Articles

Global Genomic Diversity: History, Adaptation and Health


Identification: Rotimi, Charles

Credits: None available.

Global Genomic Diversity: History, Adaptation and Health
 
Charles N. Rotimi
National Institutes of Health, USA
 
The global appreciation of the extent of human genomic diversity and the implications for understanding human history and health is growing at a tremendous pace. This success story is due to several factors including improved sequencing technologies and computation infrastructure, lower costs and perhaps more importantly, the engagement of populations with diversity ancestral backgrounds. As a result, we are gaining insights that is improving our understanding of why susceptibility to common diseases varies among individuals, families and populations. Furthermore, we are using this new knowledge to improve the efficacy and safety of therapeutic drugs.  Notably, deeper understanding of global genomic diversity is allowing scientists to address fundamental questions about our origins, our differences, and our similarities. In this presentation, I will provide a brief review of the current knowledge of human genomic diversity and how this knowledge is contributing to our understanding of human evolutionary history, health and the complex issues surrounding group identity including the notion of “race”. Using multiple examples, I will show how genetic adaptations that took place across Africa, particularly against fatal pathogens and ecological forces, have resulted in elevated frequencies of alleles conferring survival advantages detectable in present-day African ancestry individuals on the continent and in the Diaspora. These examples will also illustrate how some of these alleles have become maladaptive in modern-day environments.
 
 
 

Using Multiplexed Functional Assays to Understand the Effects of Genetic Variation


Identification: Starita, Lea

Credits: None available.

Using Multiplexed Functional Assays to Understand the Effects of Genetic Variation
 
Lea M. Starita1,2, Gregory M. Findlay1, Kenneth Matreyek1, Douglas Fowler1,2 , Jay Shendure1,2
1Department of Genome Sciences, University of Washington, Seattle, WA, USA; 2The Brotman Baty Institute for Precision Medicine, Seattle, WA, USA
 
Variants of uncertain significance (VUS) fundamentally limit the utility of genetic information in a clinical setting. The challenge of VUS is best exemplified by the tumor suppressor gene BRCA1. Germline BRCA1 loss-of-function (LOF) variants predispose women to early-onset breast and ovarian cancers. Although BRCA1 has been sequenced in millions of women, the risk associated with most newly observed variants cannot be definitively assigned. Data sharing attenuates this problem but it is unlikely to solve it, as most newly observed variants are exceedingly rare. In lieu of genetic evidence, experimental approaches can be employed to functionally characterize VUS. To date, however, such approaches have only succeeded in providing reliable interpretations for a modest number of variants. Multiplexed functional assays can provide both the throughput and validity necessary to use create and employ functional data at scale. We employed saturation genome editing to assay all possible single nucleotide variants (SNVs) in exons that encode functionally critical domains of BRCA1. Our assay measures cellular fitness in a haploid human cell line whose survival is dependent on intact BRCA1 function. The resulting functional scores for nearly 4,000 SNVs are bimodally distributed and almost perfectly concordant with established assessments of pathogenicity. We have also performed another multiplexed functional assay on the tumor suppressor PTEN and identified many variants that affect protein stability.
 
We predict that these functional scores will be directly valuable for the clinical interpretation of cancer risk based on BRCA1 and PTEN sequencing. Furthermore, we propose that this paradigm can be extended to overcome the challenge of VUS in other genes in which genetic variation is clinically actionable. Multiplexed functional assays may be an important tool to interpret variants for populations where VUS rates are high.
 

Public Perception of Animal Biotechnology


Identification: Van Eenennaam, Alison

Credits: None available.

 

Public Perception of Animal Biotechnology
 
Alison L. Van Eenennaam1, Amy E. Young1
1University of California, Davis, USA
      
Public perception of animal biotechnology is far from straightforward and the lines between animal biotechnology and other issues related to animal use are often blurred. In general, concerns about animal biotechnology are influenced by i) views around the moral status of animals, the boundary between “natural” and “unnatural”, and perceived risks and benefits of animal biotechnology to health and the environment (personal and cultural characteristics); ii) the purpose of the application, the method(s) being used, and the motivation of the research group using animal biotechnologies (research characteristics); iii) the species under consideration (animal characteristics). As such, it is difficult generalize about public perception of animal biotechnology as a discrete category. The use of artificial selection, advanced reproductive techniques, crossbreeding, and genomics to introduce useful genetic variation into breeding programs have elicited little public concern. However, the use of “modern” molecular biotechnologies such as genetic engineering (GE) to introduce useful genetic variation have been associated with considerable pushback.   The first and only GE food animal approval to date, the fast-growing AquAdvantage Atlantic salmon, followed years of regulatory delay partially resulting from the negative public perception of GE. There are a number of new animal biotechnology applications in development which combine knowledge of genomic diversity with modern biotechnologies including gene editing to specifically target traits for animal health and well-being. An open and objective evaluation of both the potential benefits and risks that these applications pose to impacted stakeholders and animals may help to shift public perception; and enable animal breeders to responsibly introduce these new biotechnologies into genetic improvement programs to the benefit of both animal and human health and well-being.
 

