1. Excellence

Genomic Atlas of Latvia (GAoL) is a pilot project and it represents a new direction for better disease detection, prognosis and therapy development.

1.1 Objectives

1) The major objective is to develop GAoL , specifically that of Latvians, Russians and Jews which reside in Latvia. For this purpose we will collect six hundred families of all three subgroups,200 from each group, prepare their pedigrees, isolate genomic DNA from each ethnic representatives and subject them to full DNA sequence about 3×10⁹ base pairs.

2) The full genomic DNA sequence will be further analysed using advanced bioinformatic tools.

3) Bioinformatic analysis will allow us to identify genomic DNA signatures (GDSs) which correlate with specific pathology. These novel GDSs will be patentable and used for individual identification of predisposed to this pathology. Specifically we will focus for GDSs correlating with neoplastic and with neurodegenerative diseases.

1.2 Relation to the work programme

Our proposal relates to the Understanding disease: systems medicine

PHC-02-2015.

The development of new evidence-based treatment relies on an improved understanding
of the very complex pathophisiology of the diseases. System medicine approaches have the potentional
to tackle this complexity through the integrational variety of biological and medical research data
and computrational modeling.We will use an European collaborative approach to assamble the necessary multidisciplinary expertise (e.g. biology, medicine,mathematics, computaional technology) for implementing biomedicine approach.
The exponential growth in generation of large amounts of genomic data from biological samples has driven the emerging field of systems medicine. This field is promising because it improves our understanding of disease processes at the systems level. However, the field is still in its young stage. There exists a great need for novel computational methods and approaches to effectively utilize and integrate various -omics data. NGS-based methods to characterize genetic variation differential expression, and other types of biological information have dramatically expanded the generation of biological data (16)

In the past, blockbuster drugs worked mostly for single-cause diseases and for ‘the average person’. However, it is now clear that many diseases are multifactorial and cannot be treated with a single medicine. Moreover, recent technologies have shown us that the human being is complex and that humans can differ a lot from each other. Systems Medicine can be applied well in oncology, cardiovascular diseases, neurodegenerative diseases, ageing, immunology, inflammation and chronic disorders.

An important problem in health care today is that many patients do not respond to medication. The estimated cost of ineffective medication in the US alone is estimated at $350 billion per year (17)

Variable treatment response is also an important reason for the enormous costs of drug development.

Reasons include that common diseases involved altered interactions between thousands of genes and environmental factors, in combinations that may vary between patients that do or do not respond to treatment. It would be very difficult to gain understanding of such alterations by studying individual genes or factors one by one. Systems Medicine offers solutions to understanding such complex alterations.

Identification of novel GDSs is crucial and instrumental for the development of novel tools which in their turn will lead to improve understanding of pathophysiology of diseases.

Identification of novel GDSs will close the knowledge gap in disease ethiology and will provide innovation in the development of evidence based treatment. In this context novel GDSs will lead to better understanding of the mechanisms common to several diseases such as cancer and neurodegenerative diseases.

This research will result in DNA sequence databases of different ethnic background with or without specific pathology. These databases will contain vast genomic and genealogical verifiable information.

Sequencing technologies have evolved rapidly over the past 5 years. Semi-automated Sanger sequencing has been used in clinical testing for many years and is still considered the gold standard.However, its limitations include low throughput and high cost, making multigene panels laborious and expensive. Recent technological advancements have radically changed the landscape of medical sequencing. Next-generation sequencing (NGS) technologies utilize clonally amplified or single-molecule templates, which are then sequenced in a massively parallel fashion. This increases throughput by several orders of magnitude.

NGS technologies are now being widely adopted in clinical settings. Three main levels of analysis, with increasing degrees of complexity, can now be performed via NGS: disease-targeted gene panels, exome sequencing (ES), and whole genome sequencing (WGS). Disease-targeted gene panels interrogate known disease-associated genes.

WGS covers both coding and noncoding regions. Given the huge amount of sequence data produced by NGS platforms, the development of accurate and efficient data handling and analysis pipelines is essential.

