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The mitochondrial proteome and human disease
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PATHOLOGY 2015 ABSTRACT SUPPLEMENT
OXPHOS disease, and to ultimately identify novel candidate genes that cause disease.
Pathology (2015), 47(S1)
CLINICAL TRANSLATION OF GENOMICS Richard A. Gibbs Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
THE MITOCHONDRIAL PROTEOME AND HUMAN DISEASE Vamsi Mootha Howard Hughes Medical Institute, and Department of Systems Biology, Harvard Medical School Department of Medicine, Massachusetts General Hospital, Boston, MA, USA Mitochondria are ancient organelles found in virtually all of our body’s organs. Owing to their bacterial ancestry, they still retain a tiny genome (mtDNA), encoding 13 proteins, while virtually all of the remaining coding capacity has been relegated to the nuclear genome. In this talk, I will present our work over the past decade aimed at systematically characterising all of the nuclear encoded proteins that reside within this organelle. By combining biochemistry, computation, mass spectrometry, and imaging, we have been able to systematically characterise the over 1000þ proteins that comprise human mitochondria. This inventory is now proving to be very useful in the discovery of genes that underlie Mendelian mitochondrial disorders, and for linking common GWAS hits back to the organelle. Moreover, with the advent of next generation sequencing, this inventory is serving as a guide in both the discovery and interpretation of genome sequences for diagnostics. Our work is helping to establish a genomic nosology for mitochondrial disease.
THE RELEVANCE OF ANCIENT DNA TO CONTEMPORARY DISEASE Alan Cooper, Laura S. Weyrich and Andrew G. Farrer Australian Centre for Ancient DNA, University of Adelaide, SA, Australia Disease prevalence and human health has been significantly impacted through time by cultural, environmental, and dietary changes. While we now know that the human microbiome significantly contributes to modern ‘Western’ diseases, including obesity, diabetes, and arthritis, we have yet to understand how historic events and factors influenced the formation of the modern human microbiome. Calcified dental plaque (calculus) provides a unique and powerful opportunity to examine ancient human oral microbiomes and investigate how these bacterial communities, and their associations to disease, have changed through time. We have used ancient DNA sequencing of ancient dental calculus to identify significant changes in the oral microbiome associated with major cultural and dietary revolutions, such as the onset of farming (Neolithic Revolution) and the Industrial Revolution, identifying how large shifts in the oral microbiome have impacted modern disease prevalence and severity. The modern human mouth appears to be in a chronic ‘diseased state’, not previously observed in human history. The incidence of several oral pathogens such as Streptococcus mutans, the causative agent of dental carries, has significantly increased through time. Together, ancient DNA studies from a variety of time periods and geographic locations around the world indicate that major dietary and cultural changes, such as the addition of carbohydrates or processed foods to our diets, have drastically altered our microbiomes and therefore directly impacted our health.
At Baylor College of Medicine we created a CLIA/CAP certified clinical sequencing laboratory (Whole Genome Laboratory; WGL) where we have as of November 2014 analysed more than 4,500 cases of childhood disease by whole exome sequencing. This cohort reveals multiple instances of rare events including uni parental disomy, phenotypes confounded by mutations at multiple loci and the role of CNVs. The rate of ‘solving’ cases is a consistent 25%.1,2 Cases that are initially unsolved are re-consented for research studies to enable discovery of new loci associated with disease. This successful example of clinical translation contrasts with the challenges and difficulty of similar efforts in cancer diagnostics and adult medicine. References 1. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 2013; 369: 1502. 2. Yang Y, Muzny DM, Xia F, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 2014; 312: 1870.
CLINICAL TRANSLATION OF SOMATIC MUTATION ANALYSIS OF CELL-FREE DNA Sarah-Jane Dawson Division of Cancer Medicine and Research, Peter MacCallum Cancer Centre, Vic, Australia Cell-free circulating DNA containing tumour-specific sequences can be identified in the plasma of cancer patients. Serial analysis of ctDNA can allow the evolving genomic landscape of a cancer to be assessed, with many potential clinical applications. Analysis of ctDNA is challenging and requires highly sensitive techniques due to the small fraction of tumor specific DNA present in the circulation, however, the application of next generation sequencing technologies is now providing new opportunities to develop ctDNA as a non-invasive ‘liquid biopsy’ alternative to tissue biopsies for use in cancer diagnostics and management. Recent research has revealed the high sensitivity of ctDNA as a molecular biomarker for disease monitoring in several solid malignancies. Furthermore, serial plasma DNA analysis is now being applied as a noninvasive tool to study genomic evolution during disease progression and treatment. I will present an overview of these recent and exciting developments as well as an update on current research that is ongoing in this field.
THE GLOBAL ALLIANCE FOR GENOMICS AND HEALTH: TOWARDS INTERNATIONAL SHARING OF GENOMIC AND CLINICAL DATA Kathryn North, AM Director, Murdoch Children’s Research Institute; Director, Victorian Clinical Genetics Service; David Danks Professor of Child Health Research, University of Melbourne, Vic, Australia The Global Alliance for Genomics and Health (GA4GH) was officially launched in March 2014. The aims of the Global Alliance are to accelerate the world-wide effort to responsibly aggregate,
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
PATHOLOGY 2015 ABSTRACT SUPPLEMENT
OXPHOS disease, and to ultimately identify novel candidate genes that cause disease.
