MAY 11, 2016 6:00 AM PDT

Natural Human Gene Knockouts and the Discovery of New Drug Targets

Speaker

Abstract

It has been estimated that every human being carries ~20 rare “natural human gene knockouts”-DNA variants in protein-coding regions of the genome that partially or completely inactivate gene products. When coupled with information about clinical phenotypes, these natural human gene knockouts can illuminate biological function of geness and further our understanding of diseass. In select cases, “protective” gene-inactivating mutations may guide the way to new therapeutic targets or confirm existing targets. With the advent of next generation sequencing facilitating genomics on massive scales, properly powered studies of human knockouts are finally possible. Here, we describe an integrated approach to sequencing-based discovery of naturally occurring human knockouts that spans genetic trait architectures, from small collections of highly related individuals with extreme phenotypic traits, to geographically- and reproductively-isolated “founder” populations harboring frequent instances of highly impactful alleles, to large scale sampling of outbred populations with rich “real-world” phenotypic data captured in electronic medical records. In collaboration with the Geisinger Health System and academic groups worldwide, we report early findings from whole exome sequencing of over 100,000 individuals spanning these population architectures and study designs. We find that the majority of genes encoding drug targets harbor mutations that are predicted to partially or completely inactivate their gene products. We highlight examples of protective and harmful clinical associations with inactivating mutations in these genes that support and invalidate therapeutic targets. We also describe exome-wide scans for gene-inactivating mutations that nominate novel candidate genes and targets in multiple clinical traits and diseases. These early insights suggest that large-scale discovery of human gene knockouts will contribute to the next wave of drug target discovery and validation.


Show Resources
You May Also Like
SEP 14, 2021 7:00 AM PDT
C.E. CREDITS
SEP 14, 2021 7:00 AM PDT
Date: September 14, 2021 Time: 7am PDT, 10am EDT, 4pm CEST A conventional thermal cycler has long been a commodity product in the lab and end-point PCR techniques can be completed almost wit...
MAY 11, 2021 10:00 AM PDT
C.E. CREDITS
MAY 11, 2021 10:00 AM PDT
Date: May 11, 2021 Time: 10:00zm PDT Your samples are some of the most valuable assets in the laboratory. After spending countless hours on extraction and preparation, your conclusions could...
FEB 24, 2021 10:00 AM PST
C.E. CREDITS
FEB 24, 2021 10:00 AM PST
DATE: February 24, 2021 TIME: 10am PST Automated lab instruments such as liquid handlers and cell sorters are increasingly common in all types of laboratories, driving fast results for labor...
MAR 16, 2021 10:00 AM PDT
C.E. CREDITS
MAR 16, 2021 10:00 AM PDT
Date: March 16, 2021 Time: 10:00am (PST) Scientific progress and breakthroughs today are often too expensive for most institutions to acquire. Each year, the National Institutes of Health (N...
APR 01, 2021 8:00 AM PDT
C.E. CREDITS
APR 01, 2021 8:00 AM PDT
Date: April 01, 2021 Time: 8:00am (PST), 11:00am (EST) Generating therapeutic antibodies is far more challenging than obtaining antibodies that merely recognize their targets. Engineering po...
JUN 09, 2021 7:00 AM PDT
C.E. CREDITS
JUN 09, 2021 7:00 AM PDT
Date: June 9, 2021 Time: 09 June 2021, 7am PDT, 10am EDT, 4pm CEST cells with dramatic implications on the validity of past cell culture related research. The fact that at least 509 cell lin...
MAY 11, 2016 6:00 AM PDT

Natural Human Gene Knockouts and the Discovery of New Drug Targets


Specialty

University

Research And Development

Gene Expression

Molecular Genetics

Dna

Big Data

Cancer Research

Tumor

Biomarkers

Cancer

Earth Science

Oncology

Gene Sequencing

Life Science

Drug Discovery

Geography

Asia50%

Europe50%

Registration Source

Website Visitors100%

Job Title

Student75%

Medical Laboratory Technician25%

Organization

Academic Institution75%

Manufacturer - Other25%


Show Resources
Loading Comments...
Show Resources