 

Therapeutic Approaches to SMA: In the Challenges is a Solution


Identification: Wirth, Brunhilde

Credits: None available.

Therapeutic Approaches to SMA: In the Challenges is a Solution
 
Brunhilde Wirth
Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany
 
Spinal muscular atrophy (SMA), a devastating neuromuscular disorder, affects around 1:6000 people, every 1:35 is carrier in Europe and it is the most frequent genetic cause of infant death. Recently, the first SMA therapy based on antisense oligonucleotides, namely Nusinersen, has been FDA- and EMA-approved. Nusinersen restores the suboptimal full-length SMN2 transcript expression and elevates SMN protein level. SMN is crucial for all cells but particularly for motor neurons and neuromuscular junctions. In the most severe type I form, which accounts for ~60% of SMA patients, who usually carry only two SMN2 copies, the elevated SMN level may be still insufficient to restore motor neuron function lifelong. We show that genetic SMA protective modifiers might provide additional independent functional support for motor neuron function.
Here I will talk about two SMA protective modifier, identified in asymptomatic SMN1-deleted individuals carrying either 3 or 4 SMN2 copies. Plastin 3 (PLS3), an F-actin binding and bundling protein, which rescues SMA by overexpression and Neurocalcin delta (NCALD), a neuronal calcium sensor protein, which counteracts SMA by suppression. We found that both, PLS3 overexpression or NCALD suppression protect against SMA across species including zebrafish and mice. Moreover, both modifiers show a rescuing effect using combinatorial therapies - low dose Nusinersen and PLS3 overexpression or NCALD suppression - in severely-affected SMA mice. Lastly, both modifiers hinted us towards the main cellular mechanism in SMA, which we believe is impaired endocytosis, and which is restored by both modifiers. Recently, we identified a third protective modifier, calcineurin EF-hand protein 1 (CHP1), that interacts with PLS3 but is a calcium sensor like NCALD and protects SMA by downregulation. Most importantly, CHP1 reduction restores impaired endocytosis in SMA, by inhibiting calcineurin an important phosphatase that dephosphorylates all major proteins involved in endocytosis.
 
These three protective SMA modifiers not only unveiled the most likely disturbed pathway in SMA but also opened new avenues for therapy.
 

Genomics: A Half-Full Glass in One Health


Identification: Bonfoh, Bassirou

Credits: None available.

 

Genomics: A Half-Full Glass in One Health
 
Bassirou Bonfoh
Centre Suisse de Recherches Scientifiques en Côte d'Ivoire (CSRS)/ Afrique One-African Science Partnership for Intervention Research Excellence (ASPIRE)
      
It is undeniable that genomics has accelerated the inventory and knowledge on living organisms and the potential for increasing food production (e.g. new varieties, species) and human and animal health (e.g. diagnostic tools, vaccines, drugs). However, the health system has so far, not taken advantage of the potential of genomics. Observations show that low-income countries lack the necessary capacity to introduce animal and medical genetics services neither effective regulation and oversight of the use. We emphasize the huge potential that genomics offers to accelerate the knowledge on the adaptation of the endemic livestock species to threats, their resistance to pathogens and the evidence of the inextricable link between human, animal and environment. Based on two decades of experience in livestock production and integrated health systems in Africa, we provide what are genomics outcomes, and how the technology could accelerate sustainable livestock production systems as well as generate knowledge for quick responses to endemic and emerging diseases. The technology adoption and the behavior change towards the perception of genomics will certainly come when meanings are provided and the socio-cultural incentives are reconnected to genomics products.
 
Acknowledgments: African Academy of Sciences (AAS) Alliance for Accelerating Excellence in Science in Africa (AESA), the New Partnership for Africa's Development Planning and Coordinating (NEPAD) Agency, the Wellcome Trust [107753/A/15/Z] and the UK government (DFID).
 

 

Genetic Diagnosis of Intellectual Disability


Identification: Brunner, Han

Credits: None available.

