Genomics and Personalized Care in Health Systems Lecture 8: Gene and Disease

1. Genomics and Personalized Care in Health SystemsLecture 8: Gene and Disease Leming Zhou, PhD Department of Health Information management School of Health and Rehabilitation Sciences

2. Outline • Overview of human genetic disease • Examples of single gene disorders • Examples of complex disorders

3. 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

4. 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

5. 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

6. 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.

7. 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.

8. 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 E6V 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

9. 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

10. Rett Syndrome • Rett Syndrome is caused by mutations in the gene MECP2 on the X chromosome, encoding methyl CpG binding protein 2 • Location: Xq28 • Two transcript variants: NM_001110792 and NM_004992 • Affects almost exclusively females and one of the most common causes of mental retardation in females

11. 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 MECP2. • 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 MECP2 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 can cause even identical twins to exhibit different phenotypes.

12. 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

13. Disease Mutation Databases • Central • OMIM • GeneCards • 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

14. 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 McKusick at Johns Hopkins University (1966). • OMIM went online at NCBI in 1995. It is integrated with Entrez, MapViewer, LocusLink, and PubMed. • OMIM has a focus on Mendelian disorders. There are almost no entries on chromosomal diseases.

15. OMIM Statistics for March 2012 http://www.ncbi.nlm.nih.gov/Omim/mimstats.html

17. OMIM Record for RTT Disease Gene

18. RTT Disease Record in OMIM OMIM number Link to NCBI map viewer

19. Other Mutation Databases • GeneCards (Weizmann) • collects and integrates information from several dozen independent databases such as OMIM, GenBank, UniGene, Ensembl, MIPS. • visit http://bioinfo.weizmann.ac.il/cards/ • Human Gene Mutation Database (HGMD)

21. Human Gene Mutation Database

22. 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 disease-causing, or neutral (having no apparent effect on phenotype).