Wk1 - Genetics Flashcards
Mendelian =
to do with a single gene
Typical features of autosomal dominant features
Both males and females are affected in roughly equal numbers
Persons are affected in each generation
Males can transfer the condition to males and females and vice versa
Unaffected people do not transfer the condition
Shows vertical pattern - all generations affected
Examples of autosomal dominant inheritacne
Achondroplasia - short stature, short limbs (mutation is in FGFR3 gene)
Hypercholesterolaemia - due to a single mutant gene on chromosome 19
NF1
Inherited breast or colon cancer
ADPKD (autosomal dominant policystic kidney disease)
Autosomal recessive inheritance - features
suggests both parents are most likely carriers (more likely than a random mutation) - as requires both allels to show clinical appearance
25% chance that the individual will inherit the faulty copy from father/mother and thus be affected
Horizontal inheritance pattern i.e. siblings affected
Both females and males may be affected
May be consanguity (parents may be related) in family
Examples of autosomal recessive inheritance
Sickle cell anaemia Cystic fibrosis PKU - phenylketonuria SMA - spinal muscular atrophy Congenital adrenal hyperplasia (congenital adrenal hypoplasia is x-linked recessive)
What is variable expressivity?
- Incomplete and complete penetrance
This is when family members express different severities of a disease caused by the same gene. This is due to ‘modifier genes’ which have different affects on the phenotype
Variable expression is to do with phenotype and can occur due to environmental factors or due to modifier genes.
Incomplete penetrance - when the individual fails to express the disease, even though they carry the allele 9skips a generation in terms of phenotype)
Complete penetrance - the phenotype is fully expressed by the mutated genotype
Achondroplasia is complete penetrance
Features of x-linked recessive
Knights move pattern, No male to male transmission, mostly or only males affected
Females are carriers but are not affected:
Occasionally are ‘manifesting carriers’ - due to ‘skewed X-inactivation’ - this is when one of the X chromosomes of females get turned off very early in development (before there are 100 cells), this happens randomly.
When it is skewed, the inactivation of one X chromosome is favoured over the other, leading to an uneven number of cells with each chromosome inactivated
Any affected females are more mildly affected than males
Examples of X-linked recessive inheritacne
Duchenne and Becker’s muscular dystrophy
Red-green colour blindness
Haemophilia A and B
Features of X-linked dominant inheritance
Both males and females are usually affected, however the female heterozygote is more variably affected because of X inactivation
F:M = 2:1 (females have 2 X chromosomes, males only have 1)
Pattern is like AD but no male:male transmission
Examples of X-linked dominant inheritance
Vitamin-D resistant rickets Incontinentia pigmneti (male lethality) Rett syndrome (male lethality)
Name types of atypical mendelian inheritance
What is gonadal mosaicism?
Genetic anticipation
Pseudo-dominant inheritance
mitochondrial inheritance
A new mutation in either sperm/egg cell is known as ‘gonadal mosaicism’.
Describe genetic anticipation
increasing severity and earlier age of onset in successive generations e.g. Huntington disease, Fragile X syndrome, Myotonic dystrophy
Describe pseudo-dominant inheritance
Very unusual inheritance pattern. It normally appears like AD (vertical) but actually it is AR condition e.g.
Gilberts syndrome - due to unconjugated hyperbilirubinaemia
Carrier frequency is approx 50%
(unlikely to come up in an exam)
Describe mitochondrial inheritance
Mitochondria also have DNA (which is circular and much smaller) but it is a much smaller genome
It has 37 genes and no introns
Inherited only from the mother but to variable extents (mitochondria in the tail of the sperm don’t enter the egg)
Syndromes often affect muscle, brain and eye.
Threshold effect - in every mitochondrial disease, there is a threshold balance between normal/mutated copies you must reach before you get the disease.
What capabilities must be acquired for a cell to develop into a cancer?
Proliferative signalling
Avoidance of apoptosis (e.g. loss of p53)
Bypassing replicated senescence (where cells will stop dividing after they’ve divided a certain number of times) (e.g. inactivation of p53/RB signalling)
Insensitivity to anti-growth signalling e.g. by TGF-beta pathways
Somatic vs germline (inherited) mutations
Mutations that occur in a somatic cells is often in a sporadic form that occurs in a single cell in a developing somatic tissue. This cell is a progenitor of this specific population, and thus this mutation cannot be passed down to offspring
Somatic mutations are frequently caused by environmental factors, such as exposure to ultraviolet radiation or to certain chemicals
Germline mutations will be found in every cell descended from the zygote to which that mutant gamete contributed. If an adult is successfully produced, every on of its cells will contain the mutation
Proto-oncogenes
These are genes that are expressed in normal cells. They code for oncoproteins, which positively regulate cell proliferation and differentiation (growth factors, transcription factors andn receptor molecules). In healthy cells, the transcription of these genes is tightly controlled. Inappropriate expression of oncoproteins leads to abnormal cell growth and survival. Normally functioning proto-ocogenes can be activated into cancer-causing oncogenes in 2 ways:
- A mutation can produce an oncoprotein that is functionally altered and abnormally active. For example, intracellular signalling is affected by the hyperactive mutant raw protein.
- A normal oncoprotein can be produced in abnormally large quantities because of enhanced gene amplification or enhanced transcription
When they are activated, they are known as oncogenes, and usually they gain a function, instead of losing a function.
