genetics 2 Flashcards
frequences and second deck
what is meant by fitness
Fitness” means the relative ability of organisms to survive (long enough) to pass on their genes.
how does alleles affect fitness
not at all in most cases (neutral allele)
- sometimes decrease (deleterious allele) - rarely increase (advantageous allele)
mutation of recessive genes affects carriers yes or no
no because the dominant allele masks off the effect of the recessive allele
factors that influence whether a mutation of the recessive gene will affect the carrier
selective pressure for example sickle cell which is advantageous for malaria resistance.
de novo mutation
mutation in a first generation
what is the hardy weinberg equation
an equation to calculate how allele frequencies are transmitted from one generation to another.
findings of hardy weinberg equilibrium
1.the allele frequencies will remain constant generation to generation .
2.the relative proportion of genotype frequencies will remain constant generation to generation.
assumptions of HWE
Mutation can be ignored
- Migration is negligible (No gene flow) - Mating is random - No selective pressure - Population size is large - Allele frequencies are equal in the sexes
mutation effect on population genetics
mutations will increase the proportion of new alleles
migration effect on population genetics
there is introduction of new alleles as a result of migration or intermarriage which leads to a new gene frequency in hybrid population.
gene flow
transfer of genes by migration and mutation
non random mating effect on population genetics
non random mating will increase the mutant alleles thereby increasing the proportion of affected homozygotes.
examples of non random mating
1.Assortative mating
- Choosing of partners due to shared characteristics example Deafness & sign language
2.Consanguinity
- Marriage between close blood relatives.
-Cultural pressures for inter-marriage within clans / religions etc.
negative natural selection effect on population
there is reduced reproductive fitness
there is decreased prevalence of traits
there is gradual reduction of the mutant allele
positive effect of natural selection
increased in the reproductive fitness
increased prevalence of adaptive traits
heterozygote advantage
what is meant by heterozygous advantage
defect of a molecule in the body leading to advantageous effects on other aspects of the body.
how does small population size affect HWE
small population exhibits genetic drift which causes founder effect.
what is genetic drift
Random fluctuation of one allele transmitted to high proportion of offspring by chance.
what is founder effect
The reduction in genetic variation that results when a small subset of a large population is used to establish a new colony.
founder effect and bottle neck effect
the original population through genetic drift is reduced , there is therefore reduced genetic diversity , through what is known as the founder effect a new generation and colony is started by a few members of the original population .
cultural and geographic founder mutations
examples include ;Dominant
Hereditary breast cancer gene mutations BRCA1/2
Ashkenazi jewish
Polish
Lithuanian
Scandinavian population isolates
Orkney BRCA1 mutation
Recessive
Ashkenazi- Tay-Sachs etc.
North-west European Celtic cystic fibrosis mutation
applications of HWE
Useful for calculating risk in genetic counselling
Useful for planning population based carrier screening programmes
does cancer arise form genetic mutation yes /no
yes
somatic mutation
occurs in the autosomal chromosomes and is non inheritable
germline mutations
occurs in the sex chromosomes and can be inherited that is passed down to an offspring
tumors have the ability to divide and produce cells that are identical with them what is the name for this characteristic
they are said to have clonal expansion
examples of mutated molecules that are associated with cancer
oncogenes
tumor suppressor genes for example RB and p53
DNA damage response genes.
what are oncogenes
these are genes that have undergone mutation and could stimulate rapid cell proliferation and cause cancer.
oncogenes in cancer
one mutation is sufficient for the development of cancer because of the accelerated cell division .
tumor suppressor genes in cancer
they are the checkpoint inhibitors at the cell cycle.
they also promote apoptosis
cancer only arises when both of the tumor suppressor genes from both parents fail.
tumor suppressor genes in cancer tree
normal genes that prevent cancer to a 1st generation who undergoes mutation is susceptible to cancer but doesn`t have cancer to 2nd generation of the person who has a mutation and has a loss of the cancer gene.
DNA damage response gene and cancer
cancer arises when both of the gens fail which speeds up the accumulation of mutations in other critical genes
example of cancer that is associated with the failure of the MMR genes
colorectal cancer
failure of the mismatch repair gene results in
microsatellite instability is caused when there is a difference in a small region of the DNA form the original DNA this could be addition of base pairs
micro-satellite instability and cancer
cells with abnormal MMR tend to have accumulated errors which might lead to cancer .
