Transcript 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
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 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
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 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
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 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.
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
– 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
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 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.
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
OMIM number
Link to NCBI map viewer
Department of Health Information Management
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)
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).