Pathology (2015), 47(S1)
CLINICAL TRANSLATION OF GENOMICS Richard A. Gibbs Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
THE MITOCHONDRIAL PROTEOME AND HUMAN DISEASE Vamsi Mootha Howard Hughes Medical Institute, and Department of Systems Biology, Harvard Medical School Department of Medicine, Massachusetts General Hospital, Boston, MA, USA Mitochondria are ancient organelles found in virtually all of our body’s organs. Owing to their bacterial ancestry, they still retain a tiny genome (mtDNA), encoding 13 proteins, while virtually all of the remaining coding capacity has been relegated to the nuclear genome. In this talk, I will present our work over the past decade aimed at systematically characterising all of the nuclear encoded proteins that reside within this organelle. By combining biochemistry, computation, mass spectrometry, and imaging, we have been able to systematically characterise the over 1000þ proteins that comprise human mitochondria. This inventory is now proving to be very useful in the discovery of genes that underlie Mendelian mitochondrial disorders, and for linking common GWAS hits back to the organelle. Moreover, with the advent of next generation sequencing, this inventory is serving as a guide in both the discovery and interpretation of genome sequences for diagnostics. Our work is helping to establish a genomic nosology for mitochondrial disease.
THE RELEVANCE OF ANCIENT DNA TO CONTEMPORARY DISEASE Alan Cooper, Laura S. Weyrich and Andrew G. Farrer Australian Centre for Ancient DNA, University of Adelaide, SA, Australia Disease prevalence and human health has been significantly impacted through time by cultural, environmental, and dietary changes. While we now know that the human microbiome significantly contributes to modern ‘Western’ diseases, including obesity, diabetes, and arthritis, we have yet to understand how historic events and factors influenced the formation of the modern human microbiome. Calcified dental plaque (calculus) provides a unique and powerful opportunity to examine ancient human oral microbiomes and investigate how these bacterial communities, and their associations to disease, have changed through time. We have used ancient DNA sequencing of ancient dental calculus to identify significant changes in the oral microbiome associated with major cultural and dietary revolutions, such as the onset of farming (Neolithic Revolution) and the Industrial Revolution, identifying how large shifts in the oral microbiome have impacted modern disease prevalence and severity. The modern human mouth appears to be in a chronic ‘diseased state’, not previously observed in human history. The incidence of several oral pathogens such as Streptococcus mutans, the causative agent of dental carries, has significantly increased through time. Together, ancient DNA studies from a variety of time periods and geographic locations around the world indicate that major dietary and cultural changes, such as the addition of carbohydrates or processed foods to our diets, have drastically altered our microbiomes and therefore directly impacted our health.
At Baylor College of Medicine we created a CLIA/CAP certified clinical sequencing laboratory (Whole Genome Laboratory; WGL) where we have as of November 2014 analysed more than 4,500 cases of childhood disease by whole exome sequencing. This cohort reveals multiple instances of rare events including uni parental disomy, phenotypes confounded by mutations at multiple loci and the role of CNVs. The rate of ‘solving’ cases is a consistent 25%.1,2 Cases that are initially unsolved are re-consented for research studies to enable discovery of new loci associated with disease. This successful example of clinical translation contrasts with the challenges and difficulty of similar efforts in cancer diagnostics and adult medicine. References 1. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 2013; 369: 1502. 2. Yang Y, Muzny DM, Xia F, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 2014; 312: 1870.
CLINICAL TRANSLATION OF SOMATIC MUTATION ANALYSIS OF CELL-FREE DNA Sarah-Jane Dawson Division of Cancer Medicine and Research, Peter MacCallum Cancer Centre, Vic, Australia Cell-free circulating DNA containing tumour-specific sequences can be identified in the plasma of cancer patients. Serial analysis of ctDNA can allow the evolving genomic landscape of a cancer to be assessed, with many potential clinical applications. Analysis of ctDNA is challenging and requires highly sensitive techniques due to the small fraction of tumor specific DNA present in the circulation, however, the application of next generation sequencing technologies is now providing new opportunities to develop ctDNA as a non-invasive ‘liquid biopsy’ alternative to tissue biopsies for use in cancer diagnostics and management. Recent research has revealed the high sensitivity of ctDNA as a molecular biomarker for disease monitoring in several solid malignancies. Furthermore, serial plasma DNA analysis is now being applied as a noninvasive tool to study genomic evolution during disease progression and treatment. I will present an overview of these recent and exciting developments as well as an update on current research that is ongoing in this field.
THE GLOBAL ALLIANCE FOR GENOMICS AND HEALTH: TOWARDS INTERNATIONAL SHARING OF GENOMIC AND CLINICAL DATA Kathryn North, AM Director, Murdoch Children’s Research Institute; Director, Victorian Clinical Genetics Service; David Danks Professor of Child Health Research, University of Melbourne, Vic, Australia The Global Alliance for Genomics and Health (GA4GH) was officially launched in March 2014. The aims of the Global Alliance are to accelerate the world-wide effort to responsibly aggregate,
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.