MMR gene is meant to repair and correct errors that spontaneously occur during DNA replication for example short insertions and deletions.
what are microsatellites
they are repeated sequences of the DNA that can be made of 1 to 6 base pairs.
what is microsatellite instability
this refers to the changes in the sequences of the mirco-satellite sequences and it is the phenotypic evidence that the MMR is not working properly
phenotypic evidence that the MMR is not working properly
microsatellite instability
what is a benign tumor
lacks ability to metastasis but may be having an effect on the health ie if in the brain it is causing the brain to be squeezed hence there is pain.
what is meant by dysplasia
this are abnormal cells that could form a benign or malignant tumor or not.
malignant
they have na ability to metastasise and they are invasive .
examples of cancer syndromes caused by defect in the mismatch repair gene
HNPCC and lynch syndrome and the genes involved are the MLH1 ,MSH2,MSH6,PMS2,PMS1
example of cancer caused by a defect in the tumor suppressor gene process
breast and ovarian cancer -BRCA1 , BRCA2 GENES
FAP -APC GENE
retinoblastoma -RB GENE
li fraumeni syndrome -P53 gene
example of cancers caused by inherited oncogene dysfunction
familial medullary thyroid cancer and multiple endocrine neoplasia -RETINOBLASTOMA GENE
Examples of autosomal recessive syndromes
this is where the gene copies have inherited mutations.
Example MYH polyposis
what is a de novo mutation
mutation that happens in the first generation person.( a new mutation that is not inherited )
new mutation that occurs in the germ cell of a parent
de novo mutation
examples of diseases where de novo mutations are common
Familial adenomatous polyposis ~30% of cases
Multiple endocrine neoplasia 2B ~50% of cases
Hereditary retinoblastoma ~50% of cases
differences in non inheritable and heritable retinoblastoma
tumor in non-heritable is unilateral and heritable retinoblastoma bilateral.
there is no family history in non-inheritable cancer and there is heritable there is family history .
what are the risk factors for breast cancers
ageing
family history
early menarche ( menstrual period , more exposure to oestrogen hormone )
late menopause
oestrogen use
dietary factors example alcohol
lack of exercise
high risk genes contributing to familial breast cancer
BRCA1
BRCA2
TP53
PALB2
PTEN
STK11
CHEK2 homozygotes
ATM mutation c.7271T>G
genes that have moderate risk of contracting breast cancer
CHEK2 heterozygous mutation
ATM (except c.7271T>G)
BRIP1
high risk genes contributing to familial ovarian cancer
BRCA1
BRCA2
TP53
RAD51C
RAD51D
Mis-match repair genes
moderate risk genes contributing to familial ovarian cancer
PALB2
BARD1
lifetime risk of BRCA1 associated cancers
breast cancer (50-85%)
secondary breast cancer (40-60%)
ovarian cancer (15-45%)
possible increased risk of other cancers for example prostrate and colon
lifetime risk of BRCA2 gene cancer
breast cancer (50 -80%)
ovarian cancer ( 10-20%)
male breast cancer (6%)
increased risk of prostrate , pancreatic cancer a nd laryngeal cancer.
risk factors for colorectal cancer
Ageing
Personal history of CRC or adenomas
High-fat, low-fibre diet
Inflammatory bowel disease
Family history of CRC
adenoma to carcinoma sequence
a normal epithelium through APC mutation there is hyperproliferative epithelium that is formed and there is k ras mutation which leads to formation of an adenoma p53 mutations leads to formation of a carcinoma .
clinical features of HNPCC
early but variable at CRC diagnosis at 45 years old
tumor is at the site throughout the colon rather than the descending colon.
extracolonic cancers that are associated include ; endometrium , ovary , stomach , urinary tract , small bowel , bile ducts , sebaceous skin tumors.
FAP presentations
estimated pentrance for adenomas is 90%
the risk of extracolonic tumors that is in the upper GI, desmoid ,osteoma , thyroid , brain and other.CHRPE MAY BE PRESENT
what is FAP
familial adematous polyposis which is the formation of polyps on the walls of colon.
they increase the risk of cancer by 100%
What is Congenital hypertrophy of the retinal pigment epithelium ( CHRPE)
this is the increase in the size of the epithelium of the retina.
what is attenuated FAP symptoms
Later onset (CRC ~age 50)
Few colonic adenomas
Not associated with CHRPE
Upper GI lesions
Associated with mutations at 5’ and 3’ ends of APC gene
what are the symptoms of recessive MYH polyposis
similar to the clinical GI features of the attenuated FAP
how does modifier genes influence the genetic risk
1.they explain why families with history of cancer have no identified mutation.
2.also explains the differences in cancer penetrance in families with same mutation.
what is a modifier gene
this is a gene that is modified form the original gene that mutated therefore it is attenuated.
management of cancer risk in adenomatous polyposis syndrome
Surveillance
Surgery
Chemoprevention
advances
Exome sequencing
Genome sequencing
What to do with results . .
advances in clinical practice have been influenced by
technology
clinical assessment of the family members
history
pedigree
clinical examination
genetic test that is microarray and gene tests
synthesis
negative selection
-Reduces reproductive fitness.
- decreases the prevalence of traits.
- leads to gradual reduction of mutant allele
positive selection
- Increases reproductive fitness.
- Increases the prevalence of adaptive traits.
-Heterozygote advantage
example of heterozygous advantage
1.sickle cell anemia , thalassemia and glucose -6 -phosphate dehydrogenase deficiency all are providing resistance towards malaria.
2.cystic fibrosis offers resistance against cholera and typhoid .
3.congenital adrenal hyperplasia -influenza B
4.GM2 gangliosidosis resistance against TB