Targeted NGS panels represent the logical extension of current sequencing tests for genetically heterogeneous disorders. By limiting the content of the test to just the regions relevant to a given disease, the resulting data usually have higher analytical sensitivity and specificity for detecting mutations. It must be more appropriate to initiate testing with disease-targeted panels. (2)

This is an exciting step forward, but the overwhelming complexity of the information generated from these tests means our current practices of conveying genetic information to the family must be carefully considered. Despite the challenges, a genetic diagnosis in a family has great benefit both in reassuring unaffected family members and removing the need for lifetime clinical surveillance. (3)

A number of options exist to address deficits in the funding of translational research, particularly for oncogenomic gene expression profiling. The goal of personalized risk assessment necessitates both research progress (eg, in whole genome sequencing, as well as provider education in the differentiation of low- vs high-risk status. The public health approach supports an emphasis on genetic test validation while endorsing clinical translation research inclusion of an environmental and population-based perspective. (4)

A genetic diagnosis often leads to significant alterations in treatment, allows better prediction of disease prognosis and progression, and has implications for family members (5)

One of the current goals of genetic research is to use genomic information to further our understanding of common complex diseases. As insight into common genetic variation has expanded enormously and the technology to identify more rare variation has become available, we can utilize these advances to gain a better understanding of disease etiology. This will lead to developments in personalized medicine and P4 healthcare. (6)

1.3 Concept and approach

Our approach will help to understand the complexity of clinical fenotypes of multifactorial diseases and their co-morbidities.

Our approach will focus on WGS of three ethnic European populations : Latvians, Russians and Jews residing in Latvia. We will collect genealogical, medicobiological / clinical data on about 200 pedigrees of each ethnic group. Comparative bioinformatic analysis of WGS will allow us to identify GDSs,associated with specific pathologies.

We will concentrate on neoplastic diseases and on neurodegenerative diseases,such as Alcheimer, Parkinson disease. These newly identified GDSs, novel genomic markers will be patentable and employed further for many others European ethnic populations.

These newly discovered genomic markers will significantly adbvance our understanding of the complexity of clinical fenotypes of such miultifactorial diseases as cancers and neurodegenerative diseases.

We will use application of systems medicine approach and integrate by medical and clinical data to produce and to refine disease models. The predictive value of such model will be validated in well-fenotyped patient cohorts, taking due account of gender.
Our approach will lead to a better disease detection,prognosis and therapy development. System
medicine tools and approaches will be tailored for medical research and clinic wich represent an improvement over established practice.

The overall concept underpinning this project is a ready availability of DNAs sequences and bioinformatic analysis. Recently, the cost of full DNA sequencing of individual genome dropped from 500000$ and reached 1000 $ and will further fall down. The time of full genomic sequencing is close to several hours. Bioinformatic analysis will take much more time and it depends on how full medical/clinical and genealogical data will be collected.

The diversity of genomic variations exists among different ethnic populations. Information on population-specific genomic variants provides important insights to link between genotypes and phenotypes. To facilitate genomic medicine research, GAoL aims to detect and characterize sequence variations enriched in the coding regions of the genome. We believe the study will contribute valuable information that will have an impact on medical as well as population genetics.

The allelic heterogeneity emphasizes the importance of including diverse populations in future genetic association studies of complex traits for example such as lipids; furthermore, diverse ancestral origins across populations argues that additional knowledge can be gleaned from multiple populations.

The main idea of this approach is the feasibility of identifying unique ethnic signatures and correlating them with specific pathology. Development of these novel digital markers, the GDSs will serve as novel markers indicating ethnic identity and predisposition of individuals with specific pathologies. Combining clinical, genomic and genealogical considerations will result in development of novel and powerful markers in disease determination and progression.