Genetic Diagnosis of Intellectual Disability
 
Han G. Brunner
Radboud UMC, Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Nijmegen,The Netherlands; Maastricht University Medical Center, GROW School for Oncology and Developmental Biology, Maastricht, The Netherlands
Han.Brunner@RadboudUMC.nl
 
Severe intellectual disability with an IQ of less than 50 affects approximately 1 in 200 newborns.
Recent technological advances have clarified the genetics of ID: There are at least 1000 genes involved in causing ID. While autosomal recessive ID predominates in inbred populations, new mutations are by far the most common cause of ID in outbred populations. Whole exome trio sequencing and array analysis for structural variants can clarify up to 60% of all cases of severe ID in the Dutch population, with the majority being due to de novo events. This has implications for our ability to predict and prevent such events.  Studies of spontaneous new mutations in humans show that paternal mutations predominate by about 4:1. There is an increase in mutations with age, which is most marked in males. Also, the types of mutations that occur are slightly different between males and females. There is a large contrast with consanguineous populations where homozygosity for recessive variants predominates. The total number of known recessive and dominant ID genes is similar. Collectively more than 1000 ID genes are known, suggesting that a significant fraction of all human genes are relevant and necessary for optimal brain function. Since most ID genes are now known, and since most disruptive events affect the coding sequence, whole genome and whole exome sequencing coupled with microarrays for detection of copy number variations can conclusively diagnose a large proportion of patients. Progress will rely on better technology, more accurate calling and interpretation of genomic variants, and the development and application of more complex inheritance schemes, notably autosomal dominant inheritance with reduced penetrance, and polygenic scenarios.

Relevance of Primate Evolution to Human and Animal Diversity


Identification: Eichler, Evan

Credits: None available.

Relevance of Primate Evolution to Human and Animal Diversity
 
Evan E. Eichler
Department of Genome Sciences and Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA

Advances in sequencing technology are beginning to transform our understanding of genetic diversity. Using single-molecule, real-time (SMRT) sequencing technology, I will show how much of the missing structural variation of great ape genomes can now be resolved. New technologies highlight how radically specific regions have changed even between closely related species, such as chimpanzee and human, leading to structural variation important for the evolution of our species. In particular, great ape-duplicated sequences show extraordinary sequence complexity and are important sources for gene innovation and rearrangement associated with neurocognitive and neurodevelopmental diseases. I will present an overview of the evolution of great ape segmental duplication, their association with core duplicons, and their potential to generate neofunctional paralogs through segmental duplication fusion and truncation. I will highlight examples of novel genes that have evolved specifically within the human lineage where functional data suggest they have contributed to unique neuroadaptive aspects of humans, including an increased density of excitatory/inhibitory synapses and the expansion of the frontal cortex. The dynamic nature of duplicated regions and our ability to access their variation has broader ramifications for human health, diversity, and the emergence of adaptive traits in animals.

Using Genetics to Investigate the Developmental Origins of Health and Disease


Identification: Evans, David

Credits: None available.

Using Genetics to Investigate the Developmental Origins of Health and Disease
 
David M. Evans on behalf of the Early Growth Genetics (EGG) Consortium
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland
 
Low birth weight is observationally associated with poor perinatal outcomes and increased future risk of a range of cardio-metabolic diseases, in both first world and developing countries. However, it remains unclear which maternal exposures during pregnancy cause low birthweight (i.e. via intrauterine mechanisms) and whether low birthweight itself causes increased risk of cardio-metabolic disease in later life (the so-called Developmental Origins of Health and Disease “DOHaD”).
 
In this talk, I outline a method called Mendelian randomization which leverages results from genome-wide association studies to estimate the causal effect of environmental exposures on medically relevant outcomes. Because Mendelian randomization can be performed using publically available summary results data from genome-wide association studies, the method represents a cost-effective complement to randomized controlled trials in investigating causality, which in contrast may be expensive, impractical or unethical to implement.
 
In this talk I show how we have used Mendelian randomization to investigate whether the observational correlation between offspring birthweight and a range of maternal environmental exposures, and between low offspring birthweight and future risk of cardio-metabolic disease reflect causal relationships. I utilize results from a large trans-ethnic genome-wide association analysis of birthweight (N > 300,000) that we have performed in the UK Biobank and Early Growth Genetics Consortium, where we have used advanced statistical genetics methods to decompose genetic effects on birthweight into maternal and fetal-mediated components. I discuss how Mendelian randomization approaches can be used to inform health policy and how the approach can be used to translate findings from genome-wide association studies into clinical practice.

