Human Genome, Chromosomes and Inheritance of human Diseases

DNA structure

• DNA strands pair up in an antiparallel fashion

• Read and replicated 5’→3’

DNA replications

• DNA can be damaged during replication

  • DNA strand breaks

  • Chemical cross linking

  • Mismatched base

• When repair mechanisms are defected, disease occurs

Mutation

any heritable change in the human genome which causes a genetic disorder

Polymorphism

any variation in the human genome which has a population frequency of above 1%

Penetrance

the likelihood of having a disease if you have a genetic mutation

Classic genetic disease

mendelian disorders, one mutation is sufficient to cause the disease

• High penetrance

Multifactorial disease

multiple polymorphisms cause risk of disease

• Usually a low penetrance

Missense mutations

• Point mutations that cause a change to a single amino acid

• Usually caused by substitutions

• Most likely mutation to directly activate an oncogene

  • Other mutations tend to inactivate the gene

Changes to amino acid sequence

• Mutation may change protein sequence which may alter protein function

• Nonsense: Mutation may result in a premature stop codon

Insertion/deletion

• Causes a complete change to the entire amino acid sequence after the mutation site

• In frame - insertion/deletion of a multiple of 3 bases

• Out of frame - results in a frame shift

Promotor and splice site sequence changes

Stops transcription or causes abnormal splicing

Balanced chromosome rearrangement

When all the chromosomes are present after rearrangement

Unbalanced chromosome rearrangement

• When some of the chromosomes or parts of chromosomes are missing after chromosome rearrangement

  • Usually 1 or 3 copies of gene (which is bad news)

• Causes major developmental problems or miscarriages

Aneuploidy

• Whole extra or missing chromosome (more or less than 46)

• X chromosome aneuploidy better tolerated because of X chromosome inactivation

Translocation

Rearrangement of chromosomes

Robertsonian translocation

• Two acrocentric chromosomes stuck end to end

• Increased risk of trisomy in pregnancy

Reciprocal translocation

Two broken off chromosome pieces of non-homologous chromosomes are exchanged

aCGH gene analysis

• 1st line chromosome test

• Detects missing/duplicated pieces of chromosome

• Find polymorphisms

• Does not detect balanced rearrangements

FISH gene analysis

• Uses fluorescent probes that bind only to parts of a nucleic acid sequence with a high degree of sequence complementarity

• Often used for finding specific features in DNA for use in genetic counselling

PCR gene analysis

• Can select one small piece of human genome from a patient and amplify it

• Pieces can be selected to find mutations

Whole exome sequencing

Sequences exome - all the exons (vs. whole genome sequencing – introns and exons)

Genetic filtering

• Compares an individuals genome to a list of known genes to filter out genes which are unlikely to be disease causing

• On average approx. 3 000 000 polymorphisms are detected when sequencing the entire genome in a person

Somatic mosaicism

Refers to the occurrence of two genetically distinct populations of cells within an individual, derived from a post-zygotic mutation

• May only affect a portion of the body

• Not transmitted to progeny

• Somatic mosaicism for a chromosomal abnormality could contribute to cancer

  • Changes could activate an oncogene or delete a tumour suppressor

SNPs: Single Nucleotide Polymorphisms

• Affect gene function, some effects may make you more prone to disease e.g. by affecting transcription (alter promoter)

• Most have no effect

CVNs

• (copy number variation): extra/missing stretches of DNA; deletions or duplications

  • Number of copies of a particular gene varies from one individual to the next

Autosomal Dominant 

• Only one copy required to cause disease, disease seen in all generations

• If one parent is affected, 50% chance that the kid will be affected

• If both parents are affected, 100% chance that the kid will be affected

• A dominant mutation is present on one of the 22 a-sexual chromosomes

Autosomal recessive

• 2 copies of faulty gene required to cause disease, often only 1 generation affected

• If one parent is affected, 0% chance the kid will be affected

• If both parents are affected, 25% chance the kid will be affected

• A recessive mutation is present on one of the 22 a-sexual chromosomes

X-Linked Recessive Inheritance

• Faulty gene on X chromosome.

• Males (XY): one faulty X → disease fully expressed.

• Females (XX): one faulty X → usually carrier, mild or no symptoms (due to X inactivation).

• Carrier female’s children:

  • ¼ unaffected son

  • ¼ affected son

  • ¼ unaffected daughter

  • ¼ carrier daughter

• Affected male’s children:

  • All daughters = carriers

  • All sons = unaffected (no male-to-male transmission)

• Mild symptoms in carriers possible due to random X inactivation (about half of cells express faulty gene).

Mitochondrial inheritance

• When there’s a mutation in the mitochondrial genome (single loop)

• In many cases, a mutation in the mitochondrial genome is only present in a proportion of the mitochondria, and the proportion varies between cells within an individual

• Mitochondrial DNA is transmitted maternally, in the ovum