Tumour supressor genes
TSGs encode for proteins that prevent or suppress the growth of tumours. They usually work at the checkpoints in the cell cycle, keeping the cell under arrest or suppressed until it is needed to replicate. Inactivation of TSGs results in increased susceptibility to tumour formation. Loss of function of TSGs or their proteins products can result in uncontrolled cell growth.
- Normally inhibit progression through the cell cycle - Some promote apoptosis - Some act as stability genes (DNA - repair type genes) - Mutations cause 'loss of function' and usually require loss of wt allele
Examples of tumours suppressor genes (TSGs)
p53 - The p53 gene is known as the ‘guardian of the genome’ and it is mutated and functionally altered in over 50% of all human tumours. P53 can recognise damaged DNA and responds either through cell-cycle growth arrest at the G1 check point or through the initiation of apoptosis
Retinobastoma (Rb) - is a rare malignnat tumour of the retina. In familial cases (bilateral), a germline mutation in the RB1 gene is present, meaning that only one further somatic mutation is required for tumour formation. Other cases of retinobastoma are unilateral and sporadic, needing 2 somatic mutations on an intially fully functioning RB1 gene. This requirement for separate mutations in both alleles of a TSG has been termed Knudson’s ‘two-hit’ hypothesis of oncogenesis
Key difference between TSGs and proto-oncogenes
Mutations in one allele of the proto-oncogene is enough to cause cancer
However TSGs require 2 mutations (one in each allele) to have an effect. This is described as Knudson’s “two-hit hypothesis”
○ Both alleles that code for a protein must be mutated in order for the cancer to develop
Mutation in TSG results in ‘loss of function’
Mutation in Proto-oncogene results in ‘gain of function’
Stability genes
A type of TSG
Act to minimise genetic alterations. When activated, mutation in other genes become more common: oncogenes and TSGs are particularly triggered
Account for commonest hereditary cancer predisposition syndromes (e.g. familial breast cancer and colon cancer)
Cancer types
Sporadic - common (90-95%); late onset; single primary tumour
Familial - uncommon (5-10%)
Early onset
Often multi primaries
Most of the more common cancer predisposition syndromes are inherited in autosomal dominant fashion.
Most are due to the inheritance of an altered TSG
- Involve subsequent inactivation of the wild-type allele
- Two hits - Knudson’s hypothesis
○ E.g. deletion of one part of a chromosome DNA methylation (e.g. switching off transcription without changing its sequences)
What are the mutations in breast cancer genes
BRCA1 gene (chrom. 17) BRCA2 gene (chrom. 13)
Male breast cancer = BRCA2 gene
Function of BRCA1 and BRCA2 proteins
DNA repair by homologous recombination of double-strand breaks
There are also modifier genes that contribute towards the overall risk of getting cancer but these have a very small effect. These are known as ‘low-penetrance loci’
At least 72 loci that confer an increased susceptibility to breast cancer
These are common (in >5% of population)
Each genetic variant generally confers a small effect e.g. a 10-20% increased risk
DNA testing for familial cancer
- For affected individual who has at least 10% chance of possessing a mutation in BRCA1 or BRCA2
- Important to store DNA from blood of affected individuals who have family history of cancer (to permit future mutation analysis)
- Next-generation sequencing - they can test for multiple genes at one time
Breast cancer: possible preventative measures
- Examinations
- Screening by mammography or MRI
- Prophylactic bilateral mastectomies - reduce the breast cancer risk by at least 90%
- Prophylactic oophorectomies (+ fallopian tubes)
- Also reduces the breast cancer risk by 50-55% (when undertaken prior to menopause)
Ovarian cancer genes
- BRCA1
- BRCA2
- Strongly associated with HNPCC. Involved genes: MHL1 or MHL2
- Screening is difficult
- Prophylactic surgery
- Possible treatment: PARP inhibition (olaparib)
Genetics of colon cancer
- Strong genetics basis in 5-10% of cases
- Autosomal dominant inheritance
- Mostly: hereditary non-polyposis colon cancer HNPCC (2-3% of CRC)
○ Usually only a few polyps (less than 10)
○ +/- uterus, stomach, ovary
○ Due to inheritance of mutation in MMR (mismatch repair) system genes (important for accurate DNA replication)
Screening for those at risk of HNPCC
MMR gene mutation present
males: 80-90% lifetime risk of colon cancer
Females: 40% risk of colon cancer, 50% risk of endometrial cancer & approx 4% risk of ovarian
Colonoscopies
Genes causing HNPCC
These are mismatch repair (MMR) genes: MHL1 approx 50% MSH2 approx 40% MSH6 7-10% PMS2 <5%
Familal adenomatous polyposis (FAP)
Autosomal dominant
Characterised by the development of numerous intestinal plyps from early childhood and congenital hyperplasia of the retinal pigment epithelium (CHRPE)
The intestinal polyps are adenomas and, if left untreated, almost all affected individuals will develop colorectal cancer by the age of 40 as a result of malignant transformation of the colorectal polyps
Also increased risk of upper GI cancer
MYH Polyposis
Autosomal recessive
15-2- polyps (milder form of FAP)
High risk of malignancy
2 year colonoscopy advised
