002 + 003 Mendelian genetics Flashcards
what are Mendel’s laws?
- Genes are particulate and come in different forms called alleles
- Segregation
- Independence of assortment
describe Mendel’s law of segregation
- organisms have 2 copied of each gene but transmits only 1 to each offspring and which one is decided at random
describe Mendel’s law of independent assortment
- where alleles of more than 1 gene are segregating, segregation at each gene occurs independently of the others (exception = linkage)
what is a dominant allele
- allele that is always expressed
- will mask a recessive allele
what is a recessive allele?
- allele that is only expressed if the dominant allele is not present
- masked by the dominant allele
describe autosomal dominant inheritance
- all affected individuals will have at least 1 affected parent unless it is a new mutation
- both sexes are equally affected
- if M/m and m/m then 50% of offspring will develop
- if M/m and M/m then all offspring will develop
- e.g. Huntington’s disease, Achondroplastic dysplasia
describe autosomal recessive inheritance
- often no family history of it
- both parents need to be carriers ( Mm and Mm)
- 1/4 chance child will be affected
- more common in consanguineous families (inbreeding)
- e.g. Cystic fibrosis, Sickle cell anaemia, Tay Sachs disease
give examples of all the different exceptions to Mendelian inheritance
- Lethal alleles
- incomplete dominance
- codominance
- silent alleles
- epistasis
- pleiotropy
- genetic heterogeneity
- variable expression
- incomplete penetrance
- anticipation
- germline mosaics
- phenocopies
- incomplete ascertainment
- mitochondrial inheritance
- uniparental disomy
- autosomal linkage
describe the exception to Mendelian laws: homozygous lethals
- if you inherit the homozygous alleles for a disease that causes death as a fetus then the ratio at birth is different to the ratio at conception
e.g. Tt x Tt = TT Tt tt = 1:2:1 ratio at conception
if tt causes death of fetus then ratio at birth = 1:2:0
what is incomplete/semi-dominance/partial dominance?
- when the phenotype of the heterozygous genotype is different and often intermediate between the phenotypes of the homozygous genotypes
- e.g. familial hypercholesterolemia AA = normal, Aa = death as young adult, aa = death in childhood
explain how Sickle cell disease is incomplete/semi-dominance/partial dominance
- recessive allele condition altering the haemoglobin beta chain which causes an abnormal shape rbc which can get stuck and obstruct flow causing pain
- 2 HbS alleles = sickle cell disease
- 1 HbS 1 HbA = carrier of sickle cell disease, may have minor traits/symptoms and has resistance against malaria
what is co-dominance?
- if 2 or more alleles can be distinguished in phenotype together, they are codominant
- e.g. blood groups, A and B are codominant and O is recessive
- A and B code for 2 different H antigens on rbcs, O does not produce any antigens
give an example of codominance
- blood groups ABO
- AB = AB
- AO = A
- AA = A
- BB = B
- BO = B
- OO = O
what are silent alleles and how are they an exception to Mendelian inheritance?
- in multiple allele systems , it is sometimes not obvious that a silent allele exists = confusing results
- e.g. ABO blood groups, group A or B, don’t know it may also have O allele (AO, BO…)
what is epistasis?
- when the action of 1 gene masks the effects of another
- e.g. if both genes produce enzymes which act in the same pathway
- if gene 1 product is not made then it is not possible to tell the genotype/phenotype of gene 2
describe the Bombay phenotype example of epistasis
- ABO blood groups
- caused by incomplete synthesis of the H antigen (missing fucose group)
- gives no H antigen even if carry A or B alleles = O phenotype
- e.g. if parents, AB, BO, daughter appears to be group O, but is actually BO but incomplete synthesis of H antigen
describe pleiotropy as an exception to Mendelian inheritance
- mutations in 1 gene may have many possible effects
- problems in tracing the passage of a mutant allele through a pedigree can arise when different members of a family express a different subset of the symptoms
- pleiotropy can occur whenever a gene product is required in more than 1 tissue or organ
e.g. PKU, autism, schizophrenia, sickle cell anemia, albinism, Marfan’s syndrome
give some examples of diseases involving pleiotropy
- Phenylketonuria (PKU)
- autism and schizophrenia (CACNA1C gene)
- sickle cell anaemia
- albinism (tyrosinase gene and tyrosine metabolism
- Marfan’s syndrome (fibrillin 1 gene)
describe genetic heterogeneity as an exception to Mendelian inheritance
- genetic heterogeneity describes a condition which may be caused by mutations in more than 1 gene
- both genes may act in the same biochemical or regulatory pathway
- this often arises when the protein product of 2 genes interact
- e.g. tuberous sclerosis
describe an example of genetic heterogeneity
- tuberous sclerosis (causes benign tumours in the brain, kidneys, heart, liver, eyes, lungs, skin)
- produced by mutations in either of 2 unrelated genes, TSC1 on chromosome 9 or TSC2 on chromosome 16 which code for hamartin and tuberin