Ashkenazi Jews (AJ), identified as Jewish individuals of Central- and Eastern European ancestry, form the largest genetic isolate in the United States. AJ demonstrate distinctive genetic characteristics including high prevalence of autosomal recessive diseases and relatively high frequency of alleles that confer a strong risk of common diseases, such as Parkinson’s disease and breast and ovarian cancer. Several recent studies have employed common polymorphisms to characterize AJ as a genetically distinct population, close to other Jewish populations as well as to present-day Middle Eastern and European populations. Previous analyses of recent AJ history highlighted a narrow population bottleneck of only hundreds of individuals in late medieval times, followed by rapid expansion.(7)

Our study is the first full DNA sequence dataset available for Latvian, Russian genomes and also Jews living in Latvia. With this comprehensive catalog of mutations present in these populations, we will be able to more effectively map disease genes onto the genome and thus gain a better understanding of common disorders. We see this study serving as a vehicle for personalized medicine and a model for researchers working with other populations.

Pharmacogenetics is being used to develop personalized therapies specific to subjects from different ethnic or racial groups. To date, pharmacogenetic studies have been primarily performed in trial cohorts consisting of non-Hispanic white subjects of European descent. A «bottleneck» or collapse of genetic diversity associated with the first human colonization of Europe during the Upper Paleolithic period, followed by the recent mixing of African, European, and Native American ancestries, has resulted in different ethnic groups with varying degrees of genetic diversity. Differences in genetic ancestry might introduce genetic variation, which has the potential to alter the therapeutic efficacy of commonly used therapies. (8)

Our project is situated in the spectrum from «idea to application» .Although novel GDSs after being patented could be situated at » lab to market» position.

Our project will be linked to the international research in innovation activities in Latvia, Russia, USA and Israel.

Our project will require research demonstration and piloting of relevance of these novel pathology based GDSs.

We will also explore whether these GDSs are gender and sex affected. (http://ec.europa.eu/research/science-society/gendered-innovations/index_en.cfm)

In addition to digital GDSs we will attempt to correlate them with individual dermatoglyphic patterns.

Identification of an individual is a process based on scientific principles mainly finger printing and DNA fingerprinting. Dermatoglyphics patterns form on finger pads and the palm prenatally and remain unchanged throughout the life. Characteristic epidermal ridge pattern are formed during the third or fourth month of the foetal life.

Dermatoglyphics is the study of pattern of fine ridges on fingers and palm. It is important as unique most human traits, it is not affected by age, detailed structure of individual ridges is extremely variable and throughout post natal life they are not affected by the environment.

Advantage of including dermatoglyphic (DGDSs) is the simplicity and the reliability of recording dermatoglyphic patterns, fingerprinting, and low cost determination of dermatoglyphic patterns using special fingerprint scanner which is proved its reliability. (11)

One of us (Dr. Boris Onischuk) has a personal successful experience with this technology.
In addition only FBI collects only 14000 fingerprints in a week, thus accumulating huge database of unique genetic traits.

Recently, biometrics has been shown very useful in the law enforcement and intelligence communities by FBI.

The FBI has long been a leader in biometrics. They’ve used various forms of biometric identification since earliest days, including assuming responsibility for managing the national fingerprint collection in 1924. More recently, the Bureau’s Science and Technology Branch created the Biometric Center of Excellence (BCOE) to strengthen their ability to combat crime and terrorism with state-of-the-art biometrics technology.(10)

Recently all three countries Russia, Latvia, Israel have successfully adopted biometric technology. Biometric passports and visas are already used in most European countries.

It is important to note, that no linkage has been established yet between GDSs and dermatoglyphic patterns.

Our proposal will significantly help to establish such linkage, which would be patentable and widely used in medical, biological and cognitive analysis and performance to identify predispositions to diseases, or diminished/elevated cognitive and physical abilities. All this will become in integral part of the 21-cent. personalized medicine.

1.4 Ambition

Earlier results of this project will provide breakthrough beyond the state of the art. The ground-braking nature of our objectives and concepts involved will bring the medico-biological research significantly closer to personalized medicine. Digital analysis of individual human genomes and the dermatoglyphic analysis correlated with pathology and abilities will revolutionize this field and make it evidence-based, precised, and predictable.

