Med gene final:

1) Chaper 8: overview about method to identify disease gene, Thầy sẽ hỏi so sánh các cách
-Disease gene identification is a process by which scientists identify the mutant genotypes OR
alleles responsible for an inherited genetic disorder.
Method 1: Gene mapping
- Definition: Gene mapping refers to the process of determining the location of genes on
chromosomes. Linkage analysis is a recombinant technology used for gene mapping to
detect the chromosomal location of disease genes. (Genetic map consists of all genes
present on a particular chromosome while linkage map consists of linked genes present
on a particular chromosome)
Method 2: Physical mapping and cloning
Definition: A physical map is a graphical representation of physical locations of landmarks or
markers (such as genes, variants, and other DNA sequences of interest) within a chromosome or
genome. Positional cloning is a laboratory approach used to locate the position of a disease-
associated gene on a chromosome.
• Chromosome Morphology: Deletions, duplication, translocation mutation
• Techniques:
• Karyotypes: visible large size  serious consequences
• Array CGH
• Dosage mapping: Protein amount changed: usually 50%
 A gene can be physically mapped to a chromosome region by associating
cytogenetically observable variations (heteromorphisms, translocations, deletions,
duplications) with gene expression (including the presence of a genetic disease).
• Positional Cloning
• Causative protein known without gene information
• Sickle cell disease ~ HBB
• Making probe from protein sequence to map to the chromosome
Method 3: GWAS
- Definition: A genome-wide association study (abbreviated GWAS) help scientists
identify genes associated with a particular disease (or another trait). This method studies
the entire set of DNA (the genome) of a large group of people, searching for small
variations, called single nucleotide polymorphisms or SNPs
 - Disadvantage: Inadequate sample size, Imprecise phenotyping, Improper matching
between cases and controls, cannot replicated
Method 4: Exome and whole-genome sequencing
Exome sequencing uses for coupling targeted capture of thousands of regions of the human
genome corresponding to every gene with massively parallel DNA sequencing made it possible
to cost-effectively determine nearly all the coding variation in an individual human genome,
which sums to less than 2% of the genome, in a single experiment. Limitation: accurately infer
the presence of small deletions and insertions as well as copy number variants (CNVs)  whole-
genome sequencing (mắc nhưng h nó rẻ hơn nhiều rồi)

Cannot detech large indel in non-coding region (Bất lợi của exom squenc)
2) Autoimmune disease
Autoimmune disease happens when the body’s natural defense system can’t tell the difference
between your own cells and foreign cells, causing the body to mistakenly attack normal cells.
+ Some certain risk factors increase the chances of developing autoimmune disorders:
● Genetic inheritance
● Overweight
● Smoking
● Certain medications: Certain blood pressure medications or antibiotics
+ Common autoimmune diseases: Type 1 diabetes, Rheumatoid arthritis (RA), Psoriasis,
Multiple sclerosis, Addison’s disease, Graves’ disease, Celiac disease,....
+ The early symptoms of many autoimmune diseases are very similar, such as: fatigue, achy
muscles, swelling and redness, low-grade fever, trouble concentrating, hair loss. skin rashes,...
+ Tests that diagnose autoimmune diseases: ANA (Antinuclear Antibody) Test,
Immunoglobulins Blood Test, C-Reactive Protein (CRP) Test, Erythrocyte Sedimentation Rate
(ESR),...

3) Pleiotropic
● Pleiotropic: is a term talking about one gene affecting two or more seemingly unrelated
phenotypes and always deadly in the embryo
● Pleiotropic gene action can limit the rate of multivariate evolution when natural selection,
sexual selection or artificial selection on one trait favors one allele, while selection on other traits
favors a different allele.
● Pleiotropy can have an effect on the evolutionary rate of genes and allele frequencies.
● Example of Pleiotropy: Albinism, Autism and schizophrenia, Phenylketonuria (PKU,
Sickle cell anemia, "Mini-muscle" allele, DNA repair proteins

4) Two model in cancer development

● A cell can initiate a tumor only when it contains two damaged alleles
● A person who inherits one copy of a mutant cancer gene MUST experience a second,
somatic mutation in one or more retinoblasts in order to develop one or more retinoblastomas.
● Two somatic mutations can also occur in a single retinoblast of a nonpredisposed fetus,
producing sporadic retinoblastoma (chắc k ra)

5) Ocogene and tumor suppressor gene

Oncogenes:
Function of normal version: Promotes cell growth and proliferation.
Mutation (At cell level): Dominant (Only one copy of gene mutated).
Effect of mutation: Gain of function.
Germline mutations resulting in inherited cancer syndromes: Seen in only a few oncogenes.
Tumor suppressor genes:
Function of normal version: Regulates cell growth and proliferation, some can induce apoptosis.
Mutation (At cell level): Recessive (both copies of gene inactivated).
Effect of mutation: Loss of function.
Germline mutations resulting in inherited cancer syndromes: Seen in most tumor suppressor
genes.

