Genetic Variation and Disease II Flashcards
What are the benefits of next generation DNA sequencing?
- More sensitive to detect previously unknown SNPs
- Has made DNA sequencing cheaper
Outline the process of next-generation DNA sequencing. PART 1
- DNA chopped at random into small fragments
- Adapters attach to ends of genomic DNA fragments
- Double stranded fragments separated into single strands and attached to solid surface e.g glass slide
- Individual fragments amplified by PCR - adapters act as primer sequences
Outline the process of next-generation DNA sequencing. PART 2
- SEQUENCING REACTION - fragments act as templates for synthesis of complementary strands
- New complementary bases to which base specific cluorescent label attached, added one at a time
- Fluorescent signal read using camera to reveal base pair sequence of each fragment
- Fragments put together by aligned against a reference genome
What are the advantages of next-generation DNA sequencing?
- Entire genome can be sequenced (however requires bioinformaticians)
How would gene sequencing within a child with epilepsy work?
- SNPs within genes of interest identified
- Usually an SNP which has been reported to be associated with epilepsy
- If not, labelled as a variant of uncertain significance - identified by genetic testing but may or may not be significantly associated with disease or risk of disease.
What are alleles?
- Two or more alternative forms of a gene occupying the same genetic locus
- Carry 2 alleles at each gene locus - 1 maternally, 1 paternally inherited
Describe the Mendelian law of segregation.
- Sexually reproducing organisms possess genes that occur in pairs
- Only one member of this pair transmitted to offspring
What does Mendel’s law of segregation say about chromosomes during meiosis? PART 1
- Genes on chromosomes segregate during meiosis
- Transmitted as distinct entities from one generation to next
- Two alleles for each trait separate during meiosis
- Each gamete contains a random collection of paternally and maternally inherited chromosomes
What does Mendel’s law of segregation say about chromosomes during meiosis? PART 2
- During fertilisation, alleles pair again
- 4 possible combinations of alleles
- INDEPENDENT ASSORTMENT - genes on different loci transmitted independently
What is the main difference between dominant and recessive inheritance?
- One allele at a locus can mask another allele at same locus
- Dominant allele exerts effect in homozygous and heterozygous forms
- Recessive allele only exerts effect in homozygous form
Describe autosomal dominant disease transmission. PART 1
- Occurs when an unaffected parent mates with affected heterozygote
- Affected parent can either pass a normal or diseased allele therefore chance of child with disease is 0.5
- Affects autosomes - so males and females affected equally
Describe autosomal dominant disease transmission. PART 2
- No skipping of generations - if individual has disease, one parent must have it. Causes vertical transmission patterns
- Inheritance is independent - recurrence risk of another affected child is still 50%
- FATHER SON TRANSMISSION IS POSSIBLE
- EXAMPLE: Huntingdon’s
Describe autosomal recessive inheritance
- Most commonly both parents are heterozygous carriers
- So 25% chance of offspring having disease
- Usually observed in siblings but not normally in ealier generations
- Males and females affected equally. Consanguinity sometimes seen.
Give an example of an autosomal recessive condition.
CYSTIC FIBROSIS
What are most dominant diseases more severe in?
- More severe in homozygotes than in heterozygotes e.g achondroplasia
- Dominant alleles produce disease in heterozygotes, recessive alleles don’t (due to being masked)
What does it mean for a disease to be X-linked?
- Characteristic or traits of disease are derived from mutations or variants of an X gene
Describe X-linked recessive inheritance. PART 1
- EXAMPLES OF CONDITIONS are haemophilia A and red-green colour blindness
- Females inherit 2 copies of X gene - need to be homozygous for diseased allele, to be affected
- Most X-linked loci, only one copy of allele in somatic cell due to X-inactivation.
- Half of cells in heterozygote female express the diseased allele, half express normal allele.
Describe X-linked recessive inheritance. PART 2
- Males inheriting recessive X-linked gene are affected
- No normal X-linked allele to compensate
- X-linked recessive diseases more common in males
- Most common form of inheritance: Normal male, carrier female
Are X-linked genes transmitted from father to son?
NO
- Only transmit Y genes
- X-linked genes pass from heterozygous normal females
- If a father is affected, gene is passed to all daughters who act as carriers - transmit gene to half of their sons who are affected
Describe X-linked dominant inheritance. PART 1
- More common in females - two X chromosomes - twice as likely to inherit diseased gene
- Lethal in hemizygous males
- Heterozygous females - milder expression X-linked traits. 50% chance of passing diseased gene to offspring
- CONDITION: Hypophosphataemic rickets
Describe X-linked dominant inheritance. PART 2
- Severity varies in affected females - random X inactivation
- Uncommon skipped generations
- Father to son transmission not seen - transmit the Y gene
- Only one X-linked diseased gene required to cause disease
Describe X inactivation. PART 1
- X chromosome contain many protein coding genes
- Females have 2 copies and males have only 1 yet males and females do not differ in X-chromosome gene expression
- One X chromosome in each somatic cell randomly inactivated during female embryonic development
Describe X inactivation. PART 2
- Dosage compensation occurs - X linked gene products produced in similar amounts to males
- Two populations - one active maternally derived and one active paternally derived X chromosome
- X chromosome remains inactive in all descendants of that somatic cell
- Reactivated in germline - so egg cells receive one copy of active X chromosome
Why do some X chromosomes not undergo inactivation?
- Not inactive
- Remain homologous on Y chromosome
- Preserving equal gene dosage across males and females
- If these sections become missing, cause diseased phenotype
