Inheritance…1 Albinism and Sickle Cell Anaemia

Recap…Single factor inheritance with respect to Homozygous dominant/recessive Heterozygous genotype Classifying genetic disorders Autosomal – Chromosome 1 - 22 Sex-linked – Chromosome 23 (X, Y)

Autosomal recessive disorders An affected person usually has unaffected parents, each carrying a single copy of the mutated gene i.e. carriers (heterozygotes) Two mutated copies of the gene are present in each cell when a person has an autosomal recessive disorder A mutation is a change to the structure of a gene It occurs when a gene is damaged or changed, altering the genetic information carried by that gene Autosomal récessive disorders are typically not seen in every generation of an affected family Example: Albinism, Sickle-cell Anaemia, Cystic Fibrosis

Albinism Albinos; homozygous recessive (aa) individuals Recognized by partial or complete lack of pigment Heterozygotes have normal pigmentation (Aa) Gametes produced: A or a Offspring: 1/4 would be albinos Carriers of the gene for albinism have a 25% chance that one of their offspring will be born with albinism Two albinos will not automatically produce an albino child Though the risks are several times higher compared to normal individuals Albinism is a recessive genetic disorder, which means both parents must have the defective chromosome in order for their child's genes to be affected

Types of Albinism The National Organization for Albinism and Hypo-pigmentation (NOAH) of the USA classifies albinism into two 1. Oculocutaneous albinism types 1 – 4 (OCA): affects the eyes, hair and skin, producing the pale skin and eyes typically affiliated with albinism the four types have varying levels of genetic defects of the enzyme tyrosinase 2. Ocular albinism (OA): affects the eyes only and does not generally cause the lack of pigment associated with OCA individuals with OA appear more pale compared to other members of their family Alternative classification: Amelanosis (amelanism) and hypomelanosis 9hypomelanism) OA is less common than OCA Albinism is associated with vision defects such as photophobia (unusual sensitivity to light), nystagmus (involuntary eye movement and/or reduced or limited vision) and astigmatism (aberrations of focussing) Further classifications of albinism depend on the extent to which the individual lacks melanin. Complete lack of melanin is called amelanosis (or amelanism), while partial lack of pigment is called hypomelanosis (or hypomelanism).

Occurrence of Albinism Genes OCA appears on both X and Y chromosomes OCA autosomal as well The gene won't allow the information to be created correctly The X chromosome only carries the OA defect Almost all people with OA are male because of its location on the X chromosome OA appears on the GPR143 gene, which controls the pigments of the eye only

Causes of Albinism Several mutations may cause albinism: 1. lack of one or another enzyme along the melanin-producing pathway, or 2. inability of the enzyme tyrosinase to enter the melanocytes and convert tyrosine into melanin Tyrosinase assists in the conversion of tyrosine, an amino acid, into pigment in melanocytes

Sickle-cell Anaemia Sickle cell disease is a group of disorders that affects haemoglogin Haemoglogin (in RBCs) delivers oxygen to cells throughout the body People with this disorder have abnormal haemoglogin called haemoglogin S HbS distorts red blood cells into a sickle, or crescent shape Features of the disorder include low number of red blood cells (anaemia) repeated infections and periodic episodes of pain Symptoms vary from individual to individual Others have mild symptoms, while some are frequently hospitalized for more serious complications Abnormal versions of beta-globin can distort red blood cells into a sickle shape. The sickle-shaped red blood cells die prematurely, which can lead to anemia. Sometimes the inflexible, sickle-shaped cells get stuck in small blood vessels and can cause serious medical complications.

Causes of Sickle-cell Anaemia Mutations in the HBB gene (haemoglogin, beta; located on chromosome 11 ) cause sickle cell disease The HBB gene provides instructions for making beta-globin Haemoglogin consists of four protein subunits: two subunits called alpha-globin, and two subunits called beta-globin Various versions of beta-globin result from different mutations in the HBB gene, causing different types of sickle cell disease One HBB gene mutation produces an abnormal version of beta-globin known as haemoglogin S (HbS) Other mutations in the HBB gene lead to additional abnormal versions of beta-globin such as haemoglogin C (HbC) and haemoglogin E (HbE) Sickle-cell anaemia is the commonest form of sickle-cell disease. This is because the mutation to the HBB gene which produces haemoglogin S (HbS) is the commonest.

Expression of Sickle-cell Disease In sickle cell disease, at least one of the beta-globin subunits in haemoglogin is replaced with haemoglogin S In sickle cell anaemia, the commonest form of sickle cell disease, hemoglobin S replaces both beta-globin subunits in haemoglogin In other types of sickle cell disease, just one beta-globin subunit in haemoglogin is replaced with haemoglogin S The other beta-globin subunit is replaced with a different abnormal variant, such as hemoglobin C For example, individuals with sickle-haemoglobin C (HbSC) disease have haemoglogin molecules with haemoglogin S and haemoglogin C instead of beta-globin

Inheritance 2 ABO Blood Group; Rhesus Factor (Rh)/ Incompatibility

Multiple alleles…1 Multiple allelism is the phenomenon in which a gene has three or more alternative forms multiple allelic series Characteristics Multiple alleles of a series always occupy the same locus on a chromosome No crossing over occurs with multiple alleles of the same series they occupy the same locus Multiple alleles always influence the same trait e.g. ABO blood group

Multiple alleles…2 The normal (wild type) allele is almost always dominant The other alleles in the series (mutant types) may show dominance or there may have intermediate phenotypic effect When any two mutant multiple alleles are crossed, the phenotype is always mutant type, not the wild type Remember Multiple allelism is the phenomenon in which the same gene has more than two alternative forms In normal Mendelian inheritance, a gene has only two alleles These alleles combine in pairs to form the genotypes

The ABO blood group Erythrocytes have surface markers (antigens) which come in three or more varieties Three alleles: A, B and O Six possible genotypes: AA, AB, AO, BB, BO, and OO The ABO blood group exhibits the following phenomena: recessive alleles (IO) dominant alleles (IA and IB) co-dominance (IA and IB) multiple alleles (A, B and O)