6) Threshold model
• Used to explain for disease which is appeared to be either present or absent in individuals
(do not follow bell shaped model)
• In liability distribution,
• People on low end have little chance of developing the disease,
 • People closer to the high end of the distribution are more likely to develop the
disease
• For multifactorial diseases that are either present or absent, a threshold of liability must
be crossed before the disease is expressed.
Liability threshold concept can be used to explain recurrence risk pattern of siblings.
A lower male threshold implies that fewer disease-causing factors are required to generate the
disorder in males

7) The meaning of disease gene screening, genetic screening test in healhcare system
- Heterozygous screening: Detection of unaffected carriers of disease causing mutations.
•Examples: β-Thalassemia major decrease 75% in Greece, Cyprus, and Italy
- Presymptomatic Diagnosis:
● At-risk persons can be tested to determine whether they have inherited a disease-causing
mutation before they develop clinical symptoms of the disorder.
● Beside that presymtomatic diagnoisi can reproductive decisions, improve health
supervision.
- Genetic screening test: is a type of medical test that •Analysis of chromosomes, DNA,
RNA, proteins, or other analytes.
8) So sánh conventional medicine and precision medicine. Chọn 1 công nghệ để nói về
quá trình
Genetic information can be used to assess a person’s risk of disease and response to therapy.
Persons at high risk for a disease could therefore be encouraged to alter their health management
to reduce their risk.
genetic information can also be used to predict a person’s response to therapy and whether the
person is at increased risk for a serious adverse drug response. Drugs predicted to be less
effective or likely to cause an adverse event could be avoided.
For example, a person predicted to be at high risk for diabetes might be tested for hyperglycemia
more frequently, placed on a medical diet earlier, and treated more aggressively for glucose
intolerance.
9) Definition of genetic counselor ( câu hỏi sẽ là: is genetic counselor…..)
helping people understand and adapt to the medical, psychological, and familial implications of
genetic contributions of disease.
Fully process:
(1) interpretation of family and medical histories to assess the chance of disease occurrence or
recurrence
(2) education about inheritance, testing, management, prevention, resources, and research
(3) counseling to promote informed choices and adaptation to the risk of the condition
10) Sẽ có 1 câu : đưa 1 bệnh, xong mình phải brainstorm lại )

Question:
Problem of ref genome: can’t not apply between people different countries.
Câu hỏi mở: if you as an scientist working on a disease, now you see a weird phenotype, and you
want to identify which gene relates with this disease, and you know this is genetic disease since
their parent have it. So from where can you start indentifying this gene ?
Answer
We Screen for Mutations in the Sequence by collecting sample from two group ( normal person
and people have disease with the same phenotye).Next, we test for gene expressionin both
mRNA level and Protein level, then select list of candidate gene may relate to specific disease by
gene function. Then we do the GWAS study (apply this candidate gene in another population).
Then calculate the p-value.
Or
• Select pedigree (families with disease phenotype)
• Select marker
• Calculate for LOD score for each marker
• Narrow down the chromosome region  gene
• Confirm the mutation on specific genes

Characteristics of single gene disease ?

-Có thể gây ra bởi hai subunit của 1 protein, hoặc 2 gene có cùng một chức năng
-Can be predicted
-Frequency is low ( rare disease)
-Làm sao phân biệt single gene vs various gene disease ?
Single gene hiếm hơn nhưng 1 khi bị là nặng. Complex diseases differ from single-gene
disorders quantitatively in that multiple gene products combine to produce a phenotype in
the former

1) How genetic contribute to immune system ?

-Antibacterial peptide: If body inujured and infected by bacteria’s toxin. Cells will come
to start phagocytosis and produce proteins that binds to bacteria’s membrane.

2) Innate immune system ( cannot remember the pathogen). Innate immune syste is
activated by general features that are not found in the host but found in pathogens:
-Lipopolysaccharides
-Peptidoglycans
-Unmethylated CG
3) Cytotoxic : go around the bloodstream and tissue to detect weird cell by cell-communication
and trigger that cell to apoptosis
4) MHC3 class 2 involvement: MHC class II binds to CD4 . B-cell has exogenous material, send
to MHC II and peresnt it to T-cell receptor. T-cell receptor will check that material and will send
signal back to B-cell to become mast cell in order to create more antibodies.
5) Which type of genes is much related to disease ? Which is the genes in body reponsible for
disease regulation :
- Immune gene

6) How the omim scientists can buil the database and how to make sure that database is
correct ?
By reading public paper related to medical genetic. For example, scientist in Vietnam finds some
mutation in Thalassemia, they will public it. Then wait for other scientist to also public
mutations related to that disease. So the data will be corrected by comparison between to public
papers ( Giống kiểm tra chéo ash)

7. MHCI vs MHCII
The class I molecules present peptides at the surfaces of nearly all of the body’s cells. The
peptide–class I molecule complex is recognized by cytotoxic T cells, which kill the cell if the
class I MHC molecule presents foreign peptide.
The class II MHC molecules also present peptides at the cell surface, but only in antigen-
presenting cells of the immune system (e.g., dendritic cells, macrophages, B cells). If the class II
molecule presents foreign peptides derived from an invading microbe, they are bound by the
receptors of helper T cells; this in turn stimulates appropriate B cells to proliferate and to
produce antibodies that will help to kill the microbes.

8. precise diagnosis test and screening test

Precision diagnosis is the accurate and timely explanation of each patient's health problem and
further requires communication of that explanation to patients and surrogate decision-makers.
Both accuracy and timeliness are essential to critical care, yet computed decision support
systems (CDSS) are scarce
Screening tests are intended for asymptomatic (showing no or disguised symptoms) people,
whereas diagnostic tests are intended for those showing symptoms in need of a diagnosis.