by measuring BPG in RBCs from 13,091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. These data informed a genome-wide association study using BPG levels as a quantitative trait, which identified genetic polymorphisms in the region coding for the Rhesus blood group RHCE as critical determinants of BPG levels in erythrocytes from healthy human volunteers. Mechanistically, we suggest that the Rh group complex, which participates in the exchange of ammonium with the extracellular compartment, may contribute to intracellular alkalinization, thus favoring BPG mutase activity

A Locus in Drosophila sechellia Affecting Tolerance of a Host Plant Toxin

Many insects feed on only one or a few types of host. These host specialists often evolve a preference for chemical cues emanating from their host and develop mechanisms for circumventing their host’s defenses. Adaptations like these are central to evolutionary biology, yet our understanding of their genetics remains incomplete. Drosophila sechellia, an emerging model for the genetics of host specialization, is an island endemic that has adapted to chemical toxins present in the fruit of its host plant, Morinda citrifolia. Its sibling species, D. simulans, and many other Drosophila species do not tolerate these toxins and avoid the fruit. Earlier work found a region with a strong effect on tolerance to the major toxin, octanoic acid, on chromosome arm 3R. Using a novel assay, we narrowed this region to a small span near the centromere containing 18 genes, including three odorant binding proteins. It has been hypothesized that the evolution of host specialization is facilitated by genetic linkage between alleles contributing to host preference and alleles contributing to host usage, such as tolerance to secondary compounds. We tested this hypothesis by measuring the effect of this tolerance locus on host preference behavior. Our data were inconsistent with the linkage hypothesis, as flies bearing this tolerance region showed no increase in preference for media containing M. citrifolia toxins, which D. sechellia prefers. Thus, in contrast to some models for host preference, preference and tolerance are not tightly linked at this locus nor is increased tolerance per se sufficient to change preference. Our data are consistent with the previously proposed model that the evolution of D. sechellia as a M. citrifolia specialist occurred through a stepwise loss of aversion and gain of tolerance to M. citrifolia’s toxins

Three SRA-Domain Methylcytosine-Binding Proteins Cooperate to Maintain Global CpG Methylation and Epigenetic Silencing in Arabidopsis

Methylcytosine-binding proteins decipher the epigenetic information encoded by DNA methylation and provide a link between DNA methylation, modification of chromatin structure, and gene silencing. VARIANT IN METHYLATION 1 (VIM1) encodes an SRA (SET- and RING-associated) domain methylcytosine-binding protein in Arabidopsis thaliana, and loss of VIM1 function causes centromere DNA hypomethylation and centromeric heterochromatin decondensation in interphase. In the Arabidopsis genome, there are five VIM genes that share very high sequence similarity and encode proteins containing a PHD domain, two RING domains, and an SRA domain. To gain further insight into the function and potential redundancy among the VIM proteins, we investigated strains combining different vim mutations and transgenic vim knock-down lines that down-regulate multiple VIM family genes. The vim1 vim3 double mutant and the transgenic vim knock-down lines showed decreased DNA methylation primarily at CpG sites in genic regions, as well as repeated sequences in heterochromatic regions. In addition, transcriptional silencing was released in these plants at most heterochromatin regions examined. Interestingly, the vim1 vim3 mutant and vim knock-down lines gained ectopic CpHpH methylation in the 5S rRNA genes against a background of CpG hypomethylation. The vim1 vim2 vim3 triple mutant displayed abnormal morphological phenotypes including late flowering, which is associated with DNA hypomethylation of the 5′ region of FWA and release of FWA gene silencing. Our findings demonstrate that VIM1, VIM2, and VIM3 have overlapping functions in maintenance of global CpG methylation and epigenetic transcriptional silencing

Large genome-wide association study identifies three novel risk variants for restless legs syndrome

Funder: Scottish Government; doi: https://doi.org/10.13039/100012095Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289Abstract: Restless legs syndrome (RLS) is a common neurological sensorimotor disorder often described as an unpleasant sensation associated with an urge to move the legs. Here we report findings from a meta-analysis of genome-wide association studies of RLS including 480,982 Caucasians (cases = 10,257) and a follow up sample of 24,977 (cases = 6,651). We confirm 19 of the 20 previously reported RLS sequence variants at 19 loci and report three novel RLS associations; rs112716420-G (OR = 1.25, P = 1.5 × 10−18), rs10068599-T (OR = 1.09, P = 6.9 × 10−10) and rs10769894-A (OR = 0.90, P = 9.4 × 10−14). At four of the 22 RLS loci, cis-eQTL analysis indicates a causal impact on gene expression. Through polygenic risk score for RLS we extended prior epidemiological findings implicating obesity, smoking and high alcohol intake as risk factors for RLS. To improve our understanding, with the purpose of seeking better treatments, more genetics studies yielding deeper insights into the disease biology are needed

Dual Window Pattern Recognition Classifier for Improved Partial-Hand Prosthesis Control

This page serves as a repository for data associated with my research titled "Dual Window Pattern Recognition Classifier for Improved Partial-Hand Prosthesis Control

The Effect of Wrist Position and Hand-Grasp Pattern on Virtual Prosthesis Task Performance

This page serves as a repository for data associated with my research titled "The Effect of Wrist Position and Hand-Grasp Pattern on Virtual Prosthesis Task Performance