Download Lecture 8 - Pitt CPATH Project

Genomics and Personalized
Care in Health Systems
Lecture 8: Gene and Disease
Leming Zhou, PhD
Department of Health Information management
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
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
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OMIM Record for RTT
Disease
Gene
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RTT Disease Record in OMIM
OMIM number
Link to NCBI map viewer
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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 diseasecausing, or neutral (having no apparent effect on
phenotype).