Phenotyping and Experimental Medicine Centre for naturally occurring Gene Knock-Outs in Humans

Lead Research Organisation: Queen Mary, University of London
Department Name: Sch of Medicine & Dentistry


To improve health care, efforts are increasingly focused upon early diagnosis, approaches to disease prevention and the more effective use of available or emerging treatments. Sequencing of the genetic material (genome) is making a powerful contribution to this strategy. The information provided by this methodology seeks to identify individuals at greatest risk for disease, those most likely to benefit from particular interventions and to verify whether new therapies are hitting the key disease target. We plan to accelerate the use of genetics in medicine, through the study of genome in cases of parental relatedness (e.g. cousin marriage), which is common in certain UK ethnic groups including the health disadvantaged British-Bangladeshi and British-Pakistani communities. Recent sequencing studies show that humans whose parents were unrelated carry (mostly single copies) of ~100 genetic variants that partially switch off selected genes in their human genome. In individuals with parental relatedness, some of these variants will be seen on both copies of the genome and thus certain genes will be completely inactivated. Finding such genetic variants and examining their consequences and benefits can lead both to an increased knowledge of how human genes work and an improved understanding of the health consequences of genetic variation in the relevant communities. We have commenced a large-scale community based programme studying as many as 25,000 apparently healthy individuals. Of these, individuals found to possess natural gene inactivating variants considered to be of biomedical importance, will be invited for detailed medical assessment. This may include blood or skin biopsy samples; resting and exercise blood pressure and heart rate measurements; quantification of body composition and brain and body imaging, such as MRI scans. These studies will require the development of a purpose constructed clinical research facility, adjacent to the major hospital at Whitechapel, as the study is founded upon East London (UK) populations. The facility will allow substantial engagement of the local East London communities and enable coordination of more highly specialised assessments, to be undertaken with and through other leading medical research centres across the UK and abroad

Technical Summary

Economically efficient delivery of innovation in health care will require significant advances in the molecular pathogenesis, integrated with improvements in early disease detection, adoption of prediction and prevention of ill-health and delivery of precision in therapeutic interventions.
Whilst proven to support these endeavors, human genetics remains limited by inadequate functional annotation and stochastic discovery of bio-medically important regions of the genome. Recent studies indicate that outbred human genomes contain ~100 genuine complete loss of function (LoF) variants. Consanguineous, whether parental and/or historic, individuals carry
genomic regions identical- by-descent (autozygous), thus rare frequency variants occur as homozygous genotypes. Parental relatedness such as cousin marriage is common in certain UK ethnic groups. Dedicated clinical research facilities for the bio-medical characterisation and deep-phenotypic assessment of healthy adult individuals enriched for naturally occurring "homozygous knockout" alleles will provide for substantial advances for human biology, and sustain a rich resource for UK human experimental medicine.
Our proposal complements existing rare disease sequencing programmes, national sequencing studies (UK10K, DDD), and other UK BioResources (Cambridge and NIHR BioResources, TwinsUK and UK BioBank) and existing experimental medicine research infrastructure (NIHR/Wellcome Trust Clinical Research Facilities)
The development of a dedicated gene centric centre for clinical research will aid substantial engagement amongst East London communities and increase our broader and existing public engagement activities around genetics and genomics.

Planned Impact

The outputs from the development of a Phenotyping and Precision Medicine Centre for naturally occurring Gene Knock-Outs in Humans will impact upon the local national and global population, the broader bio-medical research community, and the commercial private sector. The programme already has made impact in public engagement and design of new early and middle years educational packages.
The local population in the East of London is by every metric amongst the most health deprived across the UK. The community is also substantial window for the challenges of global health. Whilst many factors contribute to health improvement, a large scale public engagement programme supported by 'local' and embedded facilities for clinical assessment, attracting global attention of the bio-medical and life science community, is a powerful stimulant to health awareness, programmes of illness prevention and access to innovative therapies. This would also provide a further encouragement to participation to a community that, by enlarge, would be keen to interact within a local facility but would be less able to travel even a few miles. Creation of facilities that enable access to reagents from subjects with human gene knock-outs, including whole subject physiology studies, including fundamental human and comparative genomics (e.g. collaboration with Harvard/MIT Broad Institute, Boston USA), model systems biologists, human physiologists, clinician scientists committed to experimental medicine (NIHR/Wellcome CRFs and BRCs) and the clinical community developing strategies for stratified and precision medicine. Our anticipation that identification of subjects with human complete gene knock-outs will be of substantial interest to the pharmaceutical industry has been confirmed through workshops and cluster agreements, (see letters of support and collaboration). Human gene knock-outs provide insights for molecular redundancy, target identification and most critically target validation. A number of profound novel therapeutic agents have been evolved through the detailed phenotypic assessment of human gene knockouts (e.g. antibodies to PCSK9, as a new class of drugs that reduce LDL cholesterol levels). Importantly, a number of these therapies have emerged and moved through to phase III clinical trials in a much truncated timescale: 6-7 years compared to the average of 12-14 years for molecules lacking target validation. Hence, access to subject data and co-creation of experimental medicine studies will drive therapeutic innovation across the commercial private sector, supporting local and national wealth creation.
Finally, we are not aware of a comparable programme within the UK that is focused on the scaled identification and characterization of subjects with human gene knock-outs. This emphasizes the need for local clinical research facilities capable of empowering the local communities to participate with a programme with global impact. Large scale sequencing programmes have been initiated in several countries with high levels of consanguinity, including Qatar and Saudi Arabia and whilst we consider these programmes to be synergistic, linkage to a a national health care system, offers unique and highly competitive advantages to a UK based initiative.