Genomics and Personalized Care in Health Systems

Lecture 8: Gene and Disease

Leming Zhou, PhD

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School of Health and Rehabilitation Sciences

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Outline• Overview of human genetic disease

• Examples of single gene disorders

• Examples of complex disorders

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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

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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

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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

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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.

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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.

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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

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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

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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

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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.

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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

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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

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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.

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OMIM Statistics for March 2012

  Autosomal X-Linked Y-Linked Mitochondrial Total

* Gene with known sequence 13107 641 48 35 13831

+ Gene with known sequence and phenotype 148 5 0 2 155

# 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 withsuspected mendelian basis 1789 127 2 0 1918

Total 19829 1170 59 65 21123

http://www.ncbi.nlm.nih.gov/Omim/mimstats.html

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OMIM Record for RTT

Disease

Gene

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RTT Disease Record in OMIM

Link to NCBI map viewer

OMIM number

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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)

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Human Gene Mutation Database

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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).