Complex traits are multifactorial phenotypes and are the result of numerous genes, environmental factors, and their interactions. The genetic dissection of complex traits has accelerated recently with advances in genomic technologies. In pharmacogenomics, the complexity of the processes that affect drug response and toxicity makes the selection of the right phenotype for study challenging. Once the right phenotype is selected, the genetic contribution to the trait is estimated using familial aggregation and heritability studies. This is followed by established methods of linkage or association analysis to identify the genetic variant associated with the trait. (12)

Although whole human genome sequencing can be done with readily available technical and financial resources, the need for detailed analyses of genomes of certain populations still exists. Whole genome sequencing is a valuable tool for understanding variations in the human genome across different populations. Detailed analyses of genomes of diverse origins greatly benefits research in genetics and medicine and should be conducted on a larger scale.

Understanding DNA sequence variation sheds light on the relationship between genotype and phenotype, and WGS has proven to be a powerful tool.

Latest HapMap results cover 1,184 individuals from 11 populations and involve genotyping of common SNPs and sequencing of relatively small regions (~100 Kbp). Overall, HapMap and similar consortiums have catalogued over 10 million SNPs, 3 million indels, and associated linkage-disequilibrium patterns.

This ongoing process of identifying genomic variants has paved the way for genome-wide association studies over the past few years, and disease susceptibility has been found to be associated with these variants for over a thousand regions so far. This accumulated knowledge in the post-genomic era is opening new frontiers in medicine and public health using a personalized approach, and WGS is becoming the method of choice with its ability to construct a nearly complete picture of identifying structural variations.

Despite the increasing use of human WGS for both research and clinical purposes, there remain two areas that require further attention: 1) there are populations for which WGS discovery efforts have not been done; 2) very few of the human WGS performed so far provide high-coverage sequencing results with detailed analysis. (13)

In order to provide a better and more complete picture of human genome variations, we believe more individuals from diverse populations need to be sequenced and analyzed at a sufficiently detailed level.

The innovation potential of our proposal is obvious. Wide use of patentable GDSs and DGDSs eventually will become available to the market.

Breast cancer testing BRCA1, BRCA2 testing for melanoma and Alzheimer’s disease only few examples of the DNA testing already available.

A recipient of the prestigious 2014 Lasker award Mary-Claire King is claiming that her 20 years’ experience working with families with cancer-predisposing mutations in BRCA1 and BRCA2 has lead her to conclusion, that it is time to offer genetic screening of these genes to every woman, at about age 30, in the course of routine medical care. A recent study now provides evidence that supports offering BRCA1 and BRCA2 sequencing to all women. (14)

Myriad genetics Inc. reported $112 million of revenue from BRCA testing this year.

2. Impact

2.1 Expected impacts

Our project will facilitate greatly the development of the:

1) personalized and evidence based medicine,

2) precision medicine,

3) direct-to-consumer genetic testing as well,

4) identification of individuals with elevated and/or diminished cognitive and physical abilities.

1) Personalized medicine or PM is a medical approach that proposes the customization of healthcare using molecular analysis — with medical decisions, practices, and/or products being tailored to the individual patient. In this model,diagnostic testing is often employed for selecting appropriate and optimal therapies based on the context of a patient’s genetic content. The use of genetic information has played a major role in certain aspects of personalized medicine (e.g. pharmacogenomics), and the term was first coined in the context of genetics.

Pharmacogenomics is the study of the role of genetics in drug response. It deals with the influence of genetic variation on drug response in patients by correlating gene expression with drug absorbtion, distribution, metabolism and elimination, as well as drug receptor target effects. Pharmacogenomics aims to develop rational means to optimize drug therapy, with respect to the patients’ genotype, to ensure maximum efficacy with minimal adverse effects. Through the utilization of pharmacogenomics, it is hoped that drug treatments can deviate from what is dubbed as the «one-dose-fits-all» approach. It attempts to eliminate the trial-and-error method of prescribing, allowing physicians to take into consideration their patient’s genes, the functionality of these genes, and how this may affect the efficacy of the patient’s current and/or future treatments (and where applicable, provide an explanation for the failure of past treatments). Such approaches promise the advent of «personalized medicine»; in which drugs and drug combinations are optimized for each individual’s unique genetic makeup.

