So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Human biochemical genetics

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.

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Analysis of protein-coding genetic variation in 60,706 humans

The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.

/pdf/the-uk-biobank-resource-with-deep-phenotyping-and-genomic-2fs3jmksld.pdf

The UK Biobank resource with deep phenotyping and genomic data

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

/pdf/ld-score-regression-distinguishes-confounding-from-58i9nc2cv7.pdf

LD score regression distinguishes confounding from polygenicity in genome-wide association studies :

An object-detection system suitable for use in an automated vehicle includes a transceiver, and object-detector, and a controller. The transceiver is suitable to install on a host-vehicle. The transceiver is used to receive an indicated-location of an object proximate to the host-vehicle. The object-detector is suitable to install on the host-vehicle. The object-detector is used to detect a relative-location of the object relative to the host-vehicle. The controller is in communication with the transceiver and the object-detector. The controller determines a confirmed-location of the object relative to the host-vehicle based on the indicated-location and the relative-location. Determining the confirmed-location of the object allows for selecting from a variety of optimized algorithms to better track subsequent expected motion of the object, and reducing the risk of unnecessary or erratic action by the host-vehicle caused by hacking of the wireless-transmission or deliberate malicious content in the wireless-transmission.

V2x object-location verification system for automated vehicles

A roadway-infrastructure-maintenance system using automated-vehicles to maintain a roadway includes an image-device and a controller. The imaging-device is suitable to mount on a host-vehicle. The imaging-device is used to detect an infrastructure-feature proximate to a roadway traveled by the host-vehicle. The controller is in communication with the imaging-device. The controller is configured to determine a need-for-maintenance of the infrastructure-feature. The system may include a digital-map that indicates an expected-presence of the infrastructure-feature, and the need-for-maintenance may be indicated when the infrastructure-feature is not-detected as expected. The system may also include a transmitter in communication with the controller. The transmitter may be used to communicate the need-for-maintenance to a maintenance-organization.

Roadway-Infrastructure-Maintenance System Using Automated Vehicles

This specification defines a payload format for communicating sensor and actuation information. The payload format is transported using the publish-subscribe mechanism described in XEP-0060.

Sensor-Over-XMPP

An infrastructure-device status-verification system suitable for use by an automated vehicle includes a transceiver, an object-detector, and a controller. The transceiver is suitable to install on a host-vehicle. The transceiver is used to receive an indicated-status of an infrastructure-device. The object-detector is suitable to install on the host-vehicle. The object-detector is used to determine a detected-status of the infrastructure-device. The controller is in communication with the transceiver and the object-detector. The controller determines a confirmed-status of the infrastructure-device based on the indicated-status and the detected-status. The system provides for increased confidence and security regarding information about the status of an infrastructure-device such as the traffic-signal (e.g. red, yellow, and green), thereby avoid miss-information caused by, for example, hacking or spoofing of V2I communications from the infrastructure-device, and overcome instances when the field-of-view between the object-detector and the infrastructure-device 26 becomes occluded after the confirmed-status has been established or determined.

Gaurav Bhatia

Papers

V2x object-location verification system for automated vehicles

Roadway-Infrastructure-Maintenance System Using Automated Vehicles

Sensor-Over-XMPP

Infrastructure-Device Status-Verification System For Automated Vehicles

Synthesis, in vitro anticancer activity and reactions with biomolecule of gold(I)-NHC carbene complexes