POM - GENETICS - CHROMOSOMAL ABNORMALITIES

Question 1

What are autosomes?

Answer 1

Autosomes are a type of chromosome, they are the 22 non-sex chromosomes.

Question 2

what are autosomal dominant disorders?

Answer 2

A disease caused by a single gene/allele disease. It is a disease passed down to offspring in which multiple generations are affected. The affected person normally has an affected parent, so each child of an affected person has a ½ chance of being affected. However, it may arise de novo, leading to possible mosacism (when cells have different genomes). Even if there is only 1 copy of the gene, the defective mechanism is STILL present.

Question 3

what is meant by de-novo synthesis?

Answer 3

A disease can arise de novo – a mutation is produced during development, fertilization or gamete production. Mosaicism means that some people’s cells each have a different genome.

Question 4

what does autosomal dominant mean?

Answer 4

A characteristic is autosomal dominant if you only need to inherit 1 copy of the gene for it to have an effect on the phenotype. Of 2 different alleles at a locus, only the autosomal dominant allele has an effect so an autosomal characteristic is dominant if it manifests in a heterozygote.

Question 5

when is a characteristic dominant?

Answer 5

A characteristic is dominant if it has an effect no other gene can interfere with or overide. Brown eyes arise as a person has a copy of an active OCA-2 gene, but the non-active one (2 copies needed to have blue eyes) has no overall effect).

Question 6

what are characteristics of autosomal diseases? who do they affect? what are 3 type of the effects?

Answer 6

 Males and females are EQUALLY likely to be affected
 It shows a vertical degree pattern
 They tend to be either gain-of-function, dominant negative effect, or haploinsufficient.
 Gain of function  the gene makes a protein with a new function (an active receptor, forms aggregates).
 Dominant negative effect  the mutated form interferes with the activity of proteins it binds to by forming dimers or multimers
 Haploinsufficient  the loss of 1 normal copy means that the remaining copy cannot produce enough protein for normal function (this is rare, but seen with Collagen – ie, brittle bone disease)

Question 7

what is a abnormal recessive disorder? what are the effects on carriers or homozygotes?

Answer 7

 Carriers of recessive disease have lost a single copy but the normal one is sufficient enough to maintain function
 Recessive means that two copies of the abnormal (Non-working) gene must be present in order for the disease or trait to develop
 Abnormal recessive disorders tend to be ‘loss of function’

Question 8

what is the inheritance pattern of recessive disorders?

Answer 8

 Parents and children of affected people are normally unaffected
 One or more siblings may be affected
 Each child of 2 carrier parents have a ¼ chance of being affected
 Males and females are equally affected
 There is a horizontal pedigree pattern of inheritance
 An example of a recessive disorder is cystic fibrosis, where a defective chloride ion channel leads to a loss of function leading to an impaired airway defence.

Question 9

what is consanguinuity and the effect of autosomal recessie disorders?

Answer 9

 1/5 of the world live in areas with a preference for consanguineous marriages, which elevate the risk of autosomal recessive diseases
 Due to a reduced pool of people to marriage, there is an increased likelihood of autosomal recessive disorders due to shared DNA - both parents are more likely to have the mutation

Question 10

what are the sex chromosomes? how many genes do they have and what proteins do they code for?

Answer 10

 There are 1000 – 1300 genes in the X chromosome, and out of those there are 850 protein coding genes
 There are 150 genes in the Y chromosome, only 50 – 70% are protein coding.

Question 11

what are x-linked recessive disorders? who do they affect and what is the inheritance pattern?

Answer 11

 They affect mainly males (they are dominant)
 Females are carriers and affected males are linked through females.
 Females need to be homozygous for the condition (however this is often a lethal genotype)
 Brothers of an affected son have a ½ risk of having a disorder and sisters have a ½ chance of being a carrier
 All daughters of a man with an x-linked disorder will be carriers as men only have 1 X chromosome, whereas all sons will be healthy as they inherit the Y chromosome from the father
 Haemophilia  more frequent/severe bleeds due to lacking certain blood clotting factors (VIII or IX)
 Fabry’s disease  female carriers can exhibit subtle signs of the disease

Question 12

what is the effect on x-linked dominant disorders?

Answer 12

 Similar to autosomal dominant pattern as seen in both sexes
 Offspring of an affected male: all daughters and no sons have the disease
 Conditions are often milder and more variable in females vs males.
 Some disease only present in females as the males are not viable
 An example is X – linked hypophosphatemia  the overproduction of FGF21 inhibiting kidney phosphate resorption. As the kidney cannot retain phosphate, this results in vitamin D-resistant rickets.

Question 13

what are Y-linked dominant disorders? who do they typically affect? what is the inheritance pattern?

Answer 13

 Affects only males
 With a vertical pedigree pattern
 All sons of an affected father have the condition, for example, retinitis pigmentosa Y-linked. Due to a mutation in the RPY gene, retina cells produce a defective protein

Question 14

why is mitochondria significant? how can it cause genetic disease?

Answer 14

Specialised organelle of eukaryotic cells, it shares an evolutionary past with bacteria (endosymbiosis). Mitochondria have their own haploid DNA. The majority of mitochondrial proteins are encoded by genes in cell DNA and mutations in these nuclear genes cause some mitochondrial disease. However, most mitochondrial diseases are caused by mutations in the mitochondrial DNA.

Question 15

what is the inheritance pattern of mitochondria?

Answer 15

 Mitochondria is maternally inherited only
 There is a vertical pedigree pattern
 Children of an affected mother may be affected, however children of an infected man are never affected.
 There is variability in the symptoms experienced by members of the same family
 Can initially present as unrelated multi-system symptoms
 Motor and nerve functions are commonly affected

Question 16

what is heteroplasmy? what is mitochondria endosymbiosis? how do they replicate?

Answer 16

 Mitochondria have multiple copies of the genome – however, one mitochondria may have different versions
 You need to have a certain amount (reach a threshold) in order to express the disease
 Mitochondria endosymbiosis refers to how mitochondria was once thought to be a bacteria which infected eukaryotic cells.
 Mitochondria replicate through binary fission, and can lose or gain mutated genes

Question 17

what is the effect of heteroplasmy on the severity of the disease

Answer 17

 There is many mitochondria in each cell, leading to random segregation
 The severity of symptoms depends on the number of affected mitochondria, and whether it reaches a threshold.
 Cells may differ in number of mutated mitochondria and can change over time.
 Mitochondrial diseases can develop with age due to accumulation of mutant mitochondria

Question 18

what is LHON? what type of disease is it?

Answer 18

 LHON - Leber’s hereditary optic neuropathy
 Mitochondrial disease
 There is visual loss in young adulthood, degeneration of optic nerve and retina.
 Usually affects males but can occasionally affect females.