Genomics and Personalized Care in Health Systems Lecture

Genomics and Personalized Care in Health Systems Lecture 8: Gene and Disease Leming Zhou, Ph. D Department of Health Information management School of Health and Rehabilitation Sciences

Department of Health Information Management Outline • Overview of human genetic disease • Examples of single gene disorders • Examples of complex disorders

Department of Health Information Management Disease: Consequence of Variation • Genetic variation is responsible for the adaptive changes that underlie evolution. • Some changes improve the fitness of a species. Other changes are maladaptive. • For the individual in a species, these maladaptive changes represent disease. • Molecular perspective: mutation and variation • Medical perspective: pathological condition

Department of Health Information Management Genomics and Disease • DNA databases offer the reference sequences with which to compare normal sequences and those associated with disease • Physical and genetic maps are used in gene-finding studies • Protein structure studies allow study of effects of mutation • Many functional genomics approaches applied to genes • Insight into human disease genes is provided through the study of orthologs

Department of Health Information Management Categories of Disease • Five main categories of human disease: – Single gene disorders • autosomal dominant; autosomal recessive; X-linked recessive – Complex disorders • congenital anomalies; cardiovascular; diabetes – Chromosomal disorders – Infectious disease – Environmental disease

Department of Health Information Management Example • Lead poisoning is an environmental disease. It is common (about 9% of US children have high blood levels). • However, two children exposed to the same dose of lead may have entirely different phenotypes. • This susceptibility has a genetic basis. • Conclusion: genes affect susceptibility to environmental insults, and infectious disease. Even single-gene disorders involve many genes in their phenotypic expression.

Department of Health Information Management Monogenic Disorders • Previously, a large distinction was made between monogenic (single gene) and polygenic (complex) disorders. • They are now seen to be more on a continuum. • We may define a single-gene disorder as a disorder that is caused primarily by mutation(s) in a single gene. • However, as we will see below, all monogenic disorders involve many genes.

Department of Health Information Management Sickle Cell Anemia • Sickle cell anemia is an example of a single gene disorder. • It is caused by mutations in beta globin (HBB). We saw that the E 6 V mutation is very common • This mutation causes hemoglobin molecules to aggregate, giving red blood cells a sickled appearance. • This single gene disorder is unusually prevalent because the heterozygous state confers protection to those exposed to the malaria parasite

Department of Health Information Management Rett Syndrome • Rett syndrome (RTT) is another example of a single gene disorder. • RTT is a progressive neurodevelopmental disorder • With an incidence of about 1/10, 000 births, it is a common cause of profound metal impairment in girls • Babies with RTT develop normally until the age of 6 to 18 months • Neurocognitive regression – Loss of speech and social skills (temporary “autistic-like” phase) – Loss of purposeful hand movements – Seizures

Department of Health Information Management Rett Syndrome • Rett Syndrome is caused by mutations in the gene MECP 2 on the X chromosome, encoding methyl Cp. G binding protein 2 – Location: Xq 28 – Two transcript variants: NM_001110792 and NM_004992 • Affects almost exclusively females and one of the most common causes of mental retardation in females

Department of Health Information Management Disease Principle in RTT • The problem is likely caused by a high mutation rate in fathers. • Females may be spared a more severe phenotype because of random X chromosome inactivation. – In all females, each cell chooses to express either the maternal or paternal X chromosome, early in life. Thus RTT females are a mosaic of cells expressing normal and mutated copies of MECP 2. – X-inactivation patterns in females are normally about 50 -50. However they may be skewed 99 -1, allowing a female to be a carrier. Several females have given birth to affected daughters • An identical mutation in MECP 2 in two females may result in extremely different phenotypes: – Modifier genes may affect the disease process. This is seen for many other single gene disorders. – Many epigenetic factors may influence the clinical phenotype. In RTT, the methylation status of genomic DNA could be important. Skewed X-inactivation cause even identical twins to exhibit different phenotypes.

Department of Health Information Management The Source of Disease Diversity • Many regions of the genome may be affected • There are many mechanisms of mutation • Genes and gene products interact with their molecular environments • An individual interacts with the environment in ways that may promote disease

Department of Health Information Management Disease Mutation Databases • Central – OMIM – Gene. Cards – Human Gene Mutation Database • Locus-specific databases (mutation databases) – Describe one gene in depth – Complementary to central databases – Offer specialist expertise – There are hundreds of locus-specific databases

Department of Health Information Management OMIM • Online Mendelian Inheritance in Man (OMIM) is a comprehensive database for human genes and genetic disorders, with a focus on monogenic disorders. • It was started as MIM by Victor Mc. Kusick at Johns Hopkins University (1966). • OMIM went online at NCBI in 1995. It is integrated with Entrez, Map. Viewer, Locus. Link, and Pub. Med. • OMIM has a focus on Mendelian disorders. There almost no entries on chromosomal diseases.

Department of Health Information Management OMIM Statistics for March 2012 Autosomal X-Linked Y-Linked Mitochondrial Total 13107 641 48 148 5 0 # Phenotype description, molecular basis known 3144 260 4 28 3436 % Mendelian phenotype or locus, molecular basis unknown 1641 137 5 0 1783 Other, mainly phenotypes with suspected mendelian basis 1789 127 2 0 1918 19829 1170 59 65 21123 * Gene with known sequence + Gene with known sequence and phenotype Total http: //www. ncbi. nlm. nih. gov/Omim/mimstats. html 35 13831 2 155

Department of Health Information Management OMIM Record for RTT Disease Gene

Department of Health Information Management RTT Disease Record in OMIM number Link to NCBI map viewer

Department of Health Information Management Other Mutation Databases • Gene. Cards (Weizmann) – collects and integrates information from several dozen independent databases such as OMIM, Gen. Bank, Uni. Gene, Ensembl, MIPS. – visit http: //bioinfo. weizmann. ac. il/cards/ • Human Gene Mutation Database (HGMD)

Department of Health Information Management

Department of Health Information Management Human Gene Mutation Database

Department of Health Information Management Locus-Specific Databases • Standards are being established for LSDBs – having a unique identifier for each allele – information on the source of the data – the context of the allele – type of allele, name, nucleotide variation • A mutation is defined as an allelic variant. • The allele (i. e. unique sequence change) may be diseasecausing, or neutral (having no apparent effect on phenotype).