describe variable expressivity as an exception to mendelian inheritance
- the degree and form in which a condition may manifest itself can be highly variable
- e.g. polydactyly
give an example of variable expressivity
- polydactyly
- lots of different forms of it
- e.g. small bump on side of hand, an extra finger at thumb or pinky, extra finger in middle, small finger that dangles by a thin cord…
describe incomplete penetrance as an exception to Mendelian inheritance
- in extreme cases of low expressivity, some individuals may show no symptoms for a long time or ever despite carrying a disease allele
- but their parents and children might
- 20% penetrance = 20% of people carrying the allele will get disease
- 100% penetrance = 100% of people carrying the allele will get the disease
- e.g. BRCA genes
give an example of incomplete penetrance
- BRCA genes
- mutations in BRCA1 and BRCA2 give an 80% lifetime risk of developing breast cancer
describe germline mosaicism as an exception to Mendelian inheritance
- if a mutation gives rise to a new disease allele in 1 germ cell precursor out of the many non-mutant precursors, its descendent germ cells will be diluted by many non-mutant germ cells
- this will result in offspring carrying the disease allele in non-Mendelian ratios
- most common with autosomal dominant and x-linked disorders
- e.g. osteogenesis imperfect and Duchenne muscular dystrophy
give an example of a disease associated with germline mosaicism
- osteogenesis imperfecta
- Duchenne muscular dystrophy
describe phenocopies as an exception to Mendelian inheritance
- an environmentally determined trait may mimic a genetic trait
- e.g. thalidomide - phocomelia
- many cases of polydactyly are not inherited and may be environmentally induced phenocopies
give an example of a disease associated with phenocopies
- thalidomide, used to be given to treat morning sickness to pregnant mothers would cause limb shortening, very similar to familial phocomelia, rare genetic disease
- some cases of polydactyly
describe anticipation as an exception to Mendelian inheritance
- genetic disease appears with earlier onset and increased severity in succeeding generation
- caused by expansion of trinucleotide repeats within the coding regions of some genes
e.g. Huntington’s disease, myotonic dystrophy, fragile X syndrome
give some examples of diseases associated with genetic anticipation/ trinucleotide expansion
- Huntingtons disease
- myotonic dystrophy
- fragile X syndrome
describe incomplete ascertainment as an exception to Mendelian inheritance
- Many families where both parents are carriers of an autosomal recessive mutation will not have any affected children and thus will not come to medical attention
- this biases our observations only to families with affected offspring
- if this isn’t taken into account, we may imagine that we are dealing with a disease which is inherited in a way other than autosomal reccessive
(e.g. the queen thinks the world smells of fresh paint)
describe why mitochondrial inheritance is different to Mendelian inheritance
- only mother’s mitochondrial DNA is passed onto offspring, no backup, so if mother has it all children will also get disease
- father cannot pass it on
- can be complicated by heteroplasmy (when only a proportion of mitochondrial DNA carry the disease allele), by interaction with nuclear coded genes and by somatic changes with age
what is heteroplasmy?
the presence of more than 1 type of genome/DNA in a cell or individual
- occurs more in mitochondrial DNA, where only a proportion of the DNA carries the disease allele
- e.g. MERF, MELAS
- causing variation between siblings with the same disease allele
give 3 examples of mitochondrial DNA inherited disease
- MERF = myoclonic epilepsy with ragged red fibres
- MELAS = mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes
- LHON = Leber’s hereditary optic neuropathy
explain why uniparental disomy is not Mendelian inheritance
- it is when both copies of a single chromosome may be inherited from the same parent and none from the other parent ( not an equal split of genetics from mum and dad)
- e.g. rare cases of cystic fibrosis
- give an example of uniparental disomy
- rare cases of cystic fibrosis (autosomal recessive)
- where 1 parent is heterozygous and 1 parent is homozygous dominant = should have no affected offspring
- however, the child received 2 copied of chromosome 7 carrying the recessive allele from carrier parent and none from other parent = got cystic fibrosis
explain why autosomal linkage is not Mendelian inheritance
- occurs when 2 genes are close together on the same chromosome, their alleles tend to be inherited together
- ( do not obey law of independent assortment)
- the closer the genes, the more likely they will be inherited together
what does this pedigree show?
- the disease initially links with a B allele until there is recombination, then it links with a C allele
What does this pedigree show?
Autosomal dominance
What does this pedigree show?
Autosomal recessive
What does this pedigree show?
Mitochondrial inheritance
