Inheritance and Genetic Diseases

Why sexual reproduction?

Results in greater genetic variation; this allows

Beneficial combinations of genes to come together

Deleterious combinations of genes to be removed

To survive the fight against microbes (Red Queen hypothesis

How is genetic variation generated?

1. Mutation (errors in DNA replication and repair)

2. Diploid cells (inherit one set of chromosomes from each parent)

3. Homologous recombination (HR) between chromosomes during meiosis

Differences between meiosis and mitosis

Meiosis I steps 

Interphase: the DNA replicates so there are now two identical copies of each chromosome (referred to as chromatids).

Prophase I: chromatids condense and arrange themselves into homologous pairs (called bivalents). Crossing over occurs (see below). The nuclear envelope disintegrates and spindle fibres form.

Metaphase I: homologous chromosomes line up along the equator and attach to the spindle fibre by their centromeres.

Anaphase I: homologous chromosomes are separated

Telophase I: chromosomes reach opposite poles of the cell. Nuclear envelope reforms around the chromosomes. Cytokinesis results in the formation of two daughter cells.

Meiosis II steps

Prophase II: chromosomes condense, nuclear envelope disintegrates and spindle fibres form.

Metaphase II: chromosomes attach to the spindle fibre by their centromeres.

Anaphase II: sister chromatids are separated.

Telophase II: chromatids reach opposite poles of the cell. Nuclear envelope reforms and cytokinesis takes places. Four genetically unique daughter cells are produced.

Homologous Recombination

Occurs during long prophase of meiosis I

2-3 crossover events/chromosome/meiosis

Highly similar DNA sequence binds to complementary sequence on homologous chromosome

Where does crossover occur'?

Crossovers between homologs in the human testis

4 copies of every chromosome lined up in prophase meiosis I

Genetic variation during gamete formation

1. Independent Assortment

2. Homologous Recombination

Is trisomy fatal?

Trisomy usually fatal

(unless 21, 13 or 18)

What is Patau’s Syndrome?

Trisomy 13

What is Edward’s syndrome?

Trisomy 18

Is monosomy fatal?

Monosomy fatal unless X chromosome:

Turner syndrome in females

XXY-

XXX-

XYY-

XXY: Klinefelter syndrome (male, reduced fertility, lower IQ) May go undiagnosed

XXX: undiagnosed

XYY: undiagnosed

Why does age increase trisomies?

Risk of non-dysjunction increases with maternal age Important element of pre-natal testing

How are genetic diseases passed down through the generations?

Autosomal Dominant

Autosomal Recessive

X-linked

Family history: Genetic Counselling

What are autosomal chromosomes?

Autosomal chromosomes = not sex chromosomes

Define genotype

Set of genes carried by an individual

Define phenotype

Observable characteristic of an organism

Sickle Cell Disease: Heterozygote Advantage

Positive selection for HbS allele in malaria endemic areas

Malaria parasites unable to replicate as well inside heterozygote (carrier) red blood cells…therefore SCD allele retained in the population

Sickle cell disease common in African/Caribbean families

SCD carriers more resistant to malaria

X-linked recessive disease: Haemophilia A

Blood clots slowly

Bleeding

Easy bruising

Haemorrhages

Risk for surgery/trauma

Lack of blood clotting

factor VIII

X-linked recessive trait

Deletions or inversions in F8 gene

Resulting in loss of function

Haemophilia son

Distinctive inheritance pattern

50% chance of son inheriting from carrier mother

X linked recessive disorders

Duchenne muscular dystrophy

Red-green colour blindness

Haemophilia

Polygenic disease

Genetic contribution to disease dependent on complex mendelian relationships between multiple alleles (plus impact of environment)

Disease phenotypes revealed later in life, so snps remain common (i.e. not selected against)

Difficult to quantify risk

What is polygenic risk score?

Combine gene variants associated with a specific disease together to give a polygenic risk score