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Background on Mendelian conditions, from ASHG 2014 talk
The document assesses the success rate of large-scale exome sequencing in identifying genes related to Mendelian conditions over two years at the University of Washington. It highlights that Mendelian conditions, affecting around 25 million Americans, are largely caused by rare alleles, with a significant number still lacking known causal genes. The study emphasizes the importance of understanding these conditions as they contribute to our knowledge of gene function and human genetics.
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Background on Mendelian conditions, from ASHG 2014 talk
- 1. Assessment of thesuccess rate of two years of large-scale exome sequencing efforts to identify genes for Mendelian conditions at the University of Washington Center for Mendelian Genomics Talk given at ASHG 2014, San Diego October 19, 2014 Analysis and figures unpublished, please credit: Jessica Chong, Ph.D. Michael Bamshad, M.D.
- 2. Background: Mendelian conditions • What do we mean by Mendelian conditions? • most caused by rare, large effect alleles • strong risk alleles: moderate-frequency, moderate effect gene unknown ~3,600 suspected single gene disorders ~4,500 • Mendelian conditions • 0.4% of live births • 25 million Americans with a serious genetic condition • $5 million - lifetime cost/individual • in the U.S., most common cause of death in the first year of life
- 3. Scope of Mendelianconditions • 7,296 Mendelian and monogenic conditions • 3,593 with known cause • 3,824 with no causal gene (52%) • ~300 new Mendelian conditions delineated each year
- 4. Value of studyingMendelians Knowledge of gene function in humans mostly comes from Mendelians 30% (~5,960) genes predicted to result in embryonic lethality 14% (2,776) known Mendelian genes 52% (~10,330) impact of mutation in humans not known 4% (783) Mendelian mapped but gene unknown
- 5. Value of studyingMendelians But... no known Mendelian condition associated with 86% of human genes 86% candidate Mendelian genes 30% (~5,960) genes predicted to result in embryonic lethality 14% (2,776) known Mendelian genes 52% (~10,330) impact of mutation in humans not known 4% (783) Mendelian mapped but gene unknown
- 6. Value of studyingMendelians But... no known Mendelian condition associated with 86% of human genes 86% candidate Mendelian genes 30% (~5,960) genes predicted to result in embryonic lethality 14% (2,776) known Mendelian genes 52% (~10,330) impact of mutation in humans not known 4% (783) Mendelian mapped but gene unknown
Editor's Notes
- #3 To get us all on the same page, what do we mean when we talk Mendelian conditions? We are talking about often monogenic conditions that are caused rare, large effect alleles. This spectrum of conditions can also be expanded to include strong risk alleles with moderate frequency and effect size. Mendelian conditions are individually rare and account for 0.4% of live births, however, it is estimated that in total, ~25 million Americans have a serious genetic condition and the lifetime cost per individual with such a condition is estimated to be around 5 million dollars. In US, Mendelian conditions are the most common cause of death in the first year of life. citation: http://www.rarediseases.org/medical-professionals/research-grants/policy
- #4 Currently there are at least ~7300 Mendelian and monogenic conditions currently delineated, ~3600 of these have a known cause, but no gene has been implicated in the cause of the remaining ~3800, which is over 50%. In addition, OMIM has been adding approximately 300 newly-delineated Mendelian conditions each year. First three statistics: OMIM downloaded June 25, 2014. Analysis and curation by Jessica Chong. 4th statistic per OMIM
- #5 Much of our knowledge of gene function in humans comes from the Mendelian conditions that result from mutations of those genes. Here I show a waffle chart breaking down all of the genes in the human genome into bins based on what we know about those genes. 14% of human genes have already been implicated in a Mendelian condition and 4% correspond to locus to which a Mendelian has been mapped but the specific gene is not known. From mouse knockout and screening projects, it is estimated that mutations in an additional 30% of genes likely cause a Mendelian phenotype that results in embryonic lethality but we have almost no knowledge of these genes in humans. And finally, we do not know the impact of mutation in the remaining half, or 10 thousand, genes in the genome. citation: 30% genes likely result in embryonic lethality from mouse screens, see Ayadi, A, et al. (2012). Mamm Genome 23, 600–610. citation: 4% Mendelians mapped but gene unknown; 14% known = results from analysis of OMIM data
- #6 In total, this suggests, that up to 86% of human genes are candidates for Mendelian conditions.