Major pharmacological Baltic companies Grindex and Olainfarm expressed interest in developing pharmacogenomic tests for their drugs.

2) Precision medicine is the application panoramic analysis and systems biology to analyze the cause of an individual patient’s disease at the molecular level and then to utilize targeted treatments (possibly in combination) to address that individual patient’s disease process. The patient’s response is then tracked as closely as possible, and the treatment finely adapted to the patient’s response.

3) Direct-to-consumer genetic testing refers to genetic tests that are marketed directly to consumers via television, print advertisements, or the Internet. The growing market for direct-to-consumer genetic testing may promote awareness of genetic diseases, allow consumers to take a more proactive role in their health care, and offer a means for people to learn about their ancestral origins. The growing market for direct-to-consumer genetic testing may promote awareness of genetic diseases, allow consumers to take a more proactive role in their health care, and offer a means for people to learn about their ancestral origins.

4) Genetics shape us in many ways including our potential to excel in sports. Training, diet, and other factors play a large role in developing individual potential, and our genotype influence greatly sport performance.

Genetics have a large influence over strength, muscle size and muscle fiber composition (fast or slow twitch), anaerobic threshold (AT), lung capacity, flexibility, and, to some extent, endurance.

Although many genes have been implicated in sports performance, the gene best studied for its role in running is called ACTN3. (15)

DNA testing will be useful to identify candidates which will form Olympic teams.

Significant component in human abilities by applying bioinformatic tools to the collections of genomic DNA obtained from exceptional musicians,mathematicians and chess players will allow to identify GDSs, DGDSs correlating with these abilities. In future using GDSs and DGDSs tests could be applyed for selection for entrance into conservatories, institutes and universities.

Whole genome sequencing (also known as full genome sequencing, complete genome sequencing, or entire genome sequencing) is a laboratory process that determines the complete DNA sequence of an individual genome at a single time.

An obvious advantage of next-generation sequencing techniques is the greater potential to identify the genetic component of health problems, and in the near future, at a lower cost than that of the current techniques.The sheer mass of data generated can reveal disease-causing alleles that could not be detected otherwise. Moreover, affordable technology that generates more genomic information may aid the translation of applications to further improve health care.

Identifying of patentable GDSs and DGDSs will strengthen competitiveness and growth of companies by developing innovations meeting the needs European and global markets by delivering innovations to the markets.

As socially important impact will stem from application of GDSs and DGDSs forensic cognitive research ,education , professional orientation and identification of exceptional sport abilities.

We should take into consideration that broad implementation of DGDSs and GDSs will require overcoming barriers and obstacles in regulations and in establishing of standards.

Therefore a major effort has to be invested into education of public.

References

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2. Genetics in Medicine (2013) 15,733-747, Heldi L.Rehm, Sherri J. Bale

3. Heart Rhythm. Volume 11, Issue 6, June 2014, Pages 1073-1078, Jodie Ingles, Christopher Semsarian

4. Translational Research. Volume 163, Issue 5, May 2014, Pages 466-477, Stephen M. Modella, Sharon L.R. Kardiab

5. Molecular Genetics and Metabolism Available online 28 September 2014 , G. Alkorta-Aranburua, D. Carmody

6. Biochimica et Biophysica Acta (BBA) — Molecular Basis of Disease Volume 1842, Issue 10, October 2014, Pages 1889-1895 , Marten H. Hofkera,Jingyuan Fub

7. Nature Communications 5, 09 September 2014 Article number: 4835 doi:10.1038/ncomms5835, Shai Carmi, Ken Y. Hui,Ethan Kochav

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9. Seema et al., Novel Science International Journal of Medical Science 2012, 1(6): 191-198

10. http://www.fbi.gov/about-us/cjis/fingerprints_biometrics/biometric-center-of-excellence

11. http://fingerprint-scanner-review.toptenreviews.com/
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