Comparative analysis of the chicken IFITM locus reveals positive selection and evolution of the locus.


Identification: Fife, Mark

Credits: None available.

Comparative Analysis of the Chicken IFITM Locus Reveals Positive Selection and Evolution of the Locus
 
Irene Bassano1, Swee Hoe Ong2, Maximo Sanz-Hernandez3, Michal Vinkler4, Olivier Hanotte5, Ebele Onuigbo6, Paul Kellam1,7, Thomas Whitehead8, Mark Fife8
 
1Imperial College London, Department of Medicine, Division of Infectious Diseases, Wright Fleming Wing, St Mary's Campus, Norfolk Place, London, UK; 2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK; 3Imperial College London, Department of Life Sciences, South Kensington, London UK; 4Charles University, Faculty of Science, Department of Zoology, Prague, Czech Republic; 5 International Livestock Research Institute (ILRI), Ethiopia, Addis Ababa, Ethiopia; 6Department of Pharmaceutical Microbiology and Biotechnology, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu State, Nigeria; 7Kymab Ltd, Babraham Research Campus, Cambridge; 8The Pirbright Institute, Woking, UK
 
The chicken IFITM (chIFITM) locus is clustered on chromosome 5 and contains five genes, of which three are known to be interferon stimulated genes (ISGs) with potent antiviral activity, namely chIFITM1, 2, 3. These proteins restrict viral infections by blocking fusion of the viral and host membranes, thereby interfering with viral entry and replication. Their biological activity is well documented in several animal species, but their genetic variation and biological mechanism is less well understood. Here we report the complete sequence of the IFITM locus from a wide variety of chicken breeds to examine the detailed pattern of genetic variation of the locus. We have generated chIFITM sequences from commercial breeds, indigenous chickens from Nigeria and Ethiopia, European breeds and inbred chicken lines from The Pirbright Institute, totalling of 211 chickens. Our data reveal that the chIFITM locus does not show structural variation across the populations analysed. However, SNPs in functionally important regions of the proteins were detected, in particular the European breeds and indigenous birds from Ethiopia and Nigeria, revealing some SNPs were simultaneously under positive selection. Together these data suggest that IFITM genetic variation may contribute to the capacities of different chicken populations to resist virus infection.
 
This research was supported by the BBSRC (Animal Health Research Club) grant Number BB/L003996/1 and BBSRC grant BBS/OS/GC/000015/2.
 
Keywords: variant calling, SNPs, INDELs, GATK, positive selection
 
 
 

Genomics to Enhance Poultry Health Using Biodiversity


Identification: Lamont, Susan

Credits: None available.

Genomics to Enhance Poultry Health Using Biodiversity
 
Susan J. Lamont1, George Aning2, Jack C. M. Dekkers1, Rodrigo Gallardo3, Boniface Kayang2, Terra Kelly3, Peter Msoffe4, Amandus P. Muhairwa5, Augustine Naazie2, Huaijun Zhou3      
1Iowa State University, Ames, Iowa, USA, 2University of Ghana, Accra, Ghana, 3University of California-Davis, California, USA, 4University of Dodoma, Dodoma, Tanzania, 5Sokoine University of Agriculture, Morogoro, Tanzania
 
Newcastle disease virus (NDV) causes a major constraint to efficient production of healthy poultry in developing countries and requires continuing costs to control in developed countries. Feasibility of vaccination is limited in many low-resource areas of the world. Thus, our project seeks to identify the genetic basis of response to NDV in chickens. With this information, the natural resistance characteristics of locally adapted populations can be enhanced by genetic selection. To achieve this translational goal, we studied three distinct types of chickens: inbred, commercial and African ecotypes. Two highly inbred research lines with differential response to NDV served as a discovery platform using RNA sequencing to identify genes and pathways that respond to NDV infection. A commercial layer line with global distribution was used to identify genomic regions and genes associated with response to NDV by using both a high-density (600K) SNP panel and candidate gene typing. Chickens of six ecotypes, three each from Ghana and Tanzania, were genotyped with the 600K SNP panel to determine genome-wide associations with response to NDV vaccination and with virulent NDV challenge. Results from these nine biodiverse populations were used to develop a low-density SNP panel for future validation and use in improving NDV response in the African ecotypes by genomic selection. Improving natural resistance to NDV will contribute to healthier poultry and better global security of a major protein source for the human diet and, in developing countries, will aid empowerment of women by increasing their financial income. This study was funded by the USAID Feed the Future Innovation Lab for Genomics